Conditions: Tuberculosis, Pulmonary Tuberculosis, Multidrug-Resistant Tuberculosis, MDR Tuberculosis Drug-Resistant Tuberculosis
Keywords: tuberculosis drug-resistant tuberculosis TB DR-TB pretomanid PA-824 bedaquiline TMC207 moxifloxacin pyrazinamide HRZE TB Alliance NC-008 drug-sensitive tuberculosis DS-TB
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 455
Healthy volunteers: no

Brief summary:
To evaluate the efficacy, safety and tolerability at 8 weeks (2-months), 52 weeks (12-months), and 104 Weeks (24-months) post the start of the following treatment regimens in participants with: Drug Sensitive TB (DS-TB) patients given BPaMZ for 17 Weeks ( or 4 months) vs. Standard HRZE/HR treatment given for 26 weeks (or 6 months) and Drug Resistant TB (DR-TB) patients given BPaMZ for 26 Weeks (or 6 months)

Detailed description:
Phase 2c multi-center, open-label, partially randomized clinical trial in DS-TB and DR-TB participants.

All participants in the below arms will have follow-up for a period of 104 weeks (24 months) from the start of therapy.

Participants with Drug Sensitive TB (DS-TB):

Participants with DS-TB will be randomized to one of two treatment arms. These participants will receive either BPaMZ daily for 17 weeks (4 months), or HRZE/HR combination tablets daily for 26 weeks (6 months). participants will be stratified for co-infection with human immunodeficiency virus (HIV) and cavitation.

Participants with Drug Resistant TB (DR-TB):

Participants with DR-TB will be assigned to receive BPaMZ daily for 26 weeks (6 months).

Arms:
arm 1: Bedaquiline 200 mg daily for 8 weeks then 100 mg daily for 9 weeks, together with pretomanid 200 mg + moxifloxacin 400 mg + pyrazinamide 1500 mg daily for 17 weeks (Total treatment duration 4 months arm 2: isoniazid 75 mg + rifampicin 150 mg + pyrazinamide 400 mg + ethambutol 275 mg (HRZE) combination tablets for 8 weeks AND isoniazid 75 mg + rifampicin 150 mg (HR) combination tablets for Weeks 9 to 26 arm 3: Bedaquiline 200 mg daily for 8 weeks then 100 mg daily for 18 weeks, together with pretomanid 200 mg + moxifloxacin 400 mg + pyrazinamide 1500 mg daily for 26 weeks (Total treatment duration 6 months)

Interventions: intervention 1: Pretomanid intervention 2: Bedaquiline intervention 3: Moxifloxacin intervention 4: Pyrazinamide intervention 5: HRZE intervention 6: HR
Intervention descriptions: intervention 1: 200 mg tablets intervention 2: 100 mg tablets intervention 3: 400 mg tablets intervention 4: 500 mg tablets intervention 5: isoniazid 75 mg plus rifampicin 150 mg plus pyrazinamide 400 mg plus ethambutol 275 mg combination tablets intervention 6: isoniazid 75 mg plus rifampicin 150 mg combination tablets

Protocol document:
Prot_000.pdf: 
TB Alliance 
 
Clinical Trial Report 
NC-008-(B-Pa-M-Z) 
 
SimpliciTB 
CONFIDENTIAL 
 
 
16.1 
Trial Information 
16.1.1 
Protocol and Protocol Amendments 
SimpliciTB Protocol, Version 1.0, 05OCT2017 
SimpliciTB Protocol, Version 2.0, 21FEB2018 
SimpliciTB Protocol, Version 2.0 Summary of Changes 
SimpliciTB Protocol, Version 3.0, 14JAN2019 
SimpliciTB Protocol, Version 3.0 Summary of Changes 
SimpliciTB Protocol, Version 4.0, 30SEP2019 
SimpliciTB Protocol, Version 4.0 Summary of Changes 
SimpliciTB Protocol, Memo, 17APR2020 
SimpliciTB Protocol, Russia Version 1.0, 10JUL2018 
SimpliciTB Protocol, Russia Version 1.0 Summary of Changes 
SimpliciTB Protocol, Russia Version 2.0, 25JAN2019 
SimpliciTB Protocol, Russia Version 2.0 Summary of Changes 
SimpliciTB Protocol, Russia Version 3.0, 01OCT2019 
SimpliciTB Protocol, Russia Version 3.0 Summary of Changes 
 
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+.
  
CONFIDENTIAL  
 
 
 
Protocol Number: 
NC-008 (B-Pa-M-Z) 
Title: 
An Open-Label, Partially Randomized Trial to Evaluate the Efficacy, 
Safety and Tolerability of a 4-month Treatment of Bedaquiline plus 
Pretomanid plus Moxifloxacin plus Pyrazinamide (BPaMZ) 
Compared to a 6-month Treatment of HRZE/HR (Control) in Adult 
Participants 
with 
Drug-Sensitive 
Smear-Positive 
Pulmonary 
Tuberculosis (DS-TB) and a 6-month Treatment of BPaMZ in Adult 
Participants with Drug Resistant, Smear-Positive Pulmonary 
Tuberculosis (DR-TB). 
Drug(s)/Combination(s): 
Bedaquiline tablets (B), pretomanid tablets (Pa), moxifloxacin 
tablets (M), pyrazinamide tablets (Z), HRZE tablets [isoniazid (H), 
rifampicin (R), pyrazinamide (Z) and ethambutol (E)] and HR tablets 
[isoniazid (H) plus rifampicin (R) combination tablets] 
Initial Protocol 
Version/Date: 
V1.0 / 05 October 2017 
Protocol Name: 
SimpliciTB 
 
 
 
 
 
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Protocol Version: V1.0 / 05OCT2017 
Protocol Name: 
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Page 2 of 96 
PROTOCOL SIGNATURE PAGE 
Protocol Title:  An Open-Label, Partially Randomized Trial to Evaluate the Efficacy, 
Safety and Tolerability of a 4-month Treatment of Bedaquiline plus Pretomanid plus 
Moxifloxacin plus Pyrazinamide (BPaMZ) Compared to a 6-month Treatment of 
HRZE/HR (Control) in Adult Participants with Drug-Sensitive Smear-Positive Pulmonary 
Tuberculosis (DS-TB) and a 6-month Treatment of BPaMZ in Adult Participants with 
Drug Resistant, Smear-Positive Pulmonary Tuberculosis (DR-TB). 
Protocol Number: 
NC-008 (B-Pa-M-Z) 
Protocol Date: 
V1.0, 05 October 2017 
Protocol Name:  
SimpliciTB 
SPONSOR: 
Global Alliance for TB Drug Development 
I agree to the terms of this trial protocol. 
Paul Bruinenberg MD, MBA 
Signature of Senior Medical Officer 
Printed Name 
40 Wall Street, 24th Floor 
New York, NY 10005 
Phone 646-616-8671 / 646-616-8629 
E-mail: Paul.Bruinenberg@tballiance.org
Date 
LEAD INVESTIGATOR 
I agree to the terms of this trial protocol. I will conduct the trial according to the procedures 
specified herein and in accordance to the principles of Good Clinical Practice (GCP) and 
local regulations. 
Signature 
Printed Name 
Date 
Paul Bruinenberg
October 25, 2017 | 1:48 PM EDT
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CONFIDENTIAL 
Page 3 of 96 
 
 
 
 
PRINCIPAL INVESTIGATOR PROTOCOL SIGNATURE PAGE 
 
An Open-Label, Partially Randomized Trial to Evaluate the Efficacy, Safety and Tolerability 
of a 4-month Treatment of Bedaquiline plus Pretomanid plus Moxifloxacin plus 
Pyrazinamide (BPaMZ) Compared to a 6-month Treatment of HRZE/HR (Control) in Adult 
Participants with Drug-Sensitive Smear-Positive Pulmonary Tuberculosis (DS-TB) and a 6-
month Treatment of BPaMZ in Adult Participants with Drug Resistant, Smear-Positive 
Pulmonary Tuberculosis (DR-TB). 
Protocol Number:  
NC-008 (B-Pa-M-Z) 
Protocol Date:  
V1.0, 05 October 2017 
Protocol Name:  
SimpliciTB 
 
I hereby confirm that I have read the above protocol and agree to conduct this clinical trial as 
outlined in the above protocol. I will provide copies of the protocol and access to all the information 
required to conduct the clinical trial according to the above protocol to the site personnel under 
my supervision. I will discuss this material with them and ensure they are fully informed on all trial 
requirements. 
 
 
 
 
 
Signature 
 
Printed Name 
 
 
 
Date 
 
 
 
 
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Page 4 of 96 
 
Table of Contents 
Page 
List of Tables ............................................................................................................................. 8 
List of Figures ............................................................................................................................ 8 
List of Appendices ...................................................................................................................... 8 
1.0 
Synopsis ........................................................................................................................11 
1.1 
Synopsis Summary ................................................................................................11 
1.2 
Synopsis Flow Chart and Procedures .....................................................................17 
2.0 
Introduction and Rationale .............................................................................................23 
2.1 
Tuberculosis Disease .............................................................................................23 
2.2 
Tuberculosis Clinical Research ..............................................................................23 
2.3 
Trial Rationale ........................................................................................................25 
2.3.1 
Trial Design Rationale ...............................................................................25 
2.3.2 
Trial Drug Regimen Rationale ...................................................................26 
2.4 
Agents used within SimpliciTB................................................................................26 
2.5 
Background of Agents to be Studied in SimpliciTB .................................................29 
2.5.1 
Bedaquiline ...............................................................................................29 
2.5.2 
Pretomanid ................................................................................................35 
2.5.3 
Moxifloxacin (M) ........................................................................................41 
2.5.4 
Pyrazinamide (Z) .......................................................................................43 
2.6 
Overall Benefit/Risk Assessment ............................................................................44 
2.6.1 
Bedaquiline ...............................................................................................45 
2.6.2 
Pretomanid ................................................................................................45 
2.6.3 
Moxifloxacin ..............................................................................................46 
2.6.4 
Pyrazinamide ............................................................................................46 
2.6.5 
HRZE/HR Control ......................................................................................46 
3.0 
Trial Objectives ..............................................................................................................47 
3.1 
Primary Objectives .................................................................................................47 
3.2 
Secondary Objectives ............................................................................................47 
3.3 
Exploratory Objectives ...........................................................................................48 
4.0 
Trial Design ...................................................................................................................48 
4.1 
Summary of Trial Design ........................................................................................48 
4.2 
Treatment Plan: Schedule of Assessments ............................................................49 
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5.0 
Trial Population .............................................................................................................49 
5.1 
Inclusion Criteria ....................................................................................................50 
5.2 
Exclusion Criteria ...................................................................................................51 
5.3 
Restrictions ............................................................................................................54 
5.4 
Treatment Discontinuation and/or Early Withdrawal ...............................................56 
5.4.1 
Early Withdrawal .......................................................................................57 
5.4.2 
Unscheduled Visits ....................................................................................58 
5.4.3 
Lost-to-Follow-up ......................................................................................58 
5.4.4 
Early Withdrawal due to TB .......................................................................58 
5.5 
Participant Progress Definitions ..............................................................................60 
5.6 
Trial Stopping Rules ...............................................................................................60 
6.0 
Treatment ......................................................................................................................61 
6.1 
IMP Administration .................................................................................................61 
6.1.1 
Instructions for Dosing of Test Regimen (BPaMZ): ....................................61 
6.1.2 
Instructions for Dosing Control Treatment Regimen (HRZE/HR): ..............61 
6.2 
Participant Compliance ..........................................................................................61 
6.3 
Treatment Modification(s) .......................................................................................61 
6.4 
IMP Packaging and Labelling .................................................................................62 
6.5 
Blinding and Procedures for Breaking the Blind ......................................................63 
6.6 
Handling, Storage and Accountability .....................................................................63 
7.0 
Trial Variables and Procedures......................................................................................64 
7.1 
Demographic and Background Variables and Procedures ......................................64 
7.2 
Efficacy Variables and Procedures .........................................................................64 
7.3 
Safety and Tolerability Assessments ......................................................................65 
7.4 
PK Variables and Procedures.................................................................................67 
7.5 
Mycobacteriology Characterization Variable and Procedures .................................67 
8.0 
Adverse Events .............................................................................................................68 
8.1 
Definitions ..............................................................................................................68 
8.1.1 
Adverse Event (AE) ...................................................................................68 
8.1.2 
Serious Adverse Event (SAE) ...................................................................68 
8.1.3 
Attribution/Causality ..................................................................................68 
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8.1.4 
Severity .....................................................................................................70 
8.2 
Reporting ...............................................................................................................70 
8.2.1 
Follow up of Adverse Events .....................................................................71 
8.2.2 
Clinical Laboratory Adverse Events ...........................................................71 
8.2.3 
Disease symptoms during Trial .................................................................71 
8.2.4 
Overdose ..................................................................................................72 
8.2.5 
Drug Interaction.........................................................................................72 
8.2.6 
Pregnancy .................................................................................................72 
8.3 
Monitoring for Specific Toxicities ............................................................................73 
8.3.1 
Neurological ..............................................................................................73 
8.3.2 
Musculoskeletal System and Cardiac Muscle Myalgia ..............................73 
8.3.3 
Cardiac Rhythm Disturbances ...................................................................73 
8.4 
Safety Monitoring by Data Monitoring Committee ...................................................74 
9.0 
Statistical Analysis .........................................................................................................74 
9.1 
Analysis Populations ..............................................................................................74 
9.2 
Sample Size ...........................................................................................................75 
9.3 
Interim Analyses .....................................................................................................75 
9.4 
Primary and Secondary Efficacy Endpoint Analysis ................................................75 
9.4.1 
Primary Efficacy Endpoint, Time to Culture Conversion at 8 Weeks ..........75 
9.4.2 
Key Secondary Efficacy Endpoint, Clinical outcome at 52 Weeks from 
Randomization ..........................................................................................75 
9.4.3 
Other Secondary Efficacy Endpoints .........................................................76 
9.5 
Safety and Tolerability Assessments ......................................................................76 
9.6 
Pharmacokinetics ...................................................................................................76 
9.7 
Pharmacokinetics/Pharmacodynamics ...................................................................77 
10.0 
Records Management ...................................................................................................77 
10.1 
Data Collection .......................................................................................................77 
10.2 
Source Documents .................................................................................................77 
10.3 
File Management at the Trial Centre ......................................................................77 
10.4 
Records Retention at the Trial Centre ....................................................................77 
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11.0 
Quality Control and Assurance ......................................................................................78 
11.1 
Site Procedures ......................................................................................................78 
11.2 
Monitoring ..............................................................................................................78 
11.3 
Protocol Deviations ................................................................................................79 
11.4 
Auditing ..................................................................................................................79 
12.0 
Ethics and Regulatory ...................................................................................................79 
12.1 
Basic Principles ......................................................................................................79 
12.2 
Independent Ethics Committee/Institutional Review Board (EC/IRB) Review .........79 
12.3 
Regulatory Authorities ............................................................................................80 
12.4 
Informed Consent ...................................................................................................80 
12.5 
Confidentiality .........................................................................................................80 
13.0 
Publication Policy ..........................................................................................................82 
14.0 
Protocol Amendment Policy ...........................................................................................82 
15.0 
Sponsor, Financial Aspects, Insurance and Indemnity ...................................................82 
16.0 
References ....................................................................................................................84 
Appendices ...............................................................................................................................88 
 
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List of Tables 
Table 1.  Bedaquiline Adverse Drug Reactions .........................................................................33 
Table 2.  Key findings of Pretomanid in Safety and Toxicity Trials.............................................37 
Table 3.  Summary of Phase 2b trials in which moxifloxacin were administered as part of a four-
drug regimen during the intensive phase of treatment (total treatment duration: 2 months) .......42 
Table 4: Treatment Groups .......................................................................................................49 
Table 5: Follow-up visits required for Early Withdrawal Participants ..........................................57 
Table 6: Adverse Events Attribution/Causality Ratings ..............................................................69 
Table 7: Definitions for Adverse Event Severity Gradings .........................................................70 
 
List of Figures 
Figure 1.  Unified Drug Sensitive/Drug Resistant Regimen Development Path .........................24 
Figure 2.  Log10 CFU Counts in Lungs .....................................................................................36 
Figure 3.  Mean log Colony Forming Unit Values over Time Trial CL-010 .................................39 
 
 
List of Appendices 
Appendix 1: The IUATLD Scale ................................................................................................88 
Appendix 2: Division of Microbiology and Infectious Disease (DMID) Toxicity Table .................89 
Appendix 3: Who Clinical Staging of HIV/AIDS for Adults and Adolescents ..............................90 
Appendix 4: Cardiovascular Safety ...........................................................................................92 
Appendix 5: Karnofsky Performance Status Scale Definitions Rating (%) Criteria .....................93 
Appendix 6: Tuberculosis Symptoms Profile .............................................................................94 
Appendix 7: Patient Reported Health Status Questionnaire ......................................................95 
 
 
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Abbreviations and Definition of Terms 
 
3TC 
Lamivudine 
ABC 
ABaCavir 
AE  
Adverse Event  
AFB 
Acid-fast bacilli 
AIDS 
Acquired Immune Deficiency Syndrome 
ALP 
Alkaline Phosphatase 
ALT 
ALanine aminoTransferase 
AREDS2 
Age Related Eye Disease Scale 2 
ART 
Anti-Retroviral Therapy 
AST 
ASpartate aminoTransferase 
AUC￼ 
Area Under Curve over a dosing interval 
B 
Bedaquiline 
BA 
Bacterial activity 
BMI 
Body Mass Index 
BPaMZ 
Combination of bedaquiline plus pretomanid plus moxifloxacin plus 
pyrazinamide 
C 
Clofazimine 
CFU 
Colony Forming Units 
C(max), (min) 
plasma Concentration (maximum), (minimum) 
CO2 
Carbon diOxide 
CPK 
Creatine PhosphoKinase 
CYP3A4 
Cytochrome P450 3A4 
DMID 
Division of Microbiology and Infection Disease 
DNA 
DeoxyriboNucleic Acid 
DR-TB 
drug-resistant tuberculosis 
For this particular protocol defined as TB participants with  
1. mono-resistance to rifampicin or isoniazid, OR 
2. resistance to both rifampicin and isoniazid (MDR-TB) 
(participants with fluoroquinolone resistance are excluded) 
DS-TB 
drug-sensitive tuberculosis 
DSMC 
Data Safety and  Monitoring Committee 
E 
Ethambutol 
EBA 
Early Bacteriocidal Activity 
EC 
Ethics Committee 
ECG 
ElectroCardioGram 
EFV 
EFaVirenz 
(e)CRF 
(electronic) Case Report Form 
EMS 
Early Morning Sputum 
EWD 
Early Withdrawal 
FTC 
Emtricitabine 
FSH 
Follicle-stimulating hormone 
GCP  
Good Clinical Practice 
GMR 
Geometric Mean Ratio 
H 
Isoniazid 
hERG 
Human Ether-à-go-go Related Gene 
HIV  
Human Immunodeficiency Virus 
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HRZE 
Isoniazid, Rifampicin, Pyrazinamide, Ethambutol 
HR 
Isoniazid plus rifampicin combination tablet 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IMP 
Investigational Medicinal Product 
IRB 
Institutional Review Board 
ITT 
Intent to Treat 
IUATLD 
International Union Against Tuberculosis and Lung Disease 
IWRS 
Interactive Web Randomization System 
kg 
Kilogram 
L 
Linezolid 
LH 
Luteinizing hormone 
LLN 
Lower Limit of Normal 
LPV 
LoPinaVir 
LTFU 
Long term follow up  
M 
Moxifloxacin 
MBD 
Minimum Bactericidal Dose 
MIC 
Minimum Inhibitory Concentration 
MTB 
Mycobacterium tuberculosis 
MDR-TB 
Multi Drug Resistant Tuberculosis 
MGIT 
Mycobacterial Growth Inhibiting Tube 
mITT 
Modified Intent To Treat 
ms 
millisecond 
NVP 
NeViraPine 
NO 
Nitric Oxide 
NOAEL 
No Observed Adverse Effect Level 
NRTI 
(Triple) Nucleosidase Reverse Transcriptase Inhibitor 
Pa 
Pretomanid 
PD 
PharmacoDynamic 
PP 
Per Protocol 
PK 
PharmacoKinetic 
PR 
PR interval 
R 
Rifampicin 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SSCC 
Serial sputum colony counting 
TB 
Tuberculosis 
TDF 
Tenofovir 
TEAE 
Treatment Emergent Adverse Events 
TTP 
Time To Positivity  
ULN 
Upper Limit of Normal 
WHO 
World Health Organization 
XDR-TB 
eXtensively Drug Resistant Tuberculosis 
μg(/ml) 
micrograms (per milliliter) 
Z 
pyraZinamide (tablets) 
 
 
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1.0 
Synopsis 
1.1 
Synopsis Summary 
Name of 
Sponsor/Company 
Global Alliance for TB Drug Development 
Name of Finished 
Products: 
Bedaquiline tablets (B), pretomanid tablets (Pa), moxifloxacin 
tablets (M), pyrazinamide tablets (Z), HRZE tablets [isoniazid (H), 
rifampicin (R), pyrazinamide (Z) and ethambutol (E)] and HR tablets 
[isoniazid (H) plus rifampicin (R) combination tablets] 
Protocol Number/Title: 
NC-008 / (B-Pa-M-Z)/ An Open-Label, Partially Randomized Trial 
to Evaluate the Efficacy, Safety and Tolerability of a 4-month 
Treatment of Bedaquiline plus Pretomanid plus Moxifloxacin plus 
Pyrazinamide (BPaMZ) Compared to a 6-month Treatment of 
HRZE/HR (Control) in Adult Participants with Drug-Sensitive 
Smear-Positive Pulmonary Tuberculosis (DS-TB) and a 6-month 
Treatment of BPaMZ in Adult Participants with Drug Resistant, 
Smear-Positive Pulmonary Tuberculosis (DR-TB) 
Treatment Indication: 
Pulmonary Tuberculosis (TB) 
Trial Objective(s): 
To evaluate the efficacy, safety and tolerability at 8 weeks (2-
months), 52 weeks (12-months), and 104 Weeks (24-months) post 
the start of the following treatment regimens in participants with: 
 
Drug Sensitive TB (DS-TB) 
– 
BPaMZ given for 17 Weeks (4 months) 
– 
Standard HRZE/HR treatment given for 26 weeks (6 
months) 
 
Drug Resistant TB (DR-TB)  
– 
BPaMZ given for 26 Weeks (6 months) 
 
DR-TB Defined as participants with  
1. mono-resistance to rifampicin or isoniazid, OR 
2. resistance to both rifampicin and isoniazid (MDR-TB) 
Trial Design: 
Phase 2c multi-center, open-label, partially randomized clinical trial 
in DS-TB and DR-TB participants.  
 
All participants in the below arms will have follow-up for a period of 
104 weeks (24 months) from the start of therapy. 
 
Participants with Drug Sensitive TB (DS-TB): 
 
Participants with DS-TB will be randomized to one of two treatment 
arms. These participants will receive either BPaMZ daily for 17 
weeks (4 months), or HRZE/HR combination tablets daily for 26 
weeks (6 months). participants will be stratified for co-infection with 
human immunodeficiency virus (HIV) and cavitation. 
 
Participants with Drug Resistant TB (DR-TB): 
 
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Name of 
Sponsor/Company 
Global Alliance for TB Drug Development 
Name of Finished 
Products: 
Bedaquiline tablets (B), pretomanid tablets (Pa), moxifloxacin 
tablets (M), pyrazinamide tablets (Z), HRZE tablets [isoniazid (H), 
rifampicin (R), pyrazinamide (Z) and ethambutol (E)] and HR tablets 
[isoniazid (H) plus rifampicin (R) combination tablets] 
Participants with DR-TB will be assigned to receive BPaMZ daily 
for 26 weeks (6 months). 
Patient Population: 
A total of up to 450 male and female participants, diagnosed with 
DS-TB or DR-TB, aged 18 years and over with a target of up to 
50% being HIV positive. 
 
300 DS-TB participants (150 per treatment arm) will be randomized 
and stratified for co-infection with HIV and cavitation. 
Up to 150 DR-TB participants will be enrolled 
Test product, Dose 
and Mode of 
Administration: 
The Test Treatment Regimen (BPaMZ) consists of a 
combination of the following products and will be supplied as: 
bedaquiline   100 mg tablets (B) 
pretomanid    200 mg tablets (Pa) 
moxifloxacin   400 mg tablets (M) 
pyrazinamide 500 mg tablets (Z) 
 
Instructions for Dosing of Test Regimen (BPaMZ):  
Treatment will be administered orally once daily, to be taken during 
breakfast, with a full glass of water (approximately 240 ml), for 17 
weeks (4 months) or 26 weeks (6 months) in the following dosing 
schemes: 
 
Participants with Drug Sensitive TB: (DS-TB) 
Bedaquiline 200 mg daily for 8 weeks then 100 mg daily for 9 
weeks, together with pretomanid 200 mg + moxifloxacin 400 mg + 
pyrazinamide 1500 mg daily for 17 weeks (Total treatment duration 
4 months)  
 
OR 
 
Participants with Drug Resistant TB: (DR-TB) 
Bedaquiline 200 mg daily for 8 weeks then 100 mg daily for 18 
weeks, together with pretomanid 200 mg + moxifloxacin 400 mg + 
pyrazinamide 1500 mg daily for 26 weeks (Total treatment duration 
6 months) 
Positive Control 
Product, Dose and 
Mode of 
Administration: 
The Control Treatment Regimen (HRZE/HR) will be supplied 
as:  
HRZE Tablets: (isoniazid 75 mg plus rifampicin 150 mg plus 
pyrazinamide 400 mg plus ethambutol 275 mg combination 
tablets). This combination will be given for the first 8 weeks. 
 
AND 
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Name of 
Sponsor/Company 
Global Alliance for TB Drug Development 
Name of Finished 
Products: 
Bedaquiline tablets (B), pretomanid tablets (Pa), moxifloxacin 
tablets (M), pyrazinamide tablets (Z), HRZE tablets [isoniazid (H), 
rifampicin (R), pyrazinamide (Z) and ethambutol (E)] and HR tablets 
[isoniazid (H) plus rifampicin (R) combination tablets] 
 
HR Tablets: (isoniazid 75 mg plus rifampicin 150 mg combination 
tablets). This combination will be given from Weeks 9 to 26. 
 
Instructions 
for 
Dosing 
Control 
Treatment 
Regimen 
(HRZE/HR): 
 
To be taken with a glass of water (approximately 240 ml). 
HRZE or HR should not be taken with a meal (generally, no closer 
to meals than 1 hour before or 2 hours after a meal) in the following 
dosing schemes. 
 
Treatment will be administered orally once daily only to the “control” 
randomized DS-TB participants as follows: 
 
Weeks 1-8: HRZE tablets with the daily dose per the Participant’s 
weight as follows: 30-37 kg: 2 tablets; 38-54 kg: 3 tablets; 55-70 
kg: 4 tablets; 71 kg and over: 5 tablets; 
 
Weeks 9-26: HR with daily dose per the participant's weight as 
follows: 30-39 kg: 2 tablets; 40-54 kg: 3 tablets; 55-70 kg: 4 
tablets; 71 kg and over: 5 tablets.  
 
Vitamin B6 25 mg daily supplement to be taken with the HRZE/HR 
treatment.  
Treatment 
Interruptions/Pauses: 
For All Trial Regimens:  
The trial treatment regimens may require interruptions/pauses due 
to toxicities. All dose interruptions/pauses should be discussed with 
the Sponsor’s Medical Monitor prior to implementation, unless an 
interruption/pause is required urgently for a safety concern; the 
Medical Monitor should then be informed within 24 hours of the 
interruption/pause if not discussed prior to implementation.   
The importance of adherence to the treatment schedule will be 
reinforced at each visit.  Non-adherence should prompt the 
investigator to identify, capture and address the cause(s) (e.g. side 
effects) of the non-adherence and contact the sponsor medical 
monitor.    
Action required for participants missing the following number of 
doses within the trial treatment regimens:  
• 
< 7 consecutive doses: restart treatment, no extension of 
treatment required.  
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Name of 
Sponsor/Company 
Global Alliance for TB Drug Development 
Name of Finished 
Products: 
Bedaquiline tablets (B), pretomanid tablets (Pa), moxifloxacin 
tablets (M), pyrazinamide tablets (Z), HRZE tablets [isoniazid (H), 
rifampicin (R), pyrazinamide (Z) and ethambutol (E)] and HR tablets 
[isoniazid (H) plus rifampicin (R) combination tablets] 
• 
7 to ≤ 21 consecutive doses: restart treatment, extend the 
treatment by the number of consecutive doses missed. In this 
case:  
➢ the final treatment visit should also be pushed out to the 
date of last dose.   
➢ it is not necessary to have an unscheduled visit at the time 
when the End of Treatment visit would have been.  
• 
Greater than 21 consecutive doses: discontinue treatment and 
withdraw participant from the trial.  
Any participant for whom the trial medication is discontinued 
(including for non-adherence) will be discussed with the sponsor 
medical monitor and, if applicable, the participant will be restarted 
on trial medication as soon as possible. 
Statistical Methods: 
A general description of the statistical methods planned to be used to analyze efficacy data is 
outlined below. Specific details will be provided in the statistical analysis plan (SAP,) which 
will be written and signed off prior to the first participant enrolled in the trial. 
 
The primary analysis will be conducted using culture results from liquid culture (in the 
Mycobacterial Growth Indicator Tube (MGIT) system). 
 
Criteria for Evaluation: 
 
The primary efficacy endpoint will be time to culture negativity over 8 weeks. The 
primary hypothesis to be evaluated is:  
 
In the participants with DS-TB in the experimental BPaMZ treatment regimen, the time to 
culture negativity by 8 weeks will be superior compared to the participants who are 
treated with the standard HRZE regimen. 
 
There will be three main analyses of the primary efficacy endpoint.  A modified Intent to Treat 
(mITT) analysis will be primary. A per-protocol (PP) analysis and an ITT analysis will also be 
performed for the secondary endpoint. These will be examined for consistency with the mITT 
analysis.  
 
Note: 
Culture conversion requires at least 2 consecutive culture negative samples, at least 7 days 
apart (after positive baseline confirmation). 
Participants who are documented at a visit as unable to produce sputum and who are 
clinically considered to be responding well to treatment will be considered culture negative 
at that visit.  
 
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Name of 
Sponsor/Company 
Global Alliance for TB Drug Development 
Name of Finished 
Products: 
Bedaquiline tablets (B), pretomanid tablets (Pa), moxifloxacin 
tablets (M), pyrazinamide tablets (Z), HRZE tablets [isoniazid (H), 
rifampicin (R), pyrazinamide (Z) and ethambutol (E)] and HR tablets 
[isoniazid (H) plus rifampicin (R) combination tablets] 
Secondary Endpoints 
 
A key secondary endpoint will be the proportion of participants experiencing bacteriologic 
failure or relapse or clinical failure (unfavourable outcome) at 52 weeks (12 months). The 
hypothesis to be evaluated for this endpoint is: 
 
In the participants with DS-TB in the experimental BPaMZ treatment regimen, the 
proportion experiencing an unfavourable outcome will be non-inferior compared to the 
participants who are treated with the standard HRZE regimen. 
 
Other Secondary Endpoints 
Efficacy: 
Incidence of bacteriologic failure or relapse or clinical failure at 104 weeks from the start of 
therapy.  
Proportion of participants with sputum culture conversion to negative status in liquid culture 
(MGIT) at 4, 6, 12 and 17 weeks to be explored as a potential biomarker of outcome at 52 
weeks from start of therapy. 
Change from baseline in weight. 
Change from baseline in TB symptoms. 
Change from baseline in Participant Reported Health Status. 
 
Safety and Tolerability: 
Incidence of Treatment Emergent Adverse Events (TEAEs) presented by incidence, severity, 
drug relatedness, seriousness, leading to early withdrawal, and leading to death.  
Quantitative and qualitative clinical safety laboratory measurements, including 
observed and change from baseline. 
Quantitative and qualitative electrocardiogram (ECG) results (heart rate, RR interval, 
PR interval, QRS interval, QT interval and QTc interval), including observed. QT/QTc 
intervals, change from baseline, will be categorized as these will be centrally read. 
Changes in male reproductive hormones and lens opacities. 
 
These data will be presented as descriptive analyses, and no inferential tests will be carried 
out. 
 
Pharmacokinetics (PK) and Pharmacokinetics/Pharmacodynamics (PK/PD): 
Plasma concentrations from sparse sampling will be used to update existing population PK 
models and derive exposure metrics (e.g., minimum plasma concentration [Cmin], maximum 
plasma concentration [Cmax], area under curve over a dosing interval [AUC]) for bedaquiline 
and its M2 metabolite, pretomanid, moxifloxacin, and pyrazinamide. Effects of baseline 
covariates on exposure will be assessed; so, too, will the effects of con-medications including 
antiretroviral therapy (ART), as feasible. Data from other trials may be included to enhance 
the model-based analysis. Relationships will be explored between drug exposure and efficacy 
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Name of 
Sponsor/Company 
Global Alliance for TB Drug Development 
Name of Finished 
Products: 
Bedaquiline tablets (B), pretomanid tablets (Pa), moxifloxacin 
tablets (M), pyrazinamide tablets (Z), HRZE tablets [isoniazid (H), 
rifampicin (R), pyrazinamide (Z) and ethambutol (E)] and HR tablets 
[isoniazid (H) plus rifampicin (R) combination tablets] 
and safety endpoints. These exploratory PK/PD analyses may include HIV status as a 
covariate. 
 
Exploratory: 
Evaluate whether any of the secondary endpoints predicts relapse free cure. 
Subgroup analysis of populations by HIV status  
 
No formal statistical comparisons will be made for the participants enrolled with DR-TB. 
 
Sample Size 
Primary endpoint: 150 participants per arm (DS-TB patients) will provide at least 90% power 
(5% 2-sided significance) to detect a hazard ratio (HR) of at least 2 assuming 50% of control 
participants are culture negative by 8 weeks.  
 
Additional efficacy parameters will be evaluated including the incidence of bacteriologic failure 
or relapse or clinical failure (unfavourable outcome) at 52 weeks and 104 weeks from the start 
of therapy. Time to unfavourable outcome from assignment of trial treatment through follow-
up as a function of time will be analyzed using Kaplan-Meier analysis. 
 
Trial Duration: 
Approximately 4 years (18-month enrollment period for DS-TB participants, up to 26 week-
treatment, and 104-week follow-up from start of therapy. Depending on the DR-TB 
recruitment rate, enrollment into this arm may be continued after enrollment into the DS-TB 
arms is complete). The DR-TB group may still be ongoing while the DS-TB group is halted if 
the enrollment target is reached. 
 
There will be 3 database locks, data analyses and trial reports generated for this trial:  
When all participants have completed 8 weeks (2 months) of treatment from baseline.  
When all participants have completed 52 weeks (12 months) follow-up from start of therapy. 
When all participants have completed 104 weeks (24 months) follow-up from start of therapy.  
 
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1.2 
Synopsis Flow Chart and Procedures 
Period 
Screen
-inga 
Treatment 
Follow-Upc 
Visitb 
Day -9 (DS) to -1 
Day 1 (Baseline) d 
Day 7 (Week 1) 
Week 2 
Week 3 
Week 4 
Week 5 
Week 6 
Week 7 
Week 8  
Week 12 
Week 17 
4-month treatment e 
Week 17  
6-month treatment e 
Week 22  
Week 26  
4-month treatment e 
Week 26  
6-month treatment e 
Week 39 
Week 52 
Week 65 
Week 78 
Week 104 
Early  Withdrawalc 
Visit Windowv 
N/A 
+/- 3 Days 
+/- 5 Days 
+/- 14 Days 
Written Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/Treatment/ 
Smoking History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sputum Samplingf,g 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HIV Statush and CD4 Counti 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Karnofsky Score 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Drug Screenj 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Pregnancy Testk 
X 
X 
 
 
 
 
 
 
 
X 
 
X 
X 
 
X 
X 
 
 
 
 
 
X 
Laboratory Safety Testl 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
 
X 
X 
 
 
 
 
 
X 
Male Reproductive 
Hormone Testsm 
X 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
 
 
 
 
12-lead ECGn 
X 
X 
X 
X 
 
X 
 
 
 
X 
 
X 
X 
 
X 
X 
X 
 
 
 
 
X 
Chest X-Rayo 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TB Symptoms Profile 
X 
X 
 
X 
 
X 
 
 
 
X 
 
X 
X 
 
X 
X 
 
X 
 
 
X 
X 
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Period 
Screen
-inga 
Treatment 
Follow-Upc 
Visitb 
Day -9 (DS) to -1 
Day 1 (Baseline) d 
Day 7 (Week 1) 
Week 2 
Week 3 
Week 4 
Week 5 
Week 6 
Week 7 
Week 8  
Week 12 
Week 17 
4-month treatment e 
Week 17  
6-month treatment e 
Week 22  
Week 26  
4-month treatment e 
Week 26  
6-month treatment e 
Week 39 
Week 52 
Week 65 
Week 78 
Week 104 
Early  Withdrawalc 
Patient Reported Health 
Status  
X 
X 
 
X 
 
X 
 
 
 
X 
 
X 
X 
 
X 
X 
 
X 
 
 
X 
X 
Vital Signs and weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Ophthalmic Examinationp 
X 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
X 
X 
X 
 
 
 
 
X 
Physical Examination – 
fullq 
X 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
Physical Examination – 
limitedr 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
Pharmacokinetic 
Samplings 
 
X 
 
X 
 
 
 
 
 
X 
X 
X 
X 
 
 
 
X 
 
X 
X 
X 
 
IMP Randomization/ 
Assignmentt 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IMP Compliance Checku 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 Xe 
 
X 
 
 
 
 
 
Xt 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Investigator Assessmentv 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
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GENERAL: Vital signs, ECGs and blood draws are to be performed pre-dosing unless 
otherwise specified. Vital signs and/or ECGs should be done prior to blood draws 
(safety and PK) on days with those assessments. 
a. Screening: Screening assessments can occur on different days within nine days prior to 
Day 1 dosing (randomisation).  
b. Visit Schedule (due to unforeseen circumstances): If the duration of treatment is 
extended due to dose pauses the final treatment visit should also be pushed out to the 
date of last dose. It is not necessary to have an unscheduled visit at the time that the End 
of Treatment visit would have been.   
c. Follow-up Visits for Early Withdrawal Participants: Once a participant has been 
permanently withdrawn from the trial, they will be required to attend Early Withdrawal, 
Week 52 (if not already performed) and Week 104 follow-up visits. The Week 52 and Week 
104 visits will be to collect Serious Adverse Event (SAE) information (including verification 
of survival) and participant reported TB outcome information only and may be telephonic, 
a home or a site visit. They will occur at Week 52 and/or Week 104 after the participant’s 
start of treatment date.  Refer to Table 5 for additional guidance. 
d. Day 1 (Baseline): All procedures are to be completed prior to dosing.  
e. End of Treatment Visit: IMP Compliance Check is not performed at the Week 22 visit for 
participants who have completed treatment at Week 17. 
f. Sputum Sampling: The Sputum sampling methodology/requirements and tests will be 
described in a separate document, the Mycobacteria Laboratory Manual. 
1. Days -9 to -1 (Screening). Two spot sputum samples taken 30 minutes apart will 
be collected at the research site under the coaching and observation of the trial 
staff. The following analyses will be performed on the first of these samples: 
 Smear microscopy for acid-fast bacilli (AFB); 
 Rapid molecular tests for fluoroquinolones, isoniazid and rifampicin 
resistance;  
 Liquid Culture (MGIT) for Mycobacterium tuberculosis (MTB), followed by 
a speciation test to detect presence or absence of MTB and obtain time to 
positivity (TTP) when positive. 
The second sample is collected as a back-up sample to the first sample in case it is 
technically not possible to obtain a result/s from the first sample. If the Day (-9 to -1) 
(Screening) spot sputum smear shows an indeterminate result or is AFB negative, the 
test may be repeated on a freshly collected spot sputum/s and that result will be used.  
2. All visits from Day 1 (baseline) up to and including Week 104, plus any 
unscheduled visits. Two sputum samples (ideally one early morning brought from 
home and one spot at the research site under the coaching and observation of the 
trial staff; if the participant forgets to bring in the Early Morning Sputum (EMS), 
then two spots are to be collected at the site, at least 30 min apart, and this altered 
sample collection needs to be captured within case report form [CRF]).  If both 
sputum samples at Week 8 or later are contaminated, the participant should return 
for an unscheduled visit(s) to give additional samples or to document that the 
participant is not able to produce sputum. If there is a MTB confirmed positive 
culture at or after the end of treatment [Week 17 (4-month treatment arms)/Week 
26 (6-month treatment arms)], the participant should return for an unscheduled 
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visit(s) to give additional sputum samples a minimum of 7 days from the previous 
sample or to document that the participant is not able to produce sputum. 
Additional samples may be required in order to define a participants’ primary 
outcome status as described in Section 7.2. The following analyses will be 
performed on all sputum samples: 
 
Liquid Culture (MGIT) for MTB, followed by a speciation test to detect 
presence or absence of MTB and obtain TTP when positive. 
g. Mycobacteriology Characterisation Tests performed on:
1. Day 1 (baseline) sputum sample (or any positive sample from screening out to
Week 4 if the baseline cultures are contaminated or negative);
2. MTB confirmed positive cultures at or after Week 17 (4-month treatment arms) or
Week 26 (6-month treatment arms).
3. Refer to Mycobacteria Laboratory Manual for full details.
Mycobacterial Characterization:  
The MTB isolates will be processed for: 
•
Minimum Inhibitory Concentration (MIC) against bedaquiline, pretomanid, and
moxifloxacin;
•
Drug Susceptibility Testing for streptomycin, rifampicin, isoniazid, ethambutol,
moxifloxacin, pyrazinamide and second line TB drugs including but not limited to
fluoroquinolones, and injectables using an indirect susceptibility test in liquid
culture;
•
Extraction of organismal (MTB) DNA for whole genome sequencing, and comparison
of sequences from baseline and relapse isolates.
h. HIV Testing: If HIV status is a confirmed known positive, repeated HIV test is not needed
provided documentation is available. If HIV status is unknown or suspected negative, HIV
test should be requested. If an ELISA and/or Western Blot and/or Electro-
Chemiluminescence based HIV test was performed within 4 weeks prior to screening, it
should not be repeated as long as documentation of testing method and negative results
can be provided.
i.
CD4 Count: For all HIV-positive participants.
j.
Urine Drug Screen: Cannabinoids, cocaine, amphetamines, opiates, benzodiazepines,
barbiturates, at Screening only. Investigator to utilize to determine whether participant
meets Exclusion criteria 2. Positive results will not automatically exclude participant from
the trial.
k.
Urine Pregnancy Test: Women of childbearing potential only, whether they are sexually
active or not.
l.
Safety Laboratory Assessments: The Safety Laboratory sampling methodology and
requirements will be described in a separate document, the laboratory manual, which will
be provided prior to the trial start. The following analyses will be performed:
1. Full Blood Count (hemoglobin, hematocrit, red blood cell count, white blood cell count
with differential, platelet count).
2. Clinical Chemistry (albumin, serum urea, creatinine, direct, indirect and total bilirubin,
uric acid, total protein, alkaline phosphatase [ALP], aspartate aminotransferase [AST],
alanine aminotransferase [ALT], lipase, phosphate, sodium, potassium, calcium
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(corrected for albumin), chloride, magnesium, glucose, bicarbonate/carbon dioxide 
[CO2], creatine phosphokinase [CPK]). 
3. Urinalysis (pH, specific gravity, protein, glucose, micro-albumin, ketones, bilirubin, 
creatinine, nitrite, sodium, urobilinogen, blood, leukocytes). Microscopy will be 
completed as follow-up to abnormal urinalysis per discretion of Investigator. 
m. Male Reproductive Hormone Tests: Testosterone, follicle-stimulating hormone (FSH), 
luteinizing hormone (LH) and Inhibin B to be done on male participants in ALL treatment 
groups. 
n. Single 12-Lead ECG: To every extent possible, should be performed at approximately 
the same time of day as the site procedures (+/-1 hour) Central ECG analysis will be 
performed. Results from central reading of Day -9 to -1 (screening) ECG should be used 
to determine eligibility.  
o. Chest X-Ray: A chest x-ray (digital image) within 4 weeks prior to or at screening, will be 
obtained and read locally by Investigator or designee. Digital images will be provided to 
Sponsor, this process will be described in a separate document, the Radiology Manual. 
p. Slit Lamp Ophthalmic Examination - Slit lamp will be done at EOT and at 9 month for 4 
and 6-month treatment groups.  An additional slit lamp at 6 months for the 4-month 
treatment group. Slit lamp ophthalmology examination should be performed by an 
Ophthalmologist with AREDS2 training. Ophthalmology examinations may occur at any 
time within the window period for the applicable visit i.e. do not have to be performed on 
the same day as the site procedures. 
q. Physical Examination – Full: Height (m) will only be collected at Day -9 to -1 (screening).  
r. Physical Exam - Limited: Limited Physical exams should include weight and a gross 
neurological, pulmonary, cardiovascular and abdominal exam. 
s. Pharmacokinetic Sampling: Blood draw for PK done pre-dose (after ECGs), 1.5-3 hours 
post-dose (+/- 0.5 hour), and 4-6 (+/- 1 hour) hours post-dose. The dates and times of the 
two doses prior to the pre-dose PK sample will be collected. (PK Sampling Manual will be 
created). PK Sampling: Specific PK blood draws as follows: 
1. Day 1: pre-dose (within 2 hours prior to dosing) 
2. Week 2: pre-dose (within 2 hours prior to dosing), 1.5–3 hours post-dose and 4-6 
hours post-dose 
3. Week 8: pre-dose (within 2 hours prior to dosing), 1.5–3 hours post-dose and 4-6 
hours post-dose 
4. Week 12: pre-dose (within 2 hours prior to dosing)  
5. Week 17 or at early withdrawal if prior to week 17: pre-dose (within 2 hours prior 
to dosing) and 1.5–3 hours post-dose 
6. Weeks 39, 65, 78 and 104 – PK samples are obtained when participant is in the 
clinic 
No PK samples will be collected for HRZE/HR treatment arm. 
t. Investigational 
Medicinal 
Product 
(IMP) 
Randomization/Assignment: 
Initial 
randomization may occur once all the screening results are available and the investigator 
has determined that the participant is eligible for the trial. 
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u. IMP/Compliance Check: Trial medication administration will be supervised per local site 
practice to assure compliance to regimen. Performed at all visits and Early Withdrawal 
(EWD) if during treatment.  
v. Investigator Assessment: Principal Investigator to review participant status and assess 
whether IMP or TB treatment at current visit is considered a “success” or “failure”.  If 
considered a failure, should specify if based on bacteriology and/or clinical deterioration 
and/or radiological deterioration. To be completed as shown on the flowchart and at any 
time Investigator determines that participant fulfils criteria for outcome of treatment failure. 
w. Visit Windows: The windows noted on the flowchart for timing of visit also apply to timing 
within a visit.  Procedures should be performed within +/- 3 days of scheduled visit from 
Day 1 to Week 8 or +/- 5 Days of scheduled visit from Week 12 to Week 26 or +/- 14 days 
of scheduled visit at or after Week 39.  Sites should make every effort to ensure all other 
procedures are done on the same day when possible. 
 
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2.0 
Introduction and Rationale 
2.1 
Tuberculosis Disease 
Although some progress has been made in recent years in controlling tuberculosis (TB) globally, 
TB has remained a persistent problem in the developing countries of Africa, Asia and South 
America.  TB is currently one of the top three killer infectious diseases, and there is more TB in 
the world today than at any other time in history.  The current first-line anti-tuberculosis agents 
have been in use for over 40 years and are relatively ineffective in controlling TB as a public health 
problem.  Although the current regimens and drugs have been very successful in controlled 
clinical trials resulting in the permanent cure of more than 95% of trial participants, treatment takes 
6 months or more to complete. This, long duration treatment plus side effects, result in poor 
adherence which particularly occurs after the second month of treatment.  
The current TB treatment regimens and treatments for drug-sensitive TB are decades old. The 
available treatments have a lengthy duration of treatment, involve multi-drug therapy, and require 
large commitments of resources and infrastructure. High rates of noncompliance are common, 
which often results in increased mortality and chronic, infectious, drug-resistant cases. The 
present TB epidemic and the challenge of current treatment options demonstrate the clear need 
for effective novel TB drugs and drug regimens that are safe for drug sensitive and drug resistant 
TB disease and that are well-tolerated and will shorten the current treatment duration for patients. 
The full application of the Directly Observed Treatment, Short-Course strategy is becoming more 
and more difficult in the developing countries of the world that are also battling to control the HIV-
epidemic.  As a result of poor treatment adherence, drug resistance is becoming more common 
and fears of an epidemic with virtually untreatable strains of TB are growing.  Since the discovery 
of the rifamycins,[1] and their introduction into standard antituberculosis regimens, very few new 
classes of drugs have been evaluated with a view to their registration as antituberculosis agents.  
On December 28, 2012 the U.S. Food and Drug Administration approved bedaquiline (B) as part 
of combination therapy to treat adults with multi-drug resistant (MDR) pulmonary tuberculosis (TB) 
when other alternatives are not available. Following the declaration of TB as a global emergency 
by the World Health Organization (WHO) in 1993, there has been a resurgence of efforts to 
develop improved TB therapies and several promising new agents are presently in or approaching 
clinical evaluation.   
New combination regimens are desperately needed for two reasons: to shorten treatment to a 
duration more easily manageable by patients and public health services, and to provide more 
efficacious, safer and better tolerated, affordable treatments for the growing number of patients 
suffering from multidrug-resistant and extensively drug-resistant tuberculosis. 
2.2 
Tuberculosis Clinical Research 
TB currently must be treated with multiple drugs to achieve maximal efficacy and prevent 
resistance. To transform treatment, novel TB regimens are needed. In order to telescope the time, 
it takes to develop novel, tolerable multi-drug treatments, it is necessary to use the regimen 
development paradigm. This approach tests promising combinations of drugs together to find the 
most impactful treatment once the individual drug candidates have been tested in a robust pre-
clinical program and the establishment of the individual drug candidates’ safety and efficacy have 
been evaluated.  It evaluates novel combinations of TB drugs — instead of single drugs — as 
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part of a single development program, enabling the development of novel TB drug regimens that 
have potential to transform treatment for drug-sensitive and drug-resistant tuberculosis. This 
approach offers the potential to reduce the time previously needed to develop a novel treatment 
regimen by up to 75%, shortening the clinical development from decades to years. The steps 
followed in this development model are shown in Figure 1 Between each step on the unified 
development pathway a decision is made as to whether to proceed. 
Figure 1.  Unified Drug Sensitive/Drug Resistant Regimen Development Path 
 
Early Bactericidal Activity (EBA) Trials 
EBA trials are the backbone clinical trials to quantify the bactericidal action of anti-tuberculosis 
agents alone or in combination by either studying the fall in the number of colony forming units 
(CFU) or measuring the TTP in liquid culture of M. tuberculosis (MTB) present in the sputum of 
participants with microscopy smear-positive pulmonary TB. EBA trials have been conducted over 
2, 5, 7 and 14 days.[2]. A review of EBA trials conducted on the key anti-TB drugs has shown the 
value these trials offer to demonstrate the early anti-TB effect that a new therapeutic agent may 
have and to explore the relationships between dose, pharmacokinetics and bactericidal activity in 
participants.[3] 
8-week Bactericidal Activity (BA) Trials 
EBA methodology of quantitative colony counting on solid medium has been adapted to Phase 2, 
8-week TB treatment trials based on serial sputum colony counting (SSCC) or measurement of 
TTP liquid culture to provide a more sensitive efficacy endpoint than the previously used binary 
endpoint of rate of sputum conversion measured after 8 weeks of treatment.[4-6] Such trials are 
conducted to provide data on which to base the selection of treatment-shortening regimens.  
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2.3 
Trial Rationale 
This proposed trial (SimpliciTB) will evaluate and support that in additional to previous studies 
evaluated with BPaMZ, that this drug regimen (BPaMZ) will be safe and effective, is well-tolerated 
and could potentially shorten the current treatment duration compared to Standard HRZE/HR 
treatment for patients with drug sensitive TB disease. This study will also evaluate that this drug 
regimen (BPaMZ) given for 6 months will be safe and effective in drug resistant TB disease. 
Therefore, the study design addresses the need to find and evaluate a potential effective shorter 
regime compared to regimes (Standard HRZE/HR) that is current being used. 
2.3.1 
Trial Design Rationale 
NC-008 (B-Pa-M-Z) trial - [SimpliciTB] - is a Phase 2c multi-center, open-label, partially 
randomized clinical trial in DS-TB and DR-TB participants. This trial is to evaluate the combination 
regimen of Bedaquiline (B) plus Pretomanid (Pa) plus Moxifloxacin (M) plus Pyrazinamide 
(Z), (BPaMZ) in participants with pulmonary TB 
All participants in the below arms will have follow-up for a period of 104 weeks (24 months) from 
the start of therapy. 
Participants with Drug Sensitive TB (DS-TB): 
participants with DS-TB will be randomized to one of two treatment arms. These participants 
will receive either BPaMZ daily for 17 weeks (4 months),  
or  
HRZE/HR combination tablets daily for 26 weeks (6 months). participants will be stratified for 
co-infection with HIV and cavitation. 
Participants with Drug Resistant TB (DR-TB): 
DR-TB Defined as participants with  
1. mono-resistance to rifampicin or isoniazid, OR 
2. resistance to both rifampicin and isoniazid (multi-drug resistant tuberculosis [MDR-TB]) 
Participants with DR-TB will be assigned to receive BPaMZ daily for 26 weeks (6 months). 
Approximately 300 DS-TB participants (150 per treatment arm) will be randomized and stratified 
for co-infection with HIV and cavitation.  Up to 150 DR-TB participants will be enrolled and 
assigned 
The trial is sufficiently statistically powered to not only show superiority of 2 months’ culture 
conversion but should also demonstrate non-inferiority for cure at 12 months. (This is in the 
participants with DS-TB in the experimental BPaMZ treatment regimen, the proportion 
experiencing an unfavourable outcome will be non-inferior compared to the participants who are 
treated with the standard HRZE regimen.) 
As previously discussed in order to telescope the time it takes to develop novel, tolerable multi-
drug treatments, it is necessary to use the regimen development paradigm and utilize data 
generated in non-clinical and clinical studies regarding combining of anti-tuberculosis agents 
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which could contribute significantly to the sterilization of lesions and thus treatment shortening. 
Therefore, the study design and proposed study regimen (BPaMZ) which is supported with 
previous non- and clinical studies as outlined below should address the need and way to evaluate 
an effective shorter regime compared to regimes that is current being used. 
2.3.2 
Trial Drug Regimen Rationale 
The drug regimen BPaMZ has been studied singularly and in different combinations as outlined 
above. Moxifloxacin has been added to the B-Pa-Z regimen because of the high rate of 
pyrazinamide resistance seen in MDR-TB participants in the NC-002 trial. It essentially provides 
protection against the development of new resistance to the B-Pa-Z drugs. Based on the exciting 
and promising results seen in NC-005, this regimen can be initiated in drug sensitive and drug 
resistant TB participants whom are sensitive to the individual drugs in the regimen (excluding 
extensively drug-resistant tuberculosis [XDR-TB]) and has the potential to shorten TB treatment 
to less than 4 months in drug sensitive TB. These are also oral regimens, removing the need for 
injectables as part of MDR-TB treatment and also project to be markedly less expensive than 
current MDR-TB therapy. Additionally, these regimens can be administered in a fixed dose for all 
patients, and will therefore be simpler for health systems to deliver and patients to use. 
2.4 
Agents used within SimpliciTB 
Bedaquiline (TMC207; SirturoTM package insert)[7]  is a novel agent approved for TB treatment. 
As detailed in the Investigator’s Brochure,[8] bedaquiline is a diarylquinoline that offers a novel 
mechanism of anti-tuberculosis action by specifically inhibiting mycobacterial adenosine 
triphosphate synthase.[9, 10]) In vitro, bedaquiline potently inhibits both drug-sensitive and drug-
resistant M. Tb isolates,[10, 11], and is also bactericidal against non-replicating M. Tb.[12] In the 
murine model of TB, bedaquiline was as active as the triple combination of isoniazid (H), rifampin 
(R), and pyrazinamide (Z). Addition of bedaquiline to HRZ results in accelerated clearance of M. 
Tb.[3, 4] There appears to be a synergistic interaction with pyrazinamide: 100% of mice were 
culture negative after 8 weeks of treatment with bedaquiline and pyrazinamide compared to 0% 
of mice treated with the standard regimen of rifampicin, isoniazid and pyrazinamide.[13] 
Collectively, these findings in the mouse model have led to the suggestion that regimens 
containing bedaquiline and pyrazinamide could be effective in the treatment of both DS- and 
MDR-TB and shorten treatment duration in patients. While the combination of bedaquiline and 
PA-824 in the murine model of TB appeared somewhat antagonistic relative to bedaquiline alone, 
it was as active as the triple combination of HRZ[13] and in a subsequent trial it was more active 
in the mouse model than HRZ.[14] Thus, a novel regimen with a bedaquiline plus PA-824 core 
could be effective in the treatment of MDR-TB by providing two novel drugs for which there is no 
known pre-existing resistance.  
Pretomanid, PA-824 (Pa)[15]  is a new agent being developed by TB alliance for TB treatment.  
PA-824 is a new chemical entity and a member of a class of compounds known as nitroimidazo-
oxazines, which possess significant anti-tuberculosis activity and a unique mechanism of 
action.[16] PA-824 has been under development for several years, and entered clinical trials in 
2005. Several trials of PA-824 have also been conducted previously in healthy volunteers.  
Collectively, these trials in participants with active TB and healthy participants have defined the 
efficacy, safety and pharmacokinetic features of the drug.  Overall, PA-824 has mycobactericidal 
activity in participants and is well tolerated and bioavailable after oral dosing.  PA-824 
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demonstrated in vitro activity against both drug-sensitive (DS) and MDR-TB,[17] and in vivo activity 
in a mouse model of TB[17, 18] with a significant promise for shortening treatment of active TB. 
Moxifloxacin (M)[19]  is a microbial compound, approved in most countries around the world for 
the treatment of acute bacterial sinusitis, acute bacterial exacerbation of chronic bronchitis, 
community-acquired pneumonia, skin and soft tissue infections.  Clinical studies have been 
carried out for a number of additional indications (urinary tract infections, pelvic infections, 
pharyngitis/tonsillitis, and tuberculosis). Moxifloxacin is an 8-methoxyquinolone whose oral 
formulation (which will be used in this study) has enhanced activity against Gram-positive 
pathogens, and anaerobes while retaining useful activity against Gram-negative organisms. 
Moxifloxacin is not metabolized by or induces the cytochrome P450 system, thus the risk of 
clinically relevant drug interactions is reduced. It has a positive safety profile within the 
fluoroquinolone class at the approved daily dose of 400 mg. Moxifloxacin while not approved for 
TB by most regulatory authorities, it is regularly used in second line MDR-TB treatment. The WHO 
TB Treatment Guidelines place moxifloxacin in the category of Group 3 drugs and notes that “all 
patients [with MDR-TB] should receive a Group 3 medication if the M. tuberculosis strain is 
susceptible or if the agent is thought to have efficacy. One of the higher generation 
fluoroquinolones, such as levofloxacin or moxifloxacin, is the fluoroquinolone of choice.[5]” It is 
currently in late stage clinical development for first-line TB treatment in combination with other TB 
drugs, including pyrazinamide in two different four-month long regimens.  
Pyrazinamide (Z)[20] is a pyrazine analogue of nicotinamide and an approved anti-tuberculosis 
agent which is indicated for the initial treatment of active tuberculosis in adults and children when 
combined with other anti-tuberculosis agents and contributes significantly to the sterilization of 
lesions and thus treatment shortening.[21]   
Control group: HRZE combination 
The HRZE/HR combination [HRZE tablets [isoniazid (H), rifampicin (R), pyrazinamide (Z) and 
ethambutol (E)] and HR tablets [isoniazid (H) plus rifampicin (R) combination tablets] is approved 
indicated and commonly used as a 6 month treatment for drug-sensitive TB patients.  Participants 
with DS-TB that are randomized to the HRZE/HR control arm in this trial will be given standard 
weight-adjusted doses of HRZE.  Please see the HRZE package insert for more information.[22]   
Additional background data supporting the combined use of new novel agents in this 
BPaMZ regime for the treatment of TB: 
Data from preclinical studies suggest that a regimen consisting of moxifloxacin plus PA-824 plus 
pyrazinamide may not only be appropriate for treating both DS and MDR-TB but may also shorten 
duration of therapy.  Results from an 8-week Phase 2b SSCC study, NC-002-(M-Pa-Z), showed 
that this combination regimen was effective as measured by time dependent decline of viable 
bacteria in participants with DS pulmonary TB.  The combination was also shown to be safe and 
well tolerated supporting the evaluation of this combination in a Phase 3 study. In this NC-002 
study 71.4% of participants with DS-TB treated with PaMZ at the 100-mg daily dose of PA-824 
converted sputum to negative for MTB growth in liquid culture in comparison with only 37.8 % of 
participants treated with the HRZE control (p<0.05).  
Studies in mice infected with MTB demonstrated reductions in cultured colony counts from lungs 
over an 8-week period when treated with the PaMZ regimen that were substantially, and 
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statistically significantly greater, than the reductions in mice treated with an HRZ control.  
Experiments in mice found that mice did not relapse with MTB infection when treated with PaMZ 
for 4 months and followed for 3 months off treatment, in comparison to mice that required 6 
months of treatment with HRZ to prevent relapse.[14]   
Drug Resistant TB background: 
Although some progress has been made in recent years in controlling tuberculosis (TB) globally, 
TB has remained a persistent problem in many countries. TB is now the world’s leading infectious 
disease killer and is responsible for more deaths than HIV.[23] It is the leading cause of death 
among HIV-infected individuals, and there is more TB in the world today than at any other time in 
history. As a result of poor treatment adherence, in addition to primary transmission, drug 
resistance is becoming more common and fears of an epidemic with strains of extensively 
drug-resistant TB (XDR-TB) that is very difficult to treat are growing.  Novel drugs and regimens 
for TB are needed for the growing number of patients with Resistant-TB.  
The regulatory approvals of bedaquiline and delamanid have given hope that outcomes for 
patients with drug resistant TB might be improved when added to background regimens. 
Experience recently published from the C209 uncontrolled trial of bedaquiline given on a 
background of multiple drugs notes that the subset of 38 patients with XDR-TB had rates of 
sputum culture conversion to negative of 62.2%.[24] However, in this trial only one patient with 
XDR-TB was co-infected with HIV. All participants were required to have Mycobacterium 
tuberculosis (MTB) isolates susceptible to at least 3 drugs at enrolment, and patients had a 
median of only 5.4 months of treatment-free follow-up. This trial added bedaquiline for 6 months 
to a background regimen of many drugs given for 18 months or longer. While treatment success 
for MDR-TB is better than for XDR-TB, overall success in treating MDR-TB is still 
approximately 50% according to the World Health Organization 2015 Global TB Report.[23]  This 
report presented that overall, the proportion of MDR-TB patients in the 2012 cohort who 
successfully completed treatment (i.e. cured or treatment completed) was 50%; 16% died, 16% 
were lost to follow-up, 10% failed treatment, and for 8% there was no outcome information.   
With such poor historical outcomes for patients with drug resistant-TB and with the complexity, 
expense and toxicity of treatments for all forms of drug resistant TB, novel drug combinations 
are desperately needed to improve treatment outcomes. Linezolid was identified in a small 
trial as a potentially efficacious drug in patients with XDR-TB when added to a failing regimen[25] 
and this drug has increasingly been added to complex regimens to treat patients with MDR-TB. 
With the current availability of the following three drugs for which there is little, if any, pre-existing 
resistance among strains of MTB (pretomanid [Pa], bedaquiline [B], and linezolid [L]). Mice 
infected with MTB had relapse-free cures with 3 months of treatment with a B-Pa-L regimen. 
While it is not known whether that treatment duration will translate to humans, it is hypothesized 
in the design of the ongoing Nix-TB clinical trial (NiX-TB-(B-L-Pa)) that patients with pulmonary 
XDR-TB may have relapse-free cure after as little as 6 months’ treatment with the B-Pa-L 
regimen. Therefore, since 2015, the TB Alliance has sponsored a trial with a 6 month treatment 
duration with the B-Pa-L regimen in participants with XDR-TB or MDR-TB not responsive to or 
intolerant to therapy (the Nix-TB trial).[26]  Moxifloxacin has been added to the B-Pa-Z regimen 
because of the high rate of pyrazinamide resistance seen in MDR-TB participants in the NC-002 
trial. The proposed trial [SimpliciTB] allows the opportunity to assess the efficacy, safety and 
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tolerability of  BPaMZ a new 6 months regimen that may be administered orally once daily to treat 
patients with resistant -TB (Excluding participants with XDR-TB). 
Therefore, the overall purpose of the present proposed study [SimpliciTB] is to assess the 
efficacy, safety and tolerability of the BPaMZ regime after 4 months of treatment in adult 
participants with drug sensitive TB and after 6 months of treatment in participants with multi drug-
resistant TB. The trial will also generate data of the potential for a shorted treatment duration with 
the BPaMZ regime after 4 months compared to a 6 month HRZE/HR (control) treatment regime 
in adult participants with drug sensitive TB. 
This study will be conducted in accordance with the Protocol, International Good Clinical Practice 
(GCP) Guidelines, the ethical principles that have their origin in the Declaration of Helsinki and 
the applicable regulatory requirement(s). 
2.5 
Background of Agents to be Studied in SimpliciTB 
2.5.1 
Bedaquiline 
Bedaquiline (formerly known as TMC-207; SirturoTM package insert)[7] is approved agent for TB 
treatment. As detailed in the Investigator’s Brochure,[8] bedaquiline is a diarylquinoline that offers 
a novel mechanism of anti-tuberculosis action by specifically inhibiting mycobacterial adenosine 
triphosphate  synthase.[11] In vitro, bedaquiline potently inhibits both drug-sensitive and 
drug-resistant M. Tb isolates,[11, 12] and is also bactericidal against non-replicating M. tb.[12] In the 
murine model of TB, bedaquiline was as active as the triple combination of isoniazid (H), 
rifampicin (R), and pyrazinamide (Z). Addition of bedaquiline to HRZ results in accelerated 
clearance of M.tb.[1, 2]. There appears to be a synergistic interaction with pyrazinamide: 100% of 
mice were culture negative after 8 weeks of treatment with bedaquiline and pyrazinamide 
compared to 0% of mice treated with the standard regimen of rifampicin, isoniazid and 
pyrazinamide.[27].Collectively, these findings in the mouse model have led to the suggestion that 
regimens containing bedaquiline and pyrazinamide could be effective in the treatment of both 
drug sensitive and drug resistant TB and shorten treatment duration in patients. While the 
combination of bedaquiline and pretomanid in the murine model of TB appeared somewhat 
antagonistic relative to bedaquiline alone, it was as active as the triple combination of HRZ[27] and 
in a subsequent trial it was more active in the mouse model than HRZ.[28]. Thus a novel regimen 
with a bedaquiline plus pretomanid core could be effective in the treatment of MDR-TB/XDR-TB 
by providing two novel drugs for which there is no known pre-existing resistance. 
Bedaquiline is currently registered in many countries to be administered to patients with 
pulmonary tuberculosis by the following scheme: 400mg once daily for Days 1-14 followed by 
200mg three times per week for the remainder of treatment. In this trial bedaquiline will be 
administered as 200 mg daily for 8 weeks, followed by 100 mg daily for the remaining 17 weeks 
or 30 weeks if treatment is extended.  This daily dosing scheme will allow more convenient dosing 
that should ultimately enhance patient adherence and may allow the formulation of fixed dose 
combinations with other drugs.  This daily dosing regimen is supported by safety and efficacy 
demonstrated in the NC-005 trial that administered bedaquiline 200 mg daily over 8 weeks, and 
by pharmacokinetic modelling and simulation of the daily dosing scheme.  This supportive 
information is detailed below. 
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2.5.1.1 
Bedaquiline Non-clinical Studies 
Full details of the preclinical studies are provided in the current bedaquiline Investigator’s 
Brochure,[8] and Sirturo 
TM label.[7] In vitro studies have demonstrated that the range of minimum 
inhibitory concentrations (MICs) for M. tb. H37Rv, the international reference strain, and 6 fully 
drug-susceptible clinical isolates, was 0.030 to 0.120 μg/ml. The activity of bedaquiline appears 
to be specific for mycobacteria, as the MICs for non- mycobacteria were at least 500-fold higher. 
The activity of the main metabolite of bedaquiline, M2, was determined against M. tb. H37Rv in 
both solid and liquid media and its MIC was found to be 0.1 μg/ml. This MIC shows that M2 is 
active against M. tb. but 3-6 times less active than the parent compound bedaquiline. Bedaquiline 
demonstrated similar in vitro efficacy against M. tb. clinical isolates resistant to the known anti-TB 
drugs (isoniazid, rifampicin, pyrazinamide, streptomycin, ethambutol, or fluoroquinolones). As 
expected, from the lack of cross-resistance with currently used anti-tuberculosis agents, 
bedaquiline retained activity against MDR-TB isolates. 
The non-clinical safety evaluation of bedaquiline includes pharmacology, pharmacokinetics, 
toxicology and metabolism studies that were conducted in accordance with current International 
Council for Harmonisation (ICH) guidelines. Repeated dose toxicity studies were performed with 
dosing durations up to 3 months in mice and up to 6 months in rats and in dogs. Recovery was 
studied in rats and dogs. In repeated dose toxicity studies, up to 3 months in mice, up to 6 months 
in the rat and up to 9 months in dogs, bedaquiline was associated with target organ changes in 
the mononuclear phagocytic system (indicative of phospholipidosis), stomach, liver, pancreas, 
and muscle. Toxicity was often associated with an increased presence of neutrophils in some 
tissues such as the female genital tract and this was preceded by a peripheral neutrophilia. For 
more detailed information please refer to the bedaquiline IB.[8] 
Respiratory parameters in rats were unaffected by treatment. There were no effects suggestive 
of neurological impairment or delayed neurotoxicity in rats. In single dose toxicity studies, there 
were no mortalities following oral doses of up to 200 mg/kg in mice and rats. No mutagenicity or 
clastogenic effects were seen in a series of in vitro and in vivo genotoxicity tests. Bedaquiline 
was evaluated for possible developmental toxicity effects in the rat and the rabbit. No teratogenic 
effects were found. In vitro, bedaquiline slightly to moderately inhibited the delayed rectifier 
potassium current (IKr) in the human ether-à-go-go-related gene (hERG) model. Bedaquiline and 
M2 had no notable effects on IKr at 0.01 μM (0.006 and 0.005 μg/mL, respectively). However, at 
higher concentrations (0.03 to 3 μM), both compounds had a slight to strong concentration-
dependent effect with a 50% inhibitory concentration (IC50) of 0.37 μM (0.2 μg/mL) for bedaquiline 
and up to 0.45 μM (0.24 μg/mL) for M2. However, this effect did not manifest as a prolongation of 
repolarization in subsequent in vivo studies. 
There were no relevant effects on the isolated right atrium of guinea pigs in vitro, or in the isolated 
Langendorff-perfused rabbit heart. In vivo, positive chronotropic effects were seen in the 
anesthetized guinea pig after IV administration, but not in the conscious dog. In conscious, 
telemetered dogs, oral bedaquiline had no relevant effects on cardio-hemodynamic and ECG 
parameters. 
Prior to the use of pretomanid in combination with bedaquiline in clinical trial NC-001, a preclinical 
cardiovascular safety pharmacology trial was conducted in unrestrained beagle dogs with both 
drugs to explore the potential for additive effects on QT prolongation induced by the combination. 
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Results indicate that administration of 100 mg/kg bedaquiline daily, for 7 days, causes a small 
increase in QTc interval by Day 6 in some animals that is not influenced by the addition of 
100 mg/kg pretomanid on Day 7.[28] 
 The effect of pretomanid dosing alone on QT interval 
appeared to be due to discomfort related to the SC route of administration and not related to the 
plasma exposure (please see the pretomanid (formerly PA-824) Investigators Brochure for more 
detail). 
2.5.1.2 
Bedaquiline Clinical Studies 
In the clinical studies conducted to date, a total of approximately 645 participants (including 
265 healthy volunteers) have been exposed to bedaquiline in the Phase 1 and 2 clinical trials 
conducted as a part of the development program for the treatment of MDR-TB. An additional 45 
participants received bedaquiline, either as monotherapy (B) or in combination with other agents 
(B-Pa or B-Z) in trial NC-001, and 45 more in trial NC-003 (B-Pa-Z, B-Pa-C, B-Pa-Z-C). Four 
short-term Phase 2a trials enrolled treatment-naïve participants (C202, TMC207-CL001, NC-001 
and NC-003). One long-term, open-label, Phase 2 trial, in MDR-TB participants (bedaquiline- 
TiDP13-C209) and one long-term, Phase 2b trial, consisting of 2 different stages in participants 
infected with newly diagnosed sputum smear-positive pulmonary MDR-TB (bedaquiline-TiDP13-
C208), have been completed. The principal findings of these trials are summarized below. Full 
details of the completed clinical studies are provided in the current bedaquiline IB,[8] and Sirturo
TM 
label.[7]. 
The Phase 1 trials have provided a basic understanding of bedaquiline’s pharmacokinetic 
characteristics, drug- drug interaction potential, and short-term safety/tolerability profile in healthy 
participants. Bedaquiline was well absorbed with time to reach the maximum plasma 
concentration at approximately 5 hours post-dose. The maximum plasma concentration and AUC 
increased proportionally up to the highest doses studied (up to 700 mg in a single dose-ranging 
trial, 800 mg single dose in trial bedaquiline-TBC1003 and 400 mg q.d. multiple doses). 
Accumulation from Days 1 to 14 was approximately 2-fold expressed as increase in AUC, while 
trough concentrations increased up to 3.5-fold. The pharmacokinetics of bedaquiline were 
comparable between healthy participants and participants with pulmonary TB. The apparently 
close to steady-state concentrations in plasma after 14 days of daily treatment is ascribed to the 
important amount of the drug that is eliminated from the circulation during the ἀ and β phases of 
the plasma concentration-time curve. The average terminal elimination half-life of bedaquiline and 
metabolite M2 noted on extended follow-up after repeat dosing of participants with TB infection is 
about 5.5 months. 
Administration of bedaquiline as the tablet formulation with food, increased the relative 
bioavailability (by 95%) compared to administration without food, and drug-drug interaction trials 
confirmed the role of cytochrome P450 3A4 (CYP3A4) in the metabolism of bedaquiline to M2. A 
recently completed trial (DMID 10-0043) demonstrated that when given in combination, rifampicin, 
and to a lesser degree rifabutin, decreased exposure to bedaquiline presumptively due to 
induction of P450 enzymes. The clinical significance of these findings is unknown, however the 
current trial (NC-005) will not permit the concomitant use of bedaquiline with any rifamycin. 
The efficacy of bedaquiline was initially demonstrated in two monotherapy EBA studies C202 and 
TMC207- CL001. Trial C202 was a 7-day trial of three daily doses of bedaquiline (25, 100 and 
400mg) in treatment-naïve participants with MDR-TB. In this trial, the 400mg dose group 
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demonstrated positive EBA and was numerically superior to the 25 and 100mg doses. In trial 
TMC207-CL001, doses of 100, 200, 300 and 400mg daily (following a 2-day loading dose) were 
studied in participants with newly-diagnosed pulmonary TB for 14 days. There were no statistically 
significant differences between the treatment groups, although there was a numerical trend 
suggesting a positive dose-response relationship. Taken together, these studies establish that 
bedaquiline monotherapy has EBA in participants with TB and that higher doses appear to have 
greater efficacy. 
A 14 day EBA regimen trial (TB Alliance Trial NC-001-(B-M-Pa-Z)) evaluated bedaquiline 
administered as monotherapy at 400 mg/d or in combination at that dose with either pretomanid 
administered at 200 mg/d or weight-adjusted pyrazinamide, to participants with pulmonary TB at 
2 clinical sites in South Africa. The results indicate that over 14 days, the mean logCFU decreased 
by 1.3 from baseline in the 15 participants given bedaquiline 400 mg/d after a 2-day loading dose. 
In the cohort of 15 participants given bedaquiline 400 mg/d after a loading dose plus weight-
adjusted daily doses of pyrazinamide (Z), the mean logCFU decreased by 2.0 logs from baseline, 
indicating that Z potentiates the early bactericidal effect of bedaquiline. In the cohort with 15 
participants given bedaquiline 400 mg/d after a loading dose plus 200 mg/d pretomanid, the mean 
logCFU decreased by 1.9. While it appeared that the addition of pretomanid potentiated the anti-
tuberculosis activity of bedaquiline, the mean logCFU decrease of the combination was similar to 
that of two previous EBA studies using pretomanid monotherapy at 200 mg/day. 
The second 14 day EBA combination trial (NC-003) included a number of bedaquiline-containing 
arms: bedaquiline, pyrazinamide and clofazimine (B-Z-C), bedaquiline, pretomanid and 
clofazimine (B-Pa-C), bedaquiline, pretomanid, and pyrazinamide (B-Pa-Z) and bedaquiline, 
pretomanid, pyrazinamide and clofazimine (B-Pa-Z-C). Among these, B-Pa-Z had the best activity 
which was at least as good as the HRZE control (Daily Log CFU – 0.167 vs 0.151, respectively). 
The long-term efficacy of bedaquiline in participants with MDR-TB has been studied in a placebo-
controlled, randomized Phase 2b trial (C208) and an open-label, uncontrolled, Phase 2b trial 
(C209). In the Phase 2b placebo-controlled trial, C208, the addition of bedaquiline to a 5-drug 
MDR-TB regimen resulted in significantly faster time to culture conversion compared to placebo. 
During the 8-week treatment in Stage 1, 47.6% of participants in the bedaquiline group became 
MGIT culture negative compared to 8.7% of participants in the placebo group. At Week 24 in Stage 
1, after 8 weeks of investigational treatment and 24 weeks of background treatment, 81.0% of 
participants in the bedaquiline group and 65.2% of participants in the placebo group showed 
treatment success, (i.e., completed week 24 and were liquid culture negative at this time point). 
For C208 Stage 2, in the interim analysis as well as in the primary efficacy analysis, a statistically 
significant difference in time to culture conversion between the treatment groups (p < 0.0001) in 
favour of bedaquiline was shown. In both analyses, an identical number of participants with culture 
conversion at week 24 (i.e., 24-week responders [missing = failure]) was observed: 78.8% in the 
bedaquiline group and 57.6% in the placebo group, which was statistically significantly different 
(p =   0.008) based on a logistic regression model with only treatment as covariate. Microbiological 
response at Week 24 was durable in C208 Stage 2: the percentage of responders (missing = 
failure) at week 72 was 71.2% in the bedaquiline group and 56.1% in the placebo group. 
In the Phase 2b uncontrolled trial, C209, treatment with bedaquiline in combination with an 
individualized MDR- TB treatment regimen was effective against pulmonary MDR-TB both in 
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newly diagnosed and in non-newly diagnosed participants. Culture conversion rates after 
2  weeks of treatment with bedaquiline as part of an individualized anti-tuberculosis regimen were 
higher in participants with lower extent of resistance of the M. Tb strain and in participants with no 
lung cavitation compared to participants with cavitations (in one or both lungs). 
2.5.1.3 
Bedaquiline Clinical Safety 
In the clinical trials conducted to date, a total of approximately 645 participants (including 
265 healthy volunteers) have been exposed to bedaquiline in the Phase 1 and 2 clinical trials 
conducted as a part of the development program for the treatment of MDR-TB. An additional 60 
participants received bedaquiline in a monotherapy EBA trial of 14 days (trial TMC207-CL001) 45 
participants received bedaquiline, either as monotherapy (B) or in combination with other agents 
(B-Pa or B-Z) in trial NC-001 and 45 more in trial NC- 003 (B-Pa-Z, B-Pa-C, B-Pa-Z-C). In these 
trials, bedaquiline has been shown to be an effective treatment for participants with both DS and 
MDR-TB. Specifically, the regimen B-Pa-Z was demonstrated to have efficacy at least as good 
as the HRZE control in trial NC-003. Furthermore, bedaquiline is a novel agent with no pre-existing 
resistance and, based on mouse model data, may result in shortened treatment durations when 
included in novel regimens to treat both DS- and MDR-TB. Based on the combined experience in 
these clinical trials, the following known and potential risks have been identified. 
Adverse Drug Reactions for bedaquiline 
During the Investigational Treatment phase in the controlled trials, the most frequently reported 
Adverse Drug Reactions in the any bedaquiline group (> 10.0% of participants) were nausea, 
arthralgia, headache, vomiting, and dizziness. Details of Adverse Events, none of which were 
Serious, that were considered Adverse Drug Reactions are in the table below: 
Table 1.  Bedaquiline Adverse Drug Reactions 
 
 
 
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Mortality 
Overall, there was an imbalance in the number of deaths in the pooled Stage 1 and Stage 2 C208 
trial. In the pooled analysis (Stage 1 and Stage 2), 12 participants in the Any bedaquiline group 
and 5 participants in the Any Placebo group experienced a SAE leading to death; causes of death 
were varied with only death due to TB reported more than once, and none of these participants 
had a treatment-emergent QTcF ≥ 500 ms. The imbalance in deaths is primarily driven by the 
C208 Stage 2 results in which the imbalance was 10 bedaquiline participants (12.7%) compared 
to 3 placebo participants (3.7%). Based on the pooled results (Stage 1 and 2) while being followed 
in the placebo- controlled trial, 7 participants in the Any bedaquiline group and 1 Participant in the 
Any Placebo group died. Of these deaths, 1 occurred during the Investigational Treatment phase 
with bedaquiline/placebo, the remaining deaths occurred afterwards. In the Any bedaquiline 
group, causes of death were myocardial infarction, TB (2 cases), alcohol poisoning, hepatitis and 
hepatic cirrhosis (1 case), septic shock and peritonitis (1 case), and cerebrovascular accident. In 
the Any Placebo group, cause of death was hemoptysis. The Investigator considered the SAEs 
leading to death not related to bedaquiline intake in the Any bedaquiline group and doubtfully 
related to investigational medication in the Any Placebo group. The analysis of long-term follow-
up for survival outcomes in participants who prematurely discontinued in trial C208 (Stage 1 and 
2), based on data collection every 24 weeks (6 months) after withdrawal (up to LSLV in the rollover 
arm [16 Oct 2012] in Stage 2), included 9 deaths. One Participant in the bedaquiline group 
(pulmonary TB) and 2 participants in the Placebo group (TB-related illness and pulmonary TB) in 
Stage 1 died, and 4 participants in the bedaquiline group (3 participants with TB-related illness, 1 
Participant motor vehicle accident) and 2 participants in the Placebo group (both TB-related 
illness) died after they discontinued Stage 2 of the trial. None of these participants had a 
treatment-emergent QTcF ≥ 500 ms. The imbalance in deaths is unexplained.  In addition,  no  
discernible  pattern  between  death  and  sputum  culture  conversion,  relapse, sensitivity to 
other drugs used to treat TB, human immunodeficiency virus (HIV) status, or severity of disease 
was observed. 
In the uncontrolled Phase 2b trial, C209, the most frequently reported AEs during the 
investigational phase were hyperuricemia, arthralgia, nausea, vomiting, headache, diarrhea, 
blood uric acid increased, hypokalemia, pruritus, injection site pain, insomnia, and tinnitus. From 
start of the trial up to the final analysis, 12 participants died during the C209 trial due to SAEs that 
included TB (5 cases), congestive cardiac failure, renal impairment, lung infection, cardiac arrest 
(underlying cause pneumonia), hemoptysis, hypertension, and pyopneumothorax/respiratory 
failure. All of these SAEs leading to death were considered not related to bedaquiline by the 
Investigator, except for renal impairment that was judged doubtfully related to bedaquiline. 
The analysis of long-term follow-up for survival outcomes for participants who prematurely 
discontinued in trial C209, based on data collection every 24 weeks (6 months) after withdrawal, 
included 4 deaths (all described as TB-related). In total, since the start of the C209 trial, 16 
participants (6.9%) have died (12 participants during the trial and 4 participants during the survival 
follow-up phase after premature discontinuation). None of the fatal SAEs were considered related 
to bedaquiline by the Investigator and none of these participants has a treatment- emergent 
adverse event. 
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Cardiovascular safety 
During clinical trials with bedaquiline a prolongation of QTc interval was observed. The US 
Product Label for bedaquiline[7] notes that treatment initiation is not recommended in patients with: 
• 
Heart failure; 
• 
QTcF interval > 500 ms (confirmed by repeat electrocardiogram); 
• 
A personal or family history of congenital QT prolongation; 
• 
Concomitant administration of fluoroquinolone antibiotics that have a greater potential 
for significant QT prolongation (i.e., gatifloxacin, moxifloxacin and sparfloxacin). 
• 
Hypokalemia 
The US Product Label recommends that bedaquiline treatment must be discontinued if the patient 
develops clinically significant ventricular arrhythmia. An additive or synergistic effect on QT 
prolongation of bedaquiline when co-administered with other medicinal products that prolong the 
QT interval cannot be excluded. Caution is recommended when using bedaquiline concomitantly 
with medicinal products with a known risk of QT prolongation. In the event that co-administration 
of such medicinal products with bedaquiline is necessary, clinical monitoring including frequent 
ECG assessment is recommended. 
Hepatic safety 
The US product label notes increases in transaminases were seen in clinical trials during 
administration of bedaquiline with the background regimen. participants should be monitored 
during treatment. Other hepatotoxic medicinal products and alcohol should be avoided while 
taking bedaquiline, especially in those participants with diminished hepatic reserve.[7]  
Additional safety information from a recently completed trial 
In a recently completed phase I trial not yet included in the bedaquiline Investigators Brochure 
that evaluated drug-drug interactions between bedaquiline and either rifampin or rifabutin, 7 
participants experienced SAEs. Of those participants, 5 experienced SAEs of lymphocytopenia 
(all received rifabutin), which did not appear to be related to the AUC or Cmax of TMC207 or 
rifabutin. One participant experienced an SAE of elevated Creatine Kinase (rifampicin arm) and 
one experienced a grade 4 Total Bilirubin SAE (rifampicin arm). Lymphopenia was previously 
noted to be an infrequent toxicity associated with rifabutin, but not previously seen with 
bedaquiline. 
The bedaquiline/rifabutin regimen demonstrated significant reversible lymphopenia, which did not 
appear to be related to the AUC or Cmax of TMC-207 or rifabutin. 
2.5.2 
Pretomanid 
As detailed in the Investigator’s Brochure,[15] pretomanid is a new chemical entity and a member 
of a class of compounds known as nitroimidazo-oxazines, which possess significant anti-
tuberculosis activity and a unique mechanism of action.[16] Pretomanid demonstrated in vitro 
activity against both DS- and MDR-TB,[17] and in vivo activity in a mouse model of tuberculosis.[16, 
17]  
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2.5.2.1 
Pharmacology 
Key in Vitro Evaluation of Pretomanid Bactericidal Activity 
Non-clinical in vitro trials demonstrated that pretomanid was active against actively growing drug- 
sensitive and drug-resistant MTB strains as well as against non-replicating MTB. The minimum 
inhibitory concentration (MIC) of pretomanid against a variety of drug-sensitive MTB isolates in 
vitro was shown to be similar to the MIC of isoniazid (MIC of pretomanid, 0.015 to 0.25 µg/mL; 
MIC of isoniazid, 0.03 to 0.06 µg/mL). Pretomanid was efficacious in vitro against drug-resistant 
clinical isolates of MTB with MIC values ranging from 0.03 to 0.53 µg/mL. The Investigator’s 
Brochure contains further information on in vitro bactericidal activity.[16] 
Although not thoroughly elucidated at this time, pretomanid has a novel mechanism of action that 
appears to involve inhibition of the synthesis of cell wall lipids under aerobic conditions and 
generation of reactive nitrogen species under anaerobic conditions. Reduction of pretomanid by 
a deazaflavin (F420)-dependent nitroreductase has been shown to be associated with generation 
of reactive nitrogen species, including nitric oxide (NO),[29] although the exact target(s) of the 
reactive nitrogen species are not known. Transcriptional profiling trials also suggest that 
pretomanid affects both cell wall biosynthesis and the respiratory complex of MTB.[30, 31] 
2.5.2.2 
Key Non-Clinical Trials of Pretomanid 
The activity of pretomanid as a single agent or as part of a multi-drug combination regimen has 
been examined in a number of mouse trials.[13, 14, 18, 32, 33] In a mouse model of established TB, the 
activity of various doses of pretomanid (given once daily, 5 days/week, for 1 month), initiated 22 
days after inhalation infection with H37Rv MTB is shown in Figure 2. In this model, the minimum 
effective dose (MED) for pretomanid, defined as the lowest dose able to prevent the development 
of gross lung lesions and splenomegaly, was 12.5 mg/kg/day, while the minimum bactericidal 
dose (MBD), defined as the lowest dose able to reduce lung colony forming units (CFU) by 99%, 
was 100 mg/kg/day. Moreover, in these experiments, the activity of pretomanid at 100 mg/kg was 
comparable to the activity of isoniazid at 25 mg/kg. 
Figure 2.  Log10 CFU Counts in Lungs  
After One Month of Daily Treatment with the Indicated Dose (in mg/kg) of Pretomanid 
 
Arrows denote the minimum effective dose (MED) and minimum bactericidal dose (MBD). 
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2.5.2.3 
Non-Clinical Toxicology and Safety 
Pretomanid has been evaluated in an ICH recommended battery of safety pharmacology trials, in 
repeat-dose toxicity trials in rats (2 to 26 weeks) and cynomolgus monkeys (7 days to 9 months), 
in 8 genotoxicity trials, and in fertility and teratology trials in rats and rabbits.  
In the repeat-dose toxicity trials, the lowest no-observed adverse effect level (NOAELs) was 
10 mg/kg/day in a 26-week trial in rats, 50 mg/kg/day in a 13-week trial in monkeys and 
<25 mg/kg/day (based on findings of thickening of the gastrointestinal tract at all doses) in a 9-
month trial in monkeys. The major findings in safety and toxicity trials are listed below in Table 2 
and are detailed in the Investigator’s Brochure.[15] 
Table 2.  Key findings of Pretomanid in Safety and Toxicity Trials 
Nervous system-related effects.  
Rats given single oral pretomanid doses had decreased body tone, touch responses and 
decreased grooming behaviour at ≥150 mg/kg, which resolved within 24 hours. Rats given 
repeated daily doses of pretomanid had convulsions, ataxia, hypoactivity, recumbency, 
hyperactivity and sensitivity to touch, and squinting at ≥100 mg/kg/day, and early deaths 
occurred at doses ≥500 mg/kg/day. Monkeys given repeated daily doses of pretomanid had 
hypoactivity, ataxia, tremors, and convulsions at ≥450/300 mg/kg/day. These effects were 
reversible when dosing stopped and were absent at ≤30 mg/kg/day in rats and ≤150 mg/kg/day 
in monkeys. 
Testicular toxicity 
Although rat and rabbit embryonic development trials indicate no effects of PA-824 on fetal 
development, testicular atrophy in rats was observed in 3-month and 6-month repeat-dose 
toxicology trials and a Segment I fertility trial. In this fertility trial, testicular atrophy was 
associated with infertility; an approximate 30% reduction in fertility was also observed at a lower 
dose not associated with testicular atrophy. A detailed trial in sexually mature male monkeys 
demonstrated no effects on testicular histology or function in adult cynomolgus monkeys after 
3 months’ dosing.  
Cataracts 
Cataracts developed in rats with prolonged daily administration of pretomanid at doses 
≥100 mg/kg/day. In one 13-week trial in monkeys, cataracts did develop at 450/300 mg/kg/day, 
but only by the end of a 13-week recovery period. In a second 13-week trial in monkeys that 
included extensive ophthalmic examinations, cataracts did not develop at the high-dose level 
of 300 mg/kg/day. 
hERG inhibition and QT prolongation 
Altered ventricular repolarisation due to inhibition of hERG-mediated potassium current and 
manifested on the ECG as a prolonged QT interval corrected for heart rate (QTc). Pretomanid 
inhibited hERG current with IC50 values of approximately 6.2 µg/mL. Following a single 
pretomanid dose of 450 mg/kg in monkeys, QTc interval prolongation ranged from 21 to 
36 msec using Fridericia’s formula (QTcF) to correct for heart rate. Co-administration of 
pretomanid with moxifloxacin in the monkey or with bedaquiline in the dog did not result in any 
greater effect on the QT interval than with either agent alone. After repeated daily doses, the 
QTc interval in the monkey was prolonged at pretomanid doses of ≥150 mg/kg/day. 
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2.5.2.4 
Clinical Background Information 
Pretomanid has been evaluated in 8 single- and multi-dose Phase 1 trials with healthy adult male 
and female participants, with 163 participants receiving single oral doses ranging from 50 to 
1500 mg and multiple oral doses ranging from 50 to 1000 mg/day given for up to 7 days. These 
Phase 1 trials have evaluated the safety, tolerability, and pharmacokinetics (PK) of pretomanid. 
Two additional Phase 1 trials sponsored by the NIH included a Thorough QT trial and a trial of 
drug interactions among pretomanid, efavirenz and ritonavir/lopinavir.  Further details of the trials 
are in the Investigator’s Brochure.[15] 
2.5.2.5 
Pharmacokinetics 
Several Phase 1 trials have evaluated the safety, tolerability, and pharmacokinetics (PK) of 
pretomanid and have demonstrated that pretomanid has a half-life of approximately 18 hours, 
which supports daily dosing, and an effect of food with the 200-mg dose that increases total 
exposure by 88%. Interaction trials with midazolam, efavirenz and ritonavir/lopinavir demonstrate 
effects that are not likely to be clinically significant. 
Drug interaction with midazolam: Trial CL-006 was an open-label, fixed-sequence drug-drug 
interaction trial to evaluate the effects of multiple-dose administration of pretomanid on the PK of 
midazolam, a sensitive probe substrate and representative compound for drugs metabolised by 
CYP3A enzymes. Dosing with pretomanid at 400 mg/day for 14 days (to steady state) had minimal 
effect on the PK of midazolam and its 1-hydroxy metabolite as assessed by measurement of the 
Day 17: Day 1 ratios of maximum concentration (CmaxAUC0-t, and AUC0-inf. The Cmax and AUC 
values for midazolam after co-administration with pretomanid were approximately 85% of those 
observed after treatment with midazolam alone. Furthermore, midazolam and 1-hydroxy 
midazolam time to maximum concentration (-Tmax) and half-life (t1/2) values were not different in 
the presence or absence of pretomanid. Therefore, 14 days’ dosing with 400 mg/day pretomanid 
does not appear to significantly inhibit CYP3A4 in humans. 
Drug interaction with efavirenz, ritonavir/lopinavir, and rifampicin: The US NIH sponsored this 
drug interaction trial with rifampicin, a known hepatic enzyme inducer, and with the antiretroviral 
drugs efavirenz and ritonavir/lopinavir (LPV/r) in healthy participants. Participants in Arm 1 were 
randomised to Sequence 1 (pretomanid 200 mg once daily for 7 days, two-week washout period, 
efavirenz (EFV) 600 mg once daily for 14 days, then both drugs for 7 days) or Sequence 2 
(Treatment 1B: EFV, then EFV + pretomanid, washout, and pretomanid). Results indicate that 
comparing pretomanid given with EFV versus pretomanid alone in 16 participants, the geometric 
mean ratio (GMR) for Cmax was 0.71, the GMR for AUC0-24h was 0.65, and the GMR for Cmin was 
0.54. Concentrations of EFV when given with pretomanid versus given alone were similar. 
Participants in Arm 2 were randomised to Sequence 1 (pretomanid 200 mg once daily for 7 days, 
then a 2week washout period, then LPV/r 400/100 mg twice daily for 14 days, then LPV/r + 
pretomanid together for 7 days) or Sequence 2 (LPV/r, then LPV/r + pretomanid, washout, then 
pretomanid alone). Comparing pretomanid + LPV/r versus pretomanid- alone from 16 PK-
evaluable participants, the GMR for Cmax was 0.87, for AUC0-24h was 0.83, and for Cmin was 0.78. 
In Arm 3, participants received pretomanid for 7 days, then rifampicin 600 mg for 7 days, then 
pretomanid + rifampicin together for 7 days. Comparing pretomanid + rifampicin versus 
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pretomanid alone from 16 PK-evaluable participants, the GMR for Cmax, AUC0-24h, and Cmin were 
0.47, 0.34, and 0.15, respectively.  
In conclusion, compared to pretomanid alone, plasma pretomanid values (based on geometric 
mean ratios) for Cmax, AUC0-24h, and Cmin were reduced 28%, 35%, and 46% with efavirenz; 13%, 
17%, and 21% with LPV/r; and 53%, 66%, and 85% with rifampin, respectively. 
2.5.2.6 
Pretomanid Clinical Efficacy 
The first two Phase 2 trials to evaluate the early bactericidal effect (EBA) of pretomanid oral 
monotherapy (50 to 1200 mg/day for 14 days) examined the dose-response for pretomanid in 
participants with newly diagnosed pulmonary TB infection. The first trial (CL-007) demonstrated 
good EBA, but all doses in this trial (200 to 1200 mg/day) had the same activity. The second trial 
(CL-010) evaluated a lower dose range (50 to 200 mg/day) and the maximum effect on EBA was 
seen at a dose of 100 mg/day over 14 days (Figure 3).[34] 
Figure 3.  Mean log Colony Forming Unit Values over Time Trial CL-010 
 
CFU = colony-forming unit; PA-824 = pretomanid 
* Day 0 = (Day -2 + Day -1)/2 = baseline measurement 
Pretomanid has been evaluated in patients with TB as monotherapy for a maximum duration of 
14 days, the longest considered acceptable for a TB patient to be treated in a clinical trial with a 
single drug.  Trials of Pretomanid for both 14 days and for up to 6 months, in combination with 
either bedaquiline and/or linezolid, are described below.  
4
4.5
5
5.5
6
logCFU
0
2
4
6
8
10
12
14
Day
 PA-824 50mg
 PA-824 100mg
 PA-824 150mg
 PA-824 200mg
 Rifafour e275 
Bi-linear regression of logCFU vs day over treatment
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2.5.2.7 
Pretomanid Clinical Safety 
The pretomanid Investigator’s Brochure[15] provides detailed safety information. 
Across the 16 clinical trials with pretomanid completed to date, a total of 649 participants have 
been exposed to pretomanid, including 289 healthy participants across the 10 Phase 1 trials and 
360 participants with newly diagnosed smear positive pulmonary TB across 5 Phase 2 
trials.  Among the 289 healthy participants, 174 received exposure to a single dose of pretomanid 
ranging from 50 to 1500 mg and 115 received exposures to repeated daily doses of pretomanid 
(50 to 1000 mg) for up to 14 days. The 360 participants with newly diagnosed smear positive 
pulmonary TB were exposed to pretomanid either as a single agent at daily doses of 50 to 
1200 mg for 14 days or in combination with other anti-TB agents (bedaquiline, moxifloxacin, 
pyrazinamide, linezolid and/or clofazimine) at a dose of 100 mg or 200 mg for up to 26 weeks.  The 
overall safety profile determined from the clinical trials completed to date indicates pretomanid is 
well tolerated in healthy adults and in TB patients when administered alone and in combination 
with moxifloxacin, pyrazinamide, bedaquiline and clofazimine.   
Pretomanid is an investigational drug and there is limited experience in humans; the safety 
database is being developed and investigators should be vigilant to any adverse events noted in 
clinical trials.  Across these trials, the most common side effects or AEs associated with 
pretomanid exposure include: 
• 
Headache 
• 
Stomach discomfort (nausea, vomiting, flatulence, and/or diarrhoea) 
• 
Skin and subcutaneous tissue disorders 
The only adverse drug reaction identified in clinical trials completed to date as likely caused by 
pretomanid is blood creatinine increased.  A trial of the effects of repeat doses of pretomanid in 
healthy volunteers determined that the drug does not adversely affect glomerular filtration rate, 
effective renal plasma flow or filtration fraction and the elevations in serum creatinine reverse.  
The following parameters will be followed with particular care in the Phase 3 development 
program: 
• 
Hepatic Safety – Specific guidelines are included in the protocol to assure close surveillance 
and careful management of participants who have elevations in aminotransferases and/or 
bilirubin. Serious liver injury, including death in 3 participants taking a combination of 
pretomanid, pyrazinamide and moxifloxacin, has occurred during clinical trials and the risk of 
liver injury may be higher for participants taking a combination of PA-824 and pyrazinamide 
than it is for the standard HRZE treatment. Therefore, close monitoring of liver function is 
required for participants who are administered PA-824, especially when combined with 
pyrazinamide.  Administration of the regimen of PaMZ has been associated with death in 
3 participants associated with hepatic injury. Furthermore, the HRZE control regimen, and 
both pyrazinamide and moxifloxacin, has been associated with drug induced liver injury and 
in rare cases hepatic necrosis.  Consequently, hepatic safety will be under close surveillance 
in all clinical trials. 
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• 
Ophthalmologic Evaluations – while the detailed examinations in Phase 2 have not raised 
concern for humans, ophthalmologic examinations, with slit lamp exam and grading of lens 
opacities, will continue in all human trials that involve exposure to pretomanid longer than 
14 days.  These examinations will be conducted at baseline, near the end of the dosing period 
and 3 months after the end of trial drug exposure.  These examinations are to follow up on 
the finding of cataracts in rats exposed to pretomanid in clinical trials. 
• 
Cardiovascular Safety – All participants will have ECGs taken at baseline and at multiple time 
points during the trial.  Although the Thorough QT Trial in healthy participants found that 
pretomanid did not increase corrected QT intervals in a clinically meaningful way and did not 
add to the known effect of moxifloxacin, the ECGs will be carefully monitored during Phase 3.  
All ECGs will be interpreted and conduction intervals will be confirmed by a central cardiology 
service. 
• 
Central Nervous System Safety –While pretomanid alone or combined in various regimens 
has been well tolerated overall, one participant in Trial NC-002 of the Pa-M-Z regimen had a 
seizure without any prior seizure history, and some animals in toxicology trials have had 
seizures at high drug exposures.  Consequently, close surveillance will be made of 
participants in the Phase 3 trial for seizures or any central nervous system adverse events of 
potential concern. 
Of note, preclinical toxicology trials found that rats, but not primates, had testicular toxicity when 
treated with pretomanid. Clinical evaluations of potential testicular toxicity in Phase 2 trials have 
evaluated over 300 participants exposed to pretomanid over 2-6 months with evaluations of 
testosterone, LH, or Inhibin B (2 trials) or FSH values (3 trials) at baseline and after daily dosing 
of regimens containing pretomanid in various combinations with moxifloxacin, pyrazinamide and 
bedaquiline.  A review of data from the 3 trials by an independent reproductive endocrine expert 
concluded that, based on the hormone evaluations to date, there is no evidence that PA-824 is a 
testicular toxicant in men at the doses and exposure times evaluated. 
2.5.3 
Moxifloxacin (M) 
Moxifloxacin (M)[19]  is an 8-methoxyquinolone whose oral formulation (which will be used in 
this trial) has enhanced activity against Gram-positive pathogens, and anaerobes while retaining 
useful activity against Gram-negative organisms. Moxifloxacin is not metabolized by nor induces 
the cytochrome P450 system, thus the risk of clinically relevant drug interactions is reduced. It 
has a positive safety profile within the fluoroquinolone class at the approved daily dose of 400 mg. 
Moxifloxacin while not approved for TB by most regulatory authorities, it is regularly used in 
second line MDR-TB treatment. The WHO TB Treatment Guidelines place moxifloxacin in the 
category of Group 3 drugs and notes that “all patients [with MDR-TB] should receive a Group 3 
medication if the M. tuberculosis strain is susceptible or if the agent is thought to have efficacy. 
One of the higher generation fluoroquinolones, such as levofloxacin or moxifloxacin, is the 
fluoroquinolone of choice.[5]” It is currently in late stage clinical development for first-line TB 
treatment in combination with other TB drugs, including pyrazinamide in two different four-month 
long regimens.  
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2.2.3.1. 
Moxifloxacin Clinical Trials 
Moxifloxacin is commonly used as second line therapy for TB (e.g. MDR- TB), and has also been 
evaluated in several clinical studies of participants with TB, including four 8-week treatment period 
Phase 2b studies (see Table 3 below).  
Table 3.  Summary of Phase 2b trials in which moxifloxacin were administered as 
part of a four-drug regimen during the intensive phase of treatment (total treatment 
duration: 2 months) 
Trial 
Design 
Objective 
Participants 
(N) 
Status 
Trial 27 
Randomized, 
double-blind, 
controlled 
To compare the sputum culture-
conversion rate at the end of the 4-drug 
(intensive) phase of therapy using the 
standard 4-drug regimen HRZE with a 
standard regimen with M replacing E.  
336 
Completed 
OFLOTUB 
Trial 
Randomized, 
Open label, 
Controlled 
To compare the bactericidal activities of 
regimens where gatifloxacin, M, and 
ofloxacin were substituted for E in the 2-
month initial phase of standard TB 
treatment with HRZE.  
217 
Completed 
Johns 
Hopkins 
(FDA 
orphan 
drug) Trial 
Randomized, 
double-blind, 
Controlled 
To compare the sputum culture 
conversion rate at the end of the 4-drug 
(intensive) phase of therapy using a 
standard 4-drug regimen (HRZE) with a 
regimen with M replacing E (HRZM). 
170 
Completed 
Trial 28 
Randomized, 
double-blind, 
Controlled 
To compare the culture-conversion rate 
at the end of the 4-drug (intensive) 
phase of therapy using a standard 4-
drug regimen (HRZE 5 days per week) 
with a regimen with M replacing H 
(MRZE 5 days per week). 
433 
Completed 
 
2.5.3.1 
Moxifloxacin Clinical Safety 
In Trial 27,[35] the moxifloxacin-containing TB regimens (HRZM) were shown to be safe and well 
tolerated. There was no difference in SAEs between the HRZM and HRZE treatment arms, and 
most SAEs were hospitalizations thought to be unrelated to the trial treatment.  Participants 
treated with the moxifloxacin-containing regimen were more likely to report nausea (22% vs. 9%, 
p = 0.002), but this was generally mild and did not lead to treatment discontinuation as similar 
proportions of participants in both groups completed trial drug treatment (88% HRZM-treated vs. 
89% HRZE-treated).  The one death during the first 2 months of treatment was thought to be 
caused by pulmonary embolism, unrelated to tuberculosis therapy.   
In the OFLOTUB trial,[36] AEs and SAEs occurred with equal frequency in the four treatment arms.  
The most frequent AEs were raised amylase (in 41% of participants due to HIV infection), raised 
transaminase (10%), arthralgia (9%), anemia (7%), hypokalemia (6%) and vomiting (5%).  No 
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Participant was withdrawn from the trial due to an adverse event.  There were 4 deaths in the 
trial: 2 in the control group, 1 each in the moxifloxacin and ofloxacin arms.  Importantly, 
participants in this trial who received moxifloxacin and pyrazinamide in addition to isoniazid and 
rifampin had more rapid sputum clearance than participants on the four standard first line drugs 
(isoniazid, rifampin, pyrazinamide and ethambutol). This difference was evident 14 days after 
initiation of treatment. 
In the JHU trial,[37] AEs did not differ by treatment group. There were 16 SAEs (8 in each group) 
in 12 participants. Only 1 event was judged related to trial drug (grade 3 cutaneous reaction in 
the ethambutol group). Eight participants died during the trial, including 1 in each group still 
receiving trial phase treatment. No death was attributed to trial treatment. Only 5 participants 
discontinued treatment because of toxic effects; 2 participants in the moxifloxacin group stopped 
because of grade 2 nausea and vomiting and 1 because of grade 2 paraesthesias and ataxia. 
Two participants in the E group stopped because of grade 2 rash and pruritis and 1 because of 
grade 3 peripheral neuropathy.  There was no change in the QTc interval on serial 
electrocardiograms taken during the trial. 
In Trial 28,[38] the proportions of participants with SAEs during the intensive phase treatment were 
similar between arms (isoniazid 3.9% vs. moxifloxacin 4.2%; P = 0.88). Three SAEs attributed to 
trial treatment during the first 2 months occurred among the moxifloxacin group and two in the 
isoniazid group.  Seven participants died during the trial including 3 participants receiving the 
moxifloxacin treatment regimen and 4 participants receiving the isoniazid treatment regimen. The 
3 moxifloxacin participants died during the intensive phase of TB treatment. Two participants died 
from advanced pulmonary TB judged not related to trial treatment and 1 Participant (who 
developed diabetic ketoacidosis considered possibly related to trial treatment) died from possible 
acute pulmonary embolus unrelated to trial treatment. The 4 isoniazid deaths occurred during the 
continuation phase, and all 4 were considered unrelated to trial treatment.  Nausea was more 
common among participants in the moxifloxacin arm than in the isoniazid arm (19.6% vs. 11.7%, 
respectively; P = 0.03) although similar proportions reported vomiting.  However, the proportions 
of participants with hepatitis, defined as serum AST 3 times or greater than the upper limit of 
normal, were similar between treatment arms during intensive phase (isoniazid 3.4% vs. 
moxifloxacin 3.3%; P = 0.93).  Moxifloxacin has also been evaluated in combination with PA-824 
for two weeks in participants with TB (Trial NC-001) and for 8 weeks in NC002 as reviewed above 
in Section 2.2.3 (Trial NC-001). 
For additional information on moxifloxacin, refer to the IB[39] and the manufacturer’s package 
insert.[19] 
2.5.4 
Pyrazinamide (Z) 
Pyrazinamide (Z) is a standard drug used as part of the four drug HRZE regimen used for the first 
two months of intensive therapy for drug-sensitive TB as recommended by the WHO and many 
National TB programs.  Please see the Package Insert[20] for more detail.  Z is active against TB 
in vitro and it potentiates the bactericidal and sterilizing activity of both bedaquiline and PA-824 
in mouse models of TB infection.[8, 15]  Pyrazinamide enhanced the bactericidal activity of both 
bedaquiline and PA-824 in Trial NC-001-(J-M-Pa-Z) as noted by decreases over 14 days in the 
CFU counts in sputum among participants. 
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The pyrazinamide product label notes that pyrazinamide is contraindicated in persons with severe 
hepatic damage, who have shown hypersensitivity to it, and with acute gout.  The most serious 
side effect is hepatotoxicity. Its frequency appears to be dose-related and thus liver function 
should be assessed before and regularly during treatment with pyrazinamide.  Hyperuricemia 
commonly occurs and is occasionally accompanied by arthralgia and may lead to attacks of gout. 
Photosensitivity and skin rash have been reported less frequently. Other side effects that have 
been reported are anorexia, nausea and vomiting, malaise, fever, sideroblastic anemia and 
dysuria.  
Pyrazinamide may decrease the efficacy of gout therapy (e.g. allopurinol, colchicine, probenecid 
or sulphinpyrazone) and dosage adjustments of these medications may be necessary.  For 
additional information on pyrazinamide, refer to the manufacturer’s package insert. [20] 
2.6 
Overall Benefit/Risk Assessment 
Participants with pulmonary TB in this trial will be given a BPaMZ regime. These drugs individually 
and in combination are known to have anti-tuberculosis activity and is not expected to have an 
adverse impact on the ultimate cure of TB in these participants. Based on NC-005 and other 
regimens using each of the regimen drugs in different combinations there is good evidence that 
this may be a highly effective therapy for both DS and MDR TB and for DS the potential for a 
shorter regimen than 6 months is expected to be successful based on preclinical and clinical 
information as listed before.  Participants in this trial will have their TB infection carefully 
characterized, with drug sensitivity profiles established, and they will receive treatment with trial 
drugs that have demonstrated activity against M. Tb.  Participants will receive individualized 
medical attention; this will allow a continuous monitoring of the health conditions of each 
participant, any of whom can be withdrawn at any stage of the study and removed from trial 
treatment should his/her condition suggest to the Investigator that this would be in his/her best 
interest.  Multiple blood samples will be taken for safety laboratory studies, and ECGs will be 
taken at multiple time points. One concern in particular, combining two agents with known 
QT-prolonging effects (bedaquiline and moxifloxacin), has been addressed specifically by 
carefully identifying and excluding participants with risk factors that might predispose them to 
cardiac arrhythmias, screening all participants for evidence of existing cardiac disease and 
monitoring all participants with ECGs throughout the trial.  
The trial drugs in the proposed regimens to be tested in this trial have all demonstrated safety 
and efficacy in the treatment of pulmonary tuberculosis in non-clinical and clinical studies. 
Specifically, the regimen B-Pa-Z was generally well-tolerated and demonstrated bactericidal 
activity in a 14 day EBA trial. The potential risks associated with the trial drugs and regimens has 
been identified as outlined below and will be monitored carefully throughout the conduct of the 
trial. 
The BPAMZ regime is a new novel regimen treatment and is expected to be effective, safe and 
well-tolerated and might even shorten the current treatment duration for patients with TB. Based 
on data from previous trial evaluations as outlined before suggest a favourable benefit-to-risk ratio 
trials.Key monitoring and safety information regarding regimen agents 
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2.6.1 
Bedaquiline 
2.6.1.1 
Adverse Drug Reactions for bedaquiline  
Participants in the Any bedaquiline group compared to the Any Placebo group (difference > 5.0%) 
had headache (23.5% versus 11.4%, respectively), nausea (35.3% versus 25.7%, respectively), 
arthralgia (29.4% versus 20.0%, respectively), and transaminases increased (6.9% versus 1.0%, 
respectively).and diarrhoea (11.4% versus 5.9%, respectively). 
2.6.1.2 
Cardiovascular safety 
During clinical studies with bedaquiline a prolongation of QTc interval was observed. An ECG 
should be obtained prior to and after initiation of therapy with bedaquiline to monitor the QTc 
interval. 
Bedaquiline treatment initiation is not recommended in patients with: 
• 
Heart failure; 
• 
QTcF interval > 450 ms (confirmed by repeat electrocardiogram); 
• 
A personal or family history of congenital QT prolongation; 
• 
Concomitant administration of fluoroquinolone antibiotics that have a greater potential for 
significant QT prolongation (i.e., gatifloxacin, moxifloxacin and sparfloxacin). 
• 
Hypokalemia 
 
Bedaquiline treatment must be discontinued if the patient develops clinically significant ventricular 
arrhythmia. An additive or synergistic effect on QT prolongation of bedaquiline when co-
administered with other medicinal products that prolong the QT interval cannot be excluded. 
Caution is recommended when using bedaquiline concomitantly with medicinal products with a 
known risk of QT prolongation. In the event that co-administration of such medicinal products with 
bedaquiline is necessary, clinical monitoring including frequent ECG assessment is 
recommended. 
In the MDR-TB treatment arm of the present trial, moxifloxacin will be co-administered with 
bedaquiline. This is to prevent the development of resistance to the other drugs in the regimen in 
case the participant’s M. Tb strain is resistant to pyrazinamide. ECG assessments will be 
performed on all participants at baseline, each treatment visit and during the follow-up visit on 
Day 70. 
2.6.1.3 
Hepatic safety 
Increases in transaminases were seen in clinical studies during administration of bedaquiline with 
the background regimen. Participants should be monitored during treatment. 
Other hepatotoxic medicinal products and alcohol should be avoided while taking bedaquiline, 
especially in participants with diminished hepatic reserve. 
2.6.2 
Pretomanid  
The most common side effects or AEs associated with pretomanid exposure include: 
• 
Headache 
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• 
Benign, isolated and reversible elevations of serum creatinine 
• 
Stomach discomfort (nausea, vomiting, flatulence, and/or diarrhoea) 
• 
Skin and subcutaneous tissue disorders 
2.6.2.1 
Hepatic Safety 
Hepatic enzyme increases have been seen in participants treated with PA-824 in combinations 
with various other medications during the clinical development program. It is difficult to assign 
specific causality to any one drug within a regimen; nonetheless, trial NC-008 will include specific 
monitoring of hepatic enzymes. 
For additional information refer to PA-824 IB.[15] 
2.6.3 
Moxifloxacin 
In the usual daily doses of 400 mg/day, moxifloxacin is well tolerated.  As stated in the Package 
Insert[19]  the most frequent individual drug related AEs observed in clinical trials with 400 mg oral 
moxifloxacin therapy were nausea (7.5%) and diarrhoea (5.8%).  Fluoroquinolones, including 
moxifloxacin, are associated with an increased risk of tendinitis and tendon rupture in all ages.   
A known but rare side effect of fluoroquinolones, including moxifloxacin is exacerbation of 
myasthenia gravis. In addition, moxifloxacin has been shown to prolong the QT interval of the 
electrocardiogram in some participants.  It should be used with caution in participants being 
treated concomitantly with other drugs where an additive effect on the QT interval cannot be 
excluded.  
Serious and sometimes fatal hypersensitivity reactions, including anaphylactic reactions, may 
occur after the first or subsequent doses of moxifloxacin.  Also, moxifloxacin may cause peripheral 
neuropathy.  For additional information, refer to the moxifloxacin package insert.[19] 
2.6.4 
Pyrazinamide 
The dose of pyrazinamide that will be used in this trial is an approved dosage for the treatment of 
TB. The most serious side-effect of pyrazinamide is hepatotoxicity and its frequency appears to 
be dose-related. Hyperuricemia commonly occurs, occasionally accompanied by arthralgia and 
may lead to attacks of gout.  Photosensitivity and skin rash have been reported less frequently.  
Other side-effects that have been reported are anorexia, nausea and vomiting, malaise, fever, 
sideroblastic anaemia and dysuria.  Pyrazinamide may decrease the efficacy of gout therapy (e.g. 
allopurinol, colchicine, probenecid or sulphinpyrazone) and dosage adjustments of these 
medications may be necessary.  For additional information on pyrazinamide, refer to the 
manufacturer’s package insert.[20] 
2.6.5 
HRZE/HR Control 
The HRZE (isoniazid 75 mg plus rifampicin 150 mg plus pyrazinamide 400 mg plus ethambutol 
275 mg combination tablets) combination will be given the first 8 weeks and the HR (isoniazid 75 
mg plus rifampicin 150 mg combination tablets) combination will be given from Weeks 9 to 26. 
Participants with DS-TB that are randomized to the HRZE/HR control arm in this trial will be 
given standard weight-adjusted doses of HRZE.   
Please see the HRZE and HR Package Inserts[22, 40] for known and potential risks and benefits. 
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3.0 
Trial Objectives 
3.1 
Primary Objectives 
To evaluate the efficacy, safety and tolerability at 8 weeks (2-months), 52 weeks (12-months), 
and 104 Weeks (24-months) post the start of the following treatment regimens in participants with: 
 
Drug Sensitive TB (DS-TB) 
–  BPaMZ given for 17 Weeks (4 months) 
– Standard HRZE/HR treatment given for 26 weeks (6 months) 
 
Drug Resistant TB (DR-TB)  
– BPaMZ given for 26 Weeks (6 months) 
 
DR-TB Defined as participants with  
1. mono-resistance to rifampicin or isoniazid, OR 
2. resistance to both rifampicin and isoniazid (MDR-TB) 
 
3.2 
Secondary Objectives 
Efficacy: 
• 
Incidence of bacteriologic failure or relapse or clinical failure at 52 (or 12 months) and 104 (or 
24 months) weeks from the start of therapy.  
• 
Proportion of participants with sputum culture conversion to negative status in liquid culture 
(MGIT) at 4, 6, 12 and 17 weeks to be explored as a potential biomarker of outcome at 52 
weeks from start of therapy. 
• 
Change from baseline in weight. 
• 
Change from baseline in TB symptoms. 
• 
Change from baseline in Participant Reported Health Status. 
 
Safety and Tolerability: 
• 
Incidence of Treatment Emergent Adverse Events (TEAEs) presented by incidence, severity, 
drug relatedness, seriousness, leading to early withdrawal, and leading to death.  
▪ 
Quantitative and qualitative clinical safety laboratory measurements, including observed 
and change from baseline. 
▪ 
Quantitative and qualitative ECG results (heart rate, RR interval, PR interval, QRS 
interval, QT interval and QTc interval), including observed. QT/QTc intervals, change 
from baseline, will be categorized as these will be centrally read. 
• 
Changes in male reproductive hormones and lens opacities. 
 
These data will be presented as descriptive analyses, and no inferential tests will be carried out. 
 
 
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Pharmacokinetics (PK) and Pharmacokinetics/Pharmacodynamics (PK/PD): 
Plasma concentrations from sparse sampling will be used to update existing population PK 
models and derive exposure metrics (e.g., Cmin, Cmax, AUC) for bedaquiline and its M2 
metabolite, pretomanid, moxifloxacin, and pyrazinamide. Effects of baseline covariates on 
exposure will be assessed; so, too, will the effects of con-medications including antiretroviral 
therapy (ART), as feasible. Data from other trials may be included to enhance the model-based 
analysis. Relationships will be explored between drug exposure and efficacy and safety 
endpoints. These exploratory PK/PD analyses may include HIV status as a covariate. 
3.3 
Exploratory Objectives 
• 
Evaluate whether any of the secondary endpoints predicts relapse free cure. 
• 
Subgroup analysis of populations by HIV status.  
No formal statistical comparisons will be made for the participants enrolled with DR-TB. 
4.0 
Trial Design 
4.1 
Summary of Trial Design 
This is a Phase 2c, multi-center, open-label, partially randomized clinical trial conducted in 3 
treatment groups.  Participants, trial investigators and staff, including laboratory staff, will not be 
blinded to treatment allocation during the treatment phase of the trial. 
The trial will be performed globally at multiple centers located throughout all regions of the world.    
A total of 300 DS-TB participants (150 per treatment arm) will be randomized and stratified for co-
infection with HIV and cavitation.  Up to 150 DR-TB participants will be enrolled and assigned to 
the treatment arm described in Table 4 below   
Participants with Drug Sensitive TB (DS-TB): 
 
Participants with DS-TB will be randomized to one of two treatment arms. These participants will 
receive either BPaMZ daily for 17 weeks (4 months), or HRZE/HR combination tablets daily for 
26 weeks (6 months).  Participants will be stratified for co-infection with human immunodeficiency 
virus (HIV) and cavitation. 
 
Participants with Drug Resistant TB (DR-TB): 
 
Participants with DR-TB will be assigned to receive BPaMZ daily for 26 weeks (6 months). 
Eligible participants who meet all of the inclusion criteria and none of the exclusion criteria, aged 
18 and over, male or female will be assigned to one of the 3 treatment groups with a target of 
50% of the participants being HIV positive. An interactive web response system (IWRS) will be 
used which will utilize a dynamic randomization system using cavitation with a random element 
to allocate participants evenly across the arms by HIV status and type of TB (DS versus DR) after 
they have given written, informed consent during Screening Visit (Days -9 to -1) and met all 
eligibility criteria 
 
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4.2 
Treatment Plan: Schedule of Assessments 
• 
Screening Period (Day -9 to Day -1) 
• 
Treatment Period (Day 1 to Week 17 (4-month treatment); or Week 26 (6-month treatment)  
• 
Follow-Up Period (Week 39 to Week 104) 
Refer to: 
• 
Synopsis Flow Chart and Procedures (Section 1.2; flow chart) for the timing of all 
procedures and laboratory samples to done at each visit.   
• 
Trial Procedures (Section7.0, Trial Variables and Procedures) for details regarding 
specific procedures or laboratory tests. 
Each participant will receive up to 26 weeks of treatment.  The trial treatment regimens may 
require interruptions/pauses due to toxicities. All dose interruptions/pauses should be discussed 
with the Sponsor’s Medical Monitor prior to implementation, in consultation with the Sponsor 
Medical Monitor. Participants will be followed for up to 104 weeks after the start of treatment. 
Participants will receive oral daily dosing. They will be randomized to one of the following arms: 
Table 4: Treatment Groups 
 
Treatment Group 
Treatment 
Duration 
No of 
Participants 
1 Bedaquiline 200 mg daily for 8 weeks  
then 100 mg daily for 9 weeks, together with pretomanid 
200 mg + moxifloxacin 400 mg + pyrazinamide 1500 mg 
daily 
17 weeks 
(4 months) 
150 DS-TB  
2 HRZE Tablets: (isoniazid 75 mg plus rifampicin 150 mg 
plus pyrazinamide 400 mg plus ethambutol 275 mg 
combination tablets).  
 
AND THEN 
 
HR Tablets: (isoniazid 75 mg plus rifampicin 150 mg 
combination tablets) 
This combination will be given starting at Week 9. 
 
First 8 weeks  
(2 months)  
 
 
then  
 
 
17 weeks  
(4 months) 
 
Total 6 months 
150 DS-TB 
3 Bedaquiline 200 mg daily for 8 weeks then 100 mg daily 
for 18 weeks, together with pretomanid 200 mg + 
moxifloxacin 400 mg + pyrazinamide 1500 mg daily. 
26 weeks 
(6 months) 
Up to 150 
DR-TB 
 
5.0 
Trial Population 
Participant must meet all inclusion and no exclusion criteria within the screening period.  Retesting 
for laboratory or ECG parameters is allowed within the screening period.  Sponsor may consider 
replacement of late exclusions. 
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5.1 
Inclusion Criteria 
Participants are required to meet all of the following inclusion criteria during the screening period 
in order to be randomized. 
1. Signed written consent prior to undertaking any trial-related procedures. 
2. Male or female, aged 18 years or over. 
3. Body weight (in light clothing and no shoes) ≥ 30 kg. 
4. Sputum positive for tubercule bacilli (at least 1+ on the International Union Against 
Tuberculosis and Lung Disease [IUATLD]/WHO scale (Appendix 1) on smear microscopy) at 
the trial laboratory. 
5. Disease Characteristics: 
• 
Participants with one of the following pulmonary TB conditions: 
DS-TB treatment arm participants should be: 
a. sensitive to rifampicin and isoniazid by rapid sputum based test AND 
b. either newly diagnosed for TB or have a history of being untreated for at least 3 
years after cure from a previous episode of TB. 
If they are entered into the trial due to being sensitive to rifampicin and isoniazid by 
rapid molecular sputum based test, however on receipt of the rifampicin and/or 
isoniazid phenotypic resistance testing in liquid culture this shows they are rifampicin 
or isoniazid resistant, they will be: 
a. Excluded as late exclusions; 
b. Possibly replaced as determined by the Sponsor.  
DR-TB treatment arm participants should be: 
a. Resistant to rifampicin and/or isoniazid.  
A chest x-ray which in the opinion of the investigator is compatible with pulmonary TB.  
1. Contraception: 
Be of non-childbearing potential or using effective methods of birth control, as defined below: 
Non-childbearing potential: 
a. Participant - not heterosexually active or practice sexual abstinence; or  
b. Female participant or male participants female sexual partner - bilateral 
oophorectomy, 
bilateral 
tubal 
ligation 
and/or 
hysterectomy 
or has 
been 
postmenopausal with a history of no menses for at least 12 consecutive months; or  
c. Male participant or female participants male sexual partner - vasectomised or has had 
a bilateral orchidectomy minimally three months prior to screening; 
 
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Effective birth control methods: 
a. Double barrier method which can include a male condom, diaphragm, cervical cap, or 
female condom; or  
b. Female participant: Barrier method combined with hormone-based contraceptives or 
an intra-uterine device for the female participant.  
c. Male participants’ female sexual partner: Double barrier method or hormone-based 
contraceptives or an intra-uterine device for the female partner.  
And both male and female participants are willing to continue practicing birth control 
methods and are not planning to conceive throughout treatment and for 12 weeks after 
the last dose of trial medication or discontinuation from trial medication in case of 
premature discontinuation.  
(Note: Hormone-based contraception alone may not be reliable when taking IMP; 
therefore, hormone-based contraceptives alone cannot be used by female participants to 
prevent pregnancy). 
 
5.2 
Exclusion Criteria 
Participants will be excluded from participation if they meet any of the following criteria: 
Medical History and Concurrent Conditions: 
1. Any non-TB related condition where participation in the trial, as judged by the investigator, 
could compromise the well-being of the participant or prevent, limit or confound protocol 
specified assessments.  
2. Being, or about to be, treated for Malaria. 
3. Is critically ill and, in the judgment of the investigator, has a diagnosis likely to result in 
death during the trial or the follow-up period.  
4. TB meningitis or other forms of extrapulmonary tuberculosis with high risk of a poor 
outcome, or likely to require a longer course of therapy (such as TB of the bone or joint), 
as judged by the investigator. 
5. History of allergy or hypersensitivity to any of the trial IMP or related substances, including 
known allergy to any fluoroquinolone antibiotic, history of tendinopathy associated with 
quinolones or suspected hypersensitivity to any rifampicin antibiotics. 
6. For HIV infected participants any of the following: 
a. CD4+ count <100 cells/µL  
b. Karnofsky score <60% (Appendix 5)   
c. Received intravenous antifungal medication within the last 90 days 
d. WHO Clinical Stage 4 HIV disease (Appendix 3) 
7. Participants recently started or expected to need to start ART within 1 month after 
randomization. Participants may be included who have been on ARTs for greater than 30 
days prior to start of screening, or who are expected to start ART greater than 30 days 
after randomization. 
8. Resistant to fluoroquinolones (rapid, sputum-based molecular screening tests).  
a. If they are entered into the trial due to being sensitive to fluoroquinolones by rapid 
sputum based test, however on receipt of the moxifloxacin phenotypic resistance 
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testing in liquid culture they are found to be fluoroquinolones resistant, they will be 
excluded as late exclusions; 
9. Having participated in other clinical trials with investigational agents within 8 weeks prior 
to start of trial medication or currently enrolled in an investigational trial; 
10. Participants with any of the following at screening (per measurements and reading done 
by ECG): 
11. Cardiac arrhythmia requiring medication; 
12. Prolongation of QT/QTc interval with QTcF (Fridericia correction) >450 ms; 
13. History of additional risk factors for Torsade de Pointes, (e.g., heart failure, hypokalemia, 
family history of Long QT Syndrome); 
14. Any clinically significant ECG abnormality, in the opinion of the investigator. 
15. Unstable Diabetes Mellitus which required hospitalization for hyper- or hypo-glycaemia 
within the past year prior to start of screening. 
 
Previous and Concomitant Therapy 
1. Previous treatment with pretomanid or bedaquiline as part of a clinical trial. 
2. Previous treatment for TB which includes, but is not limited to, gatifloxacin, amikacin, 
cycloserine, rifabutin, kanamycin, para-aminosalicylic acid, rifapentine, thioacetazone, 
capreomycin, quinolones, thioamides, and metronidazole: 
3. For DS-TB treatment arms: Previous treatment for tuberculosis within 3 years prior to 
Day -9 to -1 (Screening). Participants who have previously received isoniazid 
prophylactically may be included in the trial as long as that treatment is/was discontinued 
at least 7 days prior to randomization into this trial. 
4. For the DR-TB/MDR-TB participants: Previous treatment for DR-TB/MDR-TB, although 
may have been on a DR-TB treatment regimen for no longer than 7 days at start of 
screening.  
5. Any diseases or conditions in which the use of the standard TB drugs or any of their 
components is contra-indicated, including but not limited to drug allergy. 
6. Use of any drug within 30 days prior to randomisation known to prolong QTc interval 
(including, but not limited to, amiodarone, amitriptyline, bepridil, chloroquine, 
chlorpromazine, cisapride, clarithromycin, disopyramide dofetilide, domperidone, 
droperidol, erythromycin, halofantrine, haloperidol, ibutilide, levomethadyl, mesoridazine, 
methadone, pentamidine, pimozide, procainamide, quinacrine, quinidine, sotalol, 
sparfloxacin, thioridazine). 
7. Use of systemic glucocorticoids within one year of start of screening (inhaled or intranasal 
glucocorticoids are allowed) due to visual opacities or cataracts 
8. For HIV infected participants, only the following types of ART are permissible:  
• 
Nevirapine (NVP) based regimen consisting of NVP in combination with any two 
nucleosidase reverse transcriptase inhibitors (NRTIs) tenofovir (TDF)/abacavir (ABC) 
and emtricitabine (FTC)/lamivudine (3TC).   
• 
Lopinavir/ritonavir based regimen consisting of lopinavir/ritonavir in combination with 
any two NRTI. TDF/ABC and FTC/3TC.  
• 
Integrase inhibitor (e.g., dolutegravir) in combination with TDF/ABC and FTC/3TC.  
• 
In participants who have viral load suppressed on efavirenz at the time of screening, 
their ART can be changed to rilpivirine in combination with TDF/ABC and FTC/3TC. 
If possible, the same nucleoside backbone should be used. 
9. In the case where participants are randomized to a rifampicin containing regime 
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• 
EFV can be used with rifampicin.  
• 
LPV needs to be double dosed.  
• 
Rilpivirine cannot be given with rifampicin 
 
 
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Diagnostic and Laboratory Abnormalities 
10. Participants with the following toxicities at screening as defined by the enhanced Division 
of Microbiology and Infectious Disease (DMID) adult toxicity table (November 2007) 
(Appendix 2) where applicable: 
• 
platelets grade 2 or greater (<100,000/mm3); 
• 
creatinine grade 2 or greater (>1.5 times upper limit of normal [ULN])  
• 
eGFR  ≤  60 mL/min/m2 
• 
haemoglobin grade 2 or greater (≤8.0 g/dL); 
• 
serum potassium less than the lower limit of normal for the laboratory. This may be 
repeated once; 
• 
AST: 
o grade 3 or greater (≥3.0 x ULN) to be excluded;  
o results between 1.5 x ULN and 3 x ULN must be discussed with and approved 
by the Sponsor Medical Monitor; 
• 
ALT: 
o grade 3 or greater (≥3.0 x ULN) to be excluded; 
o greater than ULN must be discussed with and approved by the Sponsor 
Medical Monitor; 
• 
 ALP: 
o grade 3 or greater (≥3.0 x ULN) to be excluded; 
o grade 2 (2.0 – <3.0 x ULN) must be discussed with and approved by the 
Sponsor Medical Monitor; 
• 
total bilirubin: 
o >1.5 x ULN to be excluded; 
o 1 – 1.5 x ULN must be discussed with and approved by the Sponsor Medical 
Monitor; 
• 
direct bilirubin: 
o greater than ULN to be excluded. 
All of the inclusion and none of the exclusion criteria must be met. If no single variable/value is 
outside of the ranges of acceptability, but when multiple values are close to the limits and/or 
whenever the Investigator has reason to suspect that there might be a health problem (other than 
TB), enrolment should only be considered after discussing the case with the Sponsor Medical 
Monitor. 
 
No waivers shall be granted 
 
5.3 
Restrictions 
Concomitant medications should be kept to a minimum during the trial. However, if concomitant 
medications are considered to be necessary for the participant’s welfare and are unlikely to 
interfere with the IMP, they may be given at the discretion of the investigator. For any concomitant 
medications given as a treatment for a new condition or a worsening of an existing condition 
occurring after signing of the informed consent form, the condition must be documented on the 
Adverse Event pages of the electronic Case Report Form (eCRF). 
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The prescribing information for all concomitant medication should be consulted and reviewed 
carefully. The determinations listed in the respective contraindicated, warning, and precaution 
sections must be respected in order to prevent any potentially serious and/or life-threatening drug 
interactions. 
The following recommendations should be followed with regards to concomitant medication to 
avoid possible drug interaction with the IMP: 
Participants on a moxifloxacin containing treatment arm: The IMP should be taken either 
4 hours before or 8 hours after taking the following products: 
An antacid, multivitamin, or other product that has magnesium, aluminium, iron or zinc; 
Sucralfate; 
Didanosine. 
Participants on the HRZE/HR treatment arm: Any aluminium-containing antacids should be 
taken at least one hour after the IMP dose. 
The following medicinal products are prohibited from Day -9 to Day -1 (Screening) and during the 
treatment period: 
Quinolone antimalarials (e.g., chloroquine and quinacrine). Participants who have malaria at 
screening are to be excluded. However, if a participant develops malaria during the course of 
the trial, the investigator is advised to consult the Malaria Treatment Guidance document 
regarding the interaction between moxifloxacin and bedaquiline with anti-malarial drugs. 
Investigators may also contact the Sponsor medical monitor for further guidance. 
Chronic systemic glucocorticoids (inhaled or intranasal glucocorticoids are allowed) due to 
their potential to cause visual opacities. Short term systemic glucocorticoids are allowed for 
emergency situations e.g for treatment of pulmonary exacerbation when Inhaled 
glucocorticoids is inadequate. 
Medicinal products used to treat pulmonary TB: including but not limited to gatifloxacin, 
amikacin, 
cycloserine, 
rifabutin, 
kanamycin, 
para-aminosalicylic 
acid, 
rifapentine, 
thioacetazone, capreomycin, other quinolones, thioamides, and metronidazole. 
The following medicinal products should be avoided from Day 1 and during the treatment period 
as much as possible unless discussed with the Sponsor: 
Any drug known to prolong QTc interval (including but not limited to amiodarone, bepridil, 
chloroquine, chlorpromazine, cisapride, clarithromycin, disopyramide dofetilide, domperidone, 
droperidol, erythromycin, halofantrine, haloperidol, ibutilide, levomethadyl, mesoridazine, 
methadone, pentamidine, pimozide, procainamide, quinidine, sotalol, sparfloxacin, 
thioridazine). The exception is moxifloxacin and bedaquiline administered as part of the trial 
IMP with ECG monitoring to help ensure participant safety. 
Any drug known to be hepatotoxic (including but not limited to acetaminophen/paracetamol, 
acetazolamide, allopurinol, amiodarone, amitriptyline, amoxicillin, amprenavir, atorvastatin, 
augmentin/co-amoxiclav, azathioprine, baclofen, bumetanide, captopril, carbamazepine, 
celecoxib, chlorpromazine, chlorpromazine, clindamycin, clopidogrel, contraceptive pill, co-
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trimoxazole, darunavir, delavirdine, diclofenac, doxycycline, enalapril, fluconazole, fluoxetine, 
fosamprenavir, furosemide, gliclazide, glimeperide, glipizide, ibuprofen, irbesartan, 
ketoconazole, lisinopril, loperamide, losartan, methotrexate, metolazone, mirtazepine, 
nitrofurantoin, omeprazole, other non-steroidal anti-inflammatory drugs, paroxetine, 
phenobarbital, phenothiazines, phenytoin, pravastatin, probenecid, prochlorperazine, 
risperidone, rosuvastatin, sertraline, simeprevir, simvastatin, sodium valproate, sotalol, 
sulfasalazine, sumatriptan, tamsulosin, terbinafine, tetracycline, theophyllin/uniphyllin, 
tipranavir, tolazamide, tolbutamide, topiramate, trazodone, tricyclic antidepressants, 
trimethoprim, verapamil).  
5.4 
Treatment Discontinuation and/or Early Withdrawal  
Any participant for whom the investigator decides to temporarily discontinue their IMP is to be 
discussed with the sponsor medical monitor and, if applicable, be restarted on IMP as soon as 
possible.  
A participant must be prematurely withdrawn from the trial (during the trial treatment or follow up 
periods) as a result of the following: 
• 
Withdrawal of informed consent; 
• 
Investigator considers it for safety reasons in the best interest of the participant that he/she 
be withdrawn, including a concern that the participant has symptomatic TB and/or 
bacteriological failure/relapse and requires a change in TB treatment; 
• 
Pregnancy; 
• 
At the specific request of the sponsor or termination of the trial by the sponsor; 
• 
Failure to comply with the protocol; 
• 
Lost to follow-up 
• 
Participant misses 21 or more consecutive doses of IMP; 
• 
Drug-Sensitive TB treatment arms participants, who have been entered prior to receipt of the 
rapid, sputum – based molecular pyrazinamide resistance screening test result, who on 
receipt of the result, are found to be Z resistant.  
• 
Drug-Sensitive TB treatment arms participants, who have been entered onto the trial as a 
rifampicin sensitive participant on the rapid sputum based test result, who on receipt of the 
rifampicin resistance testing using an indirect susceptibility test in liquid culture, this shows a 
rifampicin resistant result. 
• 
Participants, who have been entered onto the trial as fluoroquinolone sensitive on the rapid 
sputum based test result, who on receipt of the fluoroquinolone resistance testing using an 
indirect susceptibility test in liquid culture; this shows a fluoroquinolone resistant result. 
• 
Early withdrawal due to TB (see Section 5.4.4) 
 
A participant may withdraw from the trial at any time at his/her request (withdrawal of consent), 
or may be withdrawn at any time at the discretion of the Investigator for safety, behavioral, 
compliance or administrative issues. When a participant withdraws consent from the trial, no 
additional follow-up visits will be performed. 
Participants who withdraw from the trial after having received IMP will not be replaced.  
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All participants withdrawn from trial treatment/received at least one dose of IMP will be requested 
to return for an early withdrawal visits and applicable safety Follow Up visits, as per flow chart 
(Section 1.2) Footnote c. 
5.4.1 
Early Withdrawal 
In case of early withdrawal during the treatment or follow-up period, all efforts shall be made to 
complete the Early Withdrawal assessments.  At the early withdrawal visit the following 
information will be collected and procedures performed: 
• 
Sputum sample collection x 2 (one early morning brought from home and one spot at the 
research site under the coaching and observation of the trial staff);  
• 
Serum or Urine Pregnancy test (women of child bearing potential, whether they are sexually 
active or not); 
• 
Laboratory Safety sampling (including male reproductive hormone tests); 
• 
Single 12-lead ECG; 
• 
TB Symptoms Profile; 
• 
Patient Reported Health Status Questionnaire; 
• 
Vital Signs; 
• 
Full Physical examination including weight; 
• 
Ophthalmology Examination if required as described in Table 5 
• 
IMP Compliance Check (if participant on IMP); 
• 
Concomitant Medications; 
• 
Adverse Events. 
Once a participant has been permanently withdrawn from the trial, they will be requested to attend 
follow-up visits as described in Table 5: 
Table 5: Follow-up visits required for Early Withdrawal Participants 
Treatment 
Duration 
at 
EWD visit 
Ophthalmology 
Examination 
at 
EWDa 
Ophthalmology 
Examination Visit 
3 months after 
EWD Visita 
Month 
12 
Follow-up Visit 
Month 
24 
Follow-up Visit 
≤ 14 days 
Not required 
Not required 
Required 
Required 
15 days to ≤ 
12weeks 
Not required 
Required 
Required 
Required 
> 12 weeks  
Required 
Required 
Required, if not 
already 
performed. 
Required 
a 
If an additional visit is required for an ophthalmology examination after EWD, only the 
ophthalmology examination will be performed at this visit, and it will occur 3 months after EWD 
visit date. 
The Month 12 and 24 visits will be to collect SAE information (including verification of survival) 
and patient reported TB outcome information only and may be telephonic, a home or a site visit. 
They will occur at Month 12 and/or 24 after the participants’ start of treatment date. 
 
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5.4.2 
Unscheduled Visits 
Any visit which is conducted in addition to those required by the Trial Flow Chart should be 
considered unscheduled regardless of the reason for the visit. The assessments which are 
undertaken as part of an unscheduled visit should be as clinically indicated.  
The following situation/s would require an unscheduled visit/s: 
• 
If both sputum samples (Early Morning and Spot) at Month 2 or later are contaminated, 
the participant should return for an unscheduled visit(s) to give additional sputum samples 
x 2 (one early morning and one spot at the research site under the coaching and 
observation of the trial staff) or to document that the participant is not able to produce 
sputum. 
• 
If there is a positive culture at or after the end of treatment (Week 17 (4 month treatment 
arms)/Week 26 (6 month treatment arms)), the participant should return for an 
unscheduled visit(s) to give additional sputum samples x 2 (one early morning and one 
spot at the research site under the coaching and observation of the trial staff) or to 
document that the participant is not able to produce sputum. 
In order to be able to define a participant’s primary outcome status it may be necessary in certain 
situations to contact a participant and request they visit the site in order to collect additional 
sputum samples at Unscheduled Visits, as follows: 
o To be assessed on sputum culture results from: 
▪ 
End of Treatment Period (Week 17/26); 
▪ 
End of Follow-up Period (Month 12 and 24); 
▪ 
Early Withdrawal if applicable. 
o Confirm whether the participant has: 
▪ 
two sequential negative sputum culture results; or  
▪ 
two sequential positive sputum culture results; or  
▪ 
has been unable to produce sputum after documentation of two negative 
sputum cultures with no intervening positive and are clinically asymptomatic. 
If they do not fall into one of these categories, keep collecting Sputum samples x 2 (one 
early morning and one spot at the research site under the coaching and observation of 
the trial staff) a minimum of 7 days apart until they fall into one of the above categories. 
If in any of the above scenarios the investigator is unsure of the outcome the investigator is to 
contact the sponsor medical monitor and discuss and agree on how the patient is to be handled. 
5.4.3 
Lost-to-Follow-up 
For Lost-to-Follow-up participants, a minimum of three contact attempts (telephonic/home visit) 
will be made. If these attempts are unsuccessful the participant will be considered lost to follow-
up.  This should be clearly documented in the participant’s source documents. 
5.4.4 
Early Withdrawal due to TB 
Ultimately it is the investigator’s decision whether a participant requires Early Withdrawal from the 
trial due to a concern that the participant has symptomatic worsening TB and/or bacteriological 
failure/relapse.  
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Early Withdrawal is usually not indicated for a single positive culture.  Should a participant have 
a single positive culture result after being negative, the investigator is to evaluate whether the 
participant has signs and symptoms suggestive of active inadequately treated TB and whether it 
is in the participants best interest that he/she be withdrawn. Prior to Early Withdrawal of a 
participant due to TB, the investigator must discuss the participant with the sponsor medical 
monitor, unless the investigator cannot contact the sponsor medical monitor and considers that 
Early withdrawal must occur immediately due to immediate safety concerns with respect to the 
participant. 
If the investigator decides to withdraw a participant due to TB, additional sputum samples may 
need to be collected in order to ensure the participant’s outcome status as determined in Section 
5.5. 
All Early Withdrawal participants who are confirmed sputum positive (two sequential sputum 
positive cultures) and/or have symptomatic TB will require further TB treatment. These 
participants will be referred to their applicable DS/MDR local community TB clinics for standard 
anti-tuberculosis chemotherapy according to National TB Guidelines. The participants will be 
provided with a referral letter to take with them to the TB Clinic.  A follow-up call will be made by 
the trial site staff to the clinic to ensure the participant attended the clinic.  
 
 
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5.5 
Participant Progress Definitions 
Status 
Treatment 
Follow-Up 
Screen Failure 
Participants from whom informed consent is obtained and is 
documented in writing (i.e., participant signs an informed consent form) 
but who is not randomized 
Completed 
Treatment / 
Completed FU* 
Participants who complete 
the full course of IMP 
Participants who complete all follow-up 
visits 
Completed 
Treatment / 
Discontinued FU 
Participants who complete 
the full course of IMP 
Participants who do not complete all 
applicable follow-up visits, regardless of 
the reason (excluding LTFU) 
Completed 
Treatment / Lost 
to Follow-Up 
Participants who complete 
the full course of IMP 
Participants who are unable to be 
contacted on or before their final visit 
Discontinued 
Treatment / 
Completed FU 
Participants who discontinue 
treatment prior to completion 
of the protocol-defined 
treatment course 
Participants who complete all applicable 
follow-up visits 
Discontinued 
Treatment / 
Discontinued 
FU** 
Participants who discontinue 
treatment prior to completion 
of the protocol-defined 
treatment course 
Participants who do not complete all 
applicable follow-up visits, regardless of 
the reason (excluding LTFU) 
Lost to Follow-Up 
Participants who are unable to be contacted on or before their final 
treatment visit and it cannot be confirmed whether treatment was 
completed 
* 
Note that this includes treatment failures who complete all applicable follow-up visits 
** 
Early Withdrawal 
5.6 
Trial Stopping Rules 
There are no trial specific stopping rules.  
The trial or parts of the trial can be stopped by the Sponsor on advice from the Data Safety and 
Monitoring Committee (DSMC) after their review of applicable trial data.  In addition, the Sponsor 
has the right to stop the trial or a specific Investigational Site at any time, although this should 
only occur after consultation between involved parties.  Should this occur, the local and central 
Ethics Committee/Institutional Review Board (EC/IRB) and Regulatory Authorities will be 
informed.  Should the Trial/Investigational Site be closed prematurely, all trial materials (except 
documentation that has to remain stored at the Investigational Site) will be returned to the Sponsor 
or vendor.   The Investigator will retain all other documents until notification given by the Sponsor 
for destruction.  Participants currently on treatment will receive an appropriate regimen and all 
participants will be referred to their applicable DS-TB/DR-TB National Treatment Program. 
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6.0 
Treatment 
6.1 
IMP Administration  
6.1.1 
Instructions for Dosing of Test Regimen (BPaMZ):  
Treatment will be administered orally once daily, to be taken during breakfast, with a full glass of 
water (approximately 240 ml), for 17 weeks (4 months) or 26 weeks (6 months). 
 
6.1.2 
Instructions for Dosing Control Treatment Regimen (HRZE/HR): 
To be taken with a glass of water (approximately 240 ml). 
HRZE or HR should not be taken with a meal (generally, no closer to meals than 1 hour before or 
2 hours after a meal) in the following dosing schemes. 
Treatment will be administered orally once daily only to the “control” randomized DS-TB 
participants as follows: 
Weeks 1-8: HRZE tablets with the daily dose per the Participant’s weight as follows: 30-37 kg: 2 
tablets; 38-54 kg: 3 tablets; 55-70 kg: 4 tablets; 71 kg and over: 5 tablets; 
Weeks 9-26: HR with daily dose per the participant's weight as follows: 30-39 kg: 2 tablets; 40-54 
kg: 3 tablets; 55-70 kg: 4 tablets; 71 kg and over: 5 tablets.  
Vitamin B6 25 mg daily supplement to be taken with the HRZE/HR treatment. 
The daily dose of HRZE and HR combination tablets are dependent on the participant’s weight 
as follows:  
30-37 kg: 2 tablets 
38-54 kg: 3 tablets 
55-70 kg: 4 tablets 
>70 kg: 5 tablets 
6.2 
Participant Compliance 
During site clinic visits, the IMP will be administered by the Investigator/designated site personnel. 
During the trial, sites will be responsible for ensuring participants are taking IMP correctly and are 
fully trained on how IMP is to be taken. When possible, participants will be checked for IMP 
compliance by the Investigators or trial personnel/National TB Treatment Program personnel via 
the hand-and-mouth procedure (both the hand and the mouth of the participant will be checked 
to ensure that the participant has swallowed the IMP).  Additionally, participant cards will be 
checked for unused tablets in the blisters at each visit during the treatment phase. 
6.3 
Treatment Modification(s) 
The importance of adherence to the treatment schedule will be reinforced at each visit.  Non-
adherence should prompt the investigator to identify and address the cause(s) (e.g. side effects) 
of the non-adherence and contact the sponsor medical monitor within 24 hours.  Participants 
missing: 
• 
< 7 consecutive doses of IMP doses: restart IMP, no extension of IMP required. 
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• 
Up to ≤ 21 consecutive doses of IMP: restart IMP, extend the IMP treatment by the 
number of consecutive doses missed. In this case: the final treatment visit should also 
be pushed out to the date of last dose.  
It is not necessary to have an unscheduled visit at the time when the End of Treatment 
visit would have been. 
• 
21 or more consecutive doses of IMP, discontinue IMP and withdraw participant from the 
trial. 
Any participant for whom the trial medication is discontinued (including for non-adherence) will be 
discussed with the sponsor medical monitor and, if applicable, the participant will be restarted on 
trial medication as soon as possible.  
6.4 
IMP Packaging and Labelling 
The complete formulations of the IMP, bedaquiline and pretomanid, are found in the respective 
Investigator Brochures.[8, 15] The complete formulations of moxifloxacin and pyrazinamide are 
found in the Package Inserts.[19, 20, 22, 40]  
The IMP will be packaged as follows: 
Treatment Group Wallet Cards 
• 
Week 1-8 Cards 
 
Bedaquiline   100 mg 14 tablets (B) 
 
Pretomanid    200 mg 7 tablets (Pa) 
 
Moxifloxacin  400 mg 7 tablets (M) 
 
Pyrazinamide 500 mg 21 tablets (Z) 
 
• 
Week 9-17/26 Cards 
 
Bedaquiline   100 mg  7 tablets (B) 
 
Pretomanid    200 mg 7 tablets (Pa) 
 
Moxifloxacin  400 mg 7 tablets (M) 
 
Pyrazinamide 500 mg 21 tablets (Z) 
 
• 
Control Group Wallet Cards 
 
Weight band 1 = 30-39kg 
 
Weight band 2 = 40-54kg 
 
Weight band 3 = 55-70kg 
 
Weight band 4 = ≥71kg 
 
• 
Bi-Weekly Cards (Weeks 1-8 Cards/56 days of treatment) 
 
Weight Band 1 Contains: 28 tablets HRZE, 28 tablets HR 
 
Weight Band 2 Contains: 42 tablets HRZE, 42 tablets HR 
 
Weight Band 3 Contains: 56 tablets HRZE, 56 tablets HR  
 
Weight Band 4 Contains: 70 tablets HRZE, 70 tablets HR 
 
• 
B6 tablets in bottles 
 
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The IMP Treatment Arms will be packaged by individual weekly cards.  The Control Arms will be 
supplied with bi-weekly cards and a biweekly bottle supply of B6.  Contents of each weekly card 
is described in the IMP packaging detail listed above.  The packaging of each weekly/biweekly 
card/bottle will be labelled with, at a minimum, the following information: 
• 
Name, address and telephone number of Sponsor. 
• 
Name of medication. 
• 
Dosage, quantity and method of administration.  
• 
Reference/Lot Number. 
• 
The statement “For Clinical Trial Use Only”. 
• 
Space for completion of Name of Investigator and Site Number. 
• 
MedID: medication identification number. 
• 
Storage conditions. 
• 
Period of Use. 
• 
The statement “Keep out of reach of children”. 
• 
Expiry Date. 
• 
Directions for use. 
• 
Space for completion of participant number and visit/date dispensed. 
6.5 
Blinding and Procedures for Breaking the Blind 
As this is an open label trial there is no need for blinding or procedures to break the blind. The 
trial participants, the site staff, Sponsor, and CROs will not be blinded to treatment assignment.  
6.6 
Handling, Storage and Accountability  
The investigator or designee must confirm appropriate temperature conditions as per details on 
IMP labeling, have been maintained during transit for all trial treatment received and any 
discrepancies are reported and resolved before use of the trial treatment. 
Only participants enrolled in the trial may receive trial treatment and only authorized site staff may 
supply or administer trial treatment. All trial treatments must be stored in a secure, 
environmentally controlled, and monitored (manual or automated) area in accordance with the 
labeled storage conditions with access limited to the investigator and authorized site staff. 
The investigator, institution, or the head of the medical institution (where applicable) is responsible 
for trial treatment accountability, reconciliation, and record maintenance (i.e., receipt, 
reconciliation, and final disposition records).  Upon completion or termination of the trial, all 
unused and/or partially used IMPs must either be returned to Sponsor (or designated vendor: who 
will arrange for destruction or destroyed at site as agreed by Sponsor after final accountability has 
been confirmed; 
The Investigator/designee will immediately inform the Sponsor of any quality issues arising with 
respect to the trial medication. The Sponsor will take whatever action is required should such a 
situation arise. 
Further guidance and information for the handling, storage, accountability and final disposition of 
unused trial treatment are provided in the pharmacy manual. 
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7.0 
Trial Variables and Procedures 
The Synopsis Flowchart and Procedures in Section 1.2  should be referenced for timing, 
sequence of assessments, and specific procedures. 
7.1 
Demographic and Background Variables and Procedures 
The following demographic and background variables will be collected: 
• 
Written Informed Consent 
• 
Visit Dates 
• 
Participant Disposition 
• 
Demography (date of birth, race and gender) 
• 
Inclusion and Exclusion criteria 
• 
Clinically significant medical and TB treatment history (including past and current TB 
diagnosis, smoking and alcohol use) 
• 
Screening Coached Spot Sputum Sample: 
o Smear microscopy for acid-fast bacilli. 
o Gene Xpert, Hain Assay MTBDRplus or equivalent to determine MTB complex and 
rifamycin resistance 
• 
Urine pregnancy test: women of childbearing potential only, whether they are sexually 
active or not. (Non-childbearing potential for a female participant is defined as having 
bilateral oophorectomy, bilateral tubal ligation and/or hysterectomy or has been 
postmenopausal with a history of no menses for at least 12 consecutive months.) 
• 
Serology: HIV and CD4 count.  
o Where required by regulatory authorities or ethics committees: 
▪ 
Separate approval for this to be performed will be obtained from participants in the 
written informed consent process.  
o prior to HIV testing and on receipt of the results, participants will be counselled on HIV 
by trained counsellors if they have indicated as such on the HIV consent form. If 
requested by the participant, HIV counselling provided to the participant by the study 
site should be clearly documented in the participant’s medical records/source.  
Participants have the right to decline to know or receive their HIV test results. This 
decision should be clearly documented in the participant’s medical records/source.   
• 
Karnofsky Score (Appendix 4). 
• 
Chest X-Ray: A Chest X-Ray digital image within 4 weeks prior to screening will be 
obtained and read locally by the Investigator or designee.  Digital images will be provided to 
the Sponsor; this process will be documented in the Radiology Manual.  The Investigator is 
responsible for review and analysis for participant inclusion. 
• 
Method of Birth Control: Male and Female participants and their partners. 
• 
IMP Details: Randomization 
• 
IMP Compliance/Actual Dosing 
• 
Concomitant Medications 
7.2 
Efficacy Variables and Procedures 
Two Spot Sputum Samples are collected, one Early Morning brought from home or collected in 
the hospital ward and one spot collected at the research site under the coaching and observation 
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of the trial staff or, if no early morning sample was provided, 2 samples collected on site at least 
30 minutes apart. The Mycobacteriology sampling methodology and requirements will be 
described in a separate document, the Laboratory Manual, which will be provided prior to the trial 
start.  
The following analyses will be performed: 
• 
Liquid culture (MGIT), to detect presence or absence of MTB and obtain the TTP followed 
by a speciation test when applicable, to confirm MTB. 
 
Using these observed variables, the following derived variables will be assessed for evaluation of 
the efficacy endpoints: 
• 
Bacteriologic failure/relapse; 
• 
Time to Sputum Culture Conversion; 
• 
Number of participants with Sputum Culture Conversion. 
 
Every effort is to be made to collect sputum samples. However, in general, the inability to produce 
sputum is treated as being equivalent to having a negative culture (favourable) result.  A 
participant who never achieves culture negative status due to inability to produce sputum, but has 
completed 26 week /78 week post treatment completion follow-up and is without clinical or 
biological evidence of relapse, will be considered to have a favourable outcome. 
TB Symptoms Profile:  
• 
The TB Symptoms Profile (Appendix 6) will record participants’ ratings of the severity of 
common TB symptoms.  
 
Patient Reported Health Status Variables and Procedures:  
• 
The Patient Reported Health Status variables will be collected at the time points described 
in the Synopsis Flow Chart (Section 1.2). Patient Reported Health Status will be collected 
using the EQ-5D-5L Health Questionnaire (Appendix 7). This descriptive system consists of 
five health-related quality of life dimensions, each of which will be recorded using five levels 
of severity. Methodology: The Patient Reported Health Status methodology and 
requirements will be described in a separate document/guideline which will be provided prior 
to the trial start. 
7.3 
Safety and Tolerability Assessments 
The following safety and tolerability variables will be collected at the time points described in the 
Synopsis Flow Chart and Procedures and assessed for evaluation of the safety endpoints: 
• 
Laboratory parameters. The Safety Laboratory sampling methodology and requirements will 
be described in a separate document, the Laboratory Manual, which will be provided prior to 
the trial start. The following analyses will be performed: 
o Full Blood Count (hemoglobin, hematocrit, red blood cell count, white blood cell count 
with differential, platelet count),  
o Clinical Chemistry (albumin, serum urea, creatinine, direct, indirect and total bilirubin, 
uric acid, total protein, ALP, AST, ALT, lipase, phosphate, sodium, potassium, calcium 
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(corrected for albumin), chloride, magnesium, glucose, bicarbonate/CO2, creatine 
phosphokinase (CPK).  
o Urinalysis (pH, specific gravity, protein, glucose, micro-albumin, ketones, bilirubin, 
creatinine, nitrite, sodium, urobilinogen, blood, leukocytes). Microscopy will be 
completed as follow up to abnormal urinalysis per discretion of Investigator.  
• 
12-lead ECG: 
o Investigator Assessment: Normal, Abnormal. 
o Central Cardiologist Assessment: Heart rate, PR interval, RR interval, QT, corrected QT 
Interval (QTc) (QTcB and QTcF), QRS. 
o Methodology: 
▪ 
Timing and registration technique for ECGs will be standardized for all participants 
and will be described in a separate document which will be provided prior to the trial 
start; 
▪ 
ECGs are to be recorded for 10 seconds; 
▪ 
All ECGs are to be performed in single visit. 
▪ 
ECGs should be done before any labs when both included in a visit) 
▪ 
For each participant, the ECGs should, to every extent possible, be collected at 
approximately the same time of day (+/- 1 hours) and in the same fed/fast state 
throughout the trial (e.g. 4 hours after lunch). 
• 
Vital signs: 
o Vital Signs, including weight (should be done before any labs in light clothing and with no 
shoes) 
o Systolic and diastolic blood pressure (mmHg) to be measured supine (after 5 minutes of 
rest) using an appropriately sized cuff, and using the same type of sphygmomanometer, 
if possible by the same observer, at each relevant visit. 
o Heart rate (beats per minute). 
o Respiratory rate (breaths per minute)  
o Axillary body temperature (°C). 
• 
Physical Examination:  
o Height (m) is measured at screening only. 
o Full (complete) and Limited (gross neurological, pulmonary, cardiovascular and 
abdominal) examinations will be performed and any clinically significant findings will be 
recorded.   
o Weight (kg) (in light clothing and with no shoes).  
o Using the observed variables weight and height, calculated body mass index (BMI) will 
be derived. 
• 
Ophthalmology Slit Lamp Examination. To be done by an Ophthalmologist trained on Age-
Related Eye Disease Scale 2 (AREDS2) assessment. The ophthalmology slit lamp 
methodology and requirements will be described in a separate document, the 
Ophthalmology Guideline. The following analyses will be performed: AREDS2 opacity typing 
and grading. 
• 
Ophthalmic Examination. The ophthalmic examinations can be performed by any trained 
study staff. The screening exams must be done by the trained study staff AND an 
Ophthalmologist.  Methodology and requirements will be detailed in the Ophthalmology 
Guideline. 
o Ophthalmology History (Screening only); 
o Visual Acuity Test – Corrected. Distance Vision; 
o Colour Vision Assessment. 
• 
Adverse Events. 
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• 
Investigator Assessment:  
o Principal Investigator to review participant status at specified visits in flow chart including 
any time Investigator determines that participant fulfils criteria for primary outcome of 
treatment failure. Investigator to assess whether TB treatment is considered a “success” 
or “failure”.  If considered a failure, should specify if based on bacteriology and/or clinical 
deterioration and/or radiological deterioration. 
7.4 
PK Variables and Procedures 
Plasma concentrations from sparse sampling (see Section 1.2) will be used to update population 
PK models for bedaquiline and its M2 metabolite, pretomanid, and linezolid to further evaluate 
the effects of covariates on model parameters in this study population.  PK data from the current 
trial may be combined with prior data (e.g., from the NiX-TB trial) to enhance this population PK 
analysis. The models will be used to estimate individual exposure metrics (e.g., Cmin, Cmax, AUCτ, 
Cmean, and time above minimum inhibitory concentration) for subsequent analyses exploring 
relationships between drug exposure and efficacy and safety endpoints. 
 
 
7.5 
Mycobacteriology Characterization Variable and Procedures 
The following Mycobacterial Characterization variables will be collected: 
Positive Culture (for MTB) from: 
• 
Day 1 or if Day 1 is not available, first positive between screening through Week 4; 
• 
Pre-screening culture that was used for the tests that qualified the participant for inclusion 
into the trial to be subcultured and shipped to the central from the applicable lab for 
relevant participants/with no positive cultures from screening through week 4 and 
appropriate consent 
• 
When applicable, end of treatment or visits with positive cultures during post-treatment 
follow-up. 
The MTB isolates will be processed at the central lab(s) for: 
• 
MIC against bedaquiline, pretomanid and moxifloxacin;   
• 
Drug Susceptibility Testing in liquid culture for streptomycin, rifampicin, isoniazid, 
ethambutol, moxifloxacin and pyrazinamide, and second line TB drugs including but not 
limited to fluoroquinolones, and injectables; 
• 
Genotyping. 
All Day 1 (baseline) MTB isolates and isolates from positive cultures to be stored at the local and 
central microbiology laboratories until trial closure.  Extracted MTB DNA to be stored at the central 
microbiology laboratory until trial closure. The extracted MTB DNA and isolates will then be stored 
for potential further work to advance new assay tools and understanding of MTB as a pathogen 
for a maximum of 5 years after trial closure. The MTB isolates will be processed at the central 
lab(s) for: Positive MTB at/after end of treatment: Hain MTBDRplus and HainMTBRsl. 
 
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8.0 
Adverse Events 
8.1 
Definitions 
8.1.1 
Adverse Event (AE) 
Any untoward medical occurrence in a clinical investigation participant, temporally associated with 
the use of a trial treatment whether or not considered related to trial treatment. An adverse event 
can therefore be any unfavourable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease (new or exacerbated) temporally associated with the use of a trial 
treatment, whether or not related to the trial treatment. 
8.1.2 
Serious Adverse Event (SAE) 
Any untoward medical occurrence that at any dose: 
• 
Results in death 
• 
Is life threatening (any event in which the participant was at risk of death at the time of the 
event; it does not refer to an event, which hypothetically might have caused death if it were 
more severe); 
• 
Requires inpatient hospitalisation or prolongation of existing hospitalisation; In general, 
hospitalisation signifies that the participant has been detained (usually involving at least 
an overnight stay) at the hospital or emergency ward for observation and/or treatment that 
would not have been appropriate in the physician’s office or outpatient setting. 
Complications that occur during hospitalisation are AEs. If a complication prolongs 
hospitalisation or fulfills any other serious criteria, the event is serious. When in doubt as 
to whether “hospitalisation” occurred, or was necessary, the AE should be considered 
serious. Hospitalisation for elective treatment of a pre-existing condition that did not 
worsen from baseline is not considered an AE. 
• 
Results in persistent or significant disability/incapacity; the term disability means a 
substantial disruption of a person’s ability to conduct normal life functions. This definition 
is not intended to include experiences of relatively minor medical significance such as 
uncomplicated headache, nausea, vomiting, diarrhoea, influenza, and accidental trauma 
(e.g., sprained ankle) which may interfere with or prevent everyday life functions but do 
not constitute a substantial disruption. 
• 
Is a congenital anomaly/birth defect; or 
• 
Is a medically important event. 
Note:  Medical and scientific judgment should be exercised in deciding which is a medically 
important event that may not be immediately life-threatening or result in death or hospitalisation, 
but may jeopardize the participant or may require medical or surgical intervention to prevent one 
of the outcomes listed above.  Examples of such events are intensive treatment in an emergency 
room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do not result in 
hospitalisation, or the development of drug dependency or drug abuse.   A “suspected 
transmission of infectious agent by a medicinal product” is also considered a serious adverse 
event under the SAE criterion “Other medically important condition”.     
8.1.3 
Attribution/Causality 
• 
The investigator is obligated to assess the relationship between trial treatment and each 
occurrence of each AE/SAE. 
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• 
The investigator will use clinical judgment to determine the relationship. 
• 
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to trial treatment administration 
will be considered and investigated. 
• 
The investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment. 
• 
For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality. 
• 
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the Sponsor/designee. However, it is very 
important that the investigator always make an assessment of causality for every event 
before the initial transmission of the SAE data to the Sponsor/designee. 
• 
The investigator may change his/her opinion of causality in light of follow-up information 
and send a SAE follow-up report with the updated causality assessment. 
Table 6: Adverse Events Attribution/Causality Ratings  
Relatedness Rating 
Definition 
Not Related 
An adverse event, which is not related to the use of the drug. 
Unlikely 
An adverse event for which an alternative explanation is more likely, 
e.g., concomitant drug(s) or concomitant disease(s), and/or the 
relationship in time suggests that a causal relationship is unlikely. 
Possible 
An adverse event, which might be due to the use of the drug.  An 
alternative explanation, e.g., concomitant drug(s) or concomitant 
disease(s), is inconclusive.  The relationship in time is reasonable; 
therefore, the causal relationship cannot be excluded. 
Probable 
An adverse event, which might be due to the use of the drug.  The 
relationship in time is suggestive, e.g., confirmed by dechallenge.  An 
alternative explanation is less likely, e.g., concomitant drug(s) or 
concomitant disease(s). 
Certain 
An adverse event, which is listed as a possible adverse reaction and 
cannot be reasonably explained by an alternative explanation, e.g., 
concomitant drug(s) or concomitant disease(s).   
 
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8.1.4 
Severity 
Table 7: Definitions for Adverse Event Severity Gradings 
Grade 
Severity Rating 
Definition 
GRADE 1 
Mild 
Transient or mild discomfort (< 48 hours); no medical 
intervention/therapy required. 
GRADE 2 
Moderate 
Mild to moderate limitation in activity - some assistance may 
be needed; no or minimal medical intervention/therapy 
required. 
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. 
 
See Appendix 2 for full DMID Toxicity Tables. Above ratings should be used to estimate the grade 
for abnormalities NOT found elsewhere in the Toxicity Tables. 
8.2 
Reporting 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and non-
leading verbal questioning of the participant is the preferred method to inquire about AE 
occurrences. 
All Adverse events will be collected by the investigator from the time a participant signs the 
Informed Consent Form through to their Month 24 follow-up visit. The exception to this is Early 
Withdrawal participants who will only have SAEs collected from their time of Early Withdrawal to 
their Month 24 follow-up visit at the timepoints specified in the Flowchart (Section 1.2) and 
recorded in the CRF.   
Medical occurrences that begin after obtaining informed consent will be recorded as adverse 
events. If an adverse event started before signing of the informed consent, but is ongoing at trial 
start, it should be recorded as medical history.  If the pre-existing medical occurrence worsens 
during the trial, and adverse event will be recorded. 
All SAEs will be recorded and reported to the sponsor or designee within 24 hours of the 
information becoming known to the Investigator, as noted in the SAE reporting guidelines. The 
investigator will submit any updated SAE data to the sponsor within 24 hours of information 
becoming known to the investigator.  
The sponsor/investigator/designee will inform Regulatory Authorities and/or EC/IRB of all SAEs 
in accordance with local requirements and ICH guidelines for GCP. 
The sponsor/designee will forward Safety Notification letters to the Investigator for submission to 
the EC/IRB. 
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Investigators are not obligated to actively seek AE or SAE information in former trial participants. 
However, if the investigator learns of any SAE, including a death, at any time after a participant 
has been discharged from the trial, and he/she considers the event to be reasonably related to 
the trial treatment or trial participation, the investigator must promptly notify the sponsor, EC/IRB 
and regulatory authorities on an expedited basis in accordance with local requirements and ICH 
guidelines for GCP. 
8.2.1 
Follow up of Adverse Events 
All AEs will be followed until: 
• 
Satisfactory clinical resolution or stabilization; or 
• 
The end of the follow-up period; and  
• 
All queries on these AEs have been resolved.   
Certain long-term AEs cannot be followed until resolution within the setting of this protocol. In 
these cases follow-up will be the responsibility of the treating physician.  However, this will have 
to be agreed upon with the Sponsor Medical Monitor. 
The investigator is obligated to perform or arrange for the conduct of supplemental measurements 
and/or evaluations as medically indicated or as requested by Sponsor or representative to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may include 
additional laboratory tests or investigations, histopathological examinations, or consultation with 
other health care professionals.  Investigator should contact sponsor/designee to discuss 
appropriate medical follow-up if consultation required.  
If a participant dies during participation in the trial or during a recognized follow-up period, the 
investigator will provide sponsor/representative with a copy of any post-mortem findings including 
histopathology. 
New or updated information will be recorded in the originally completed CRF and submitted to 
sponsor within 24 hours of receipt per SAE reporting guidelines. 
8.2.2 
Clinical Laboratory Adverse Events 
Changes in the results of the Clinical Laboratory assessment results which the Investigator feels 
are clinically significant will be reported as adverse events.  It is the Investigators’ responsibility 
to review the results of all laboratory tests as they become available.  This review must be 
documented by the Investigators’ dated signature on the laboratory report.  For each abnormal 
laboratory test result, the Investigator needs to ascertain and document if this is a clinically 
significant change from baseline for that individual participant.  This determination, however, does 
not necessarily need to be made the first time an abnormal value is observed.  The Investigator 
may repeat the laboratory test or request additional tests to verify the results of the original 
laboratory tests.  If this laboratory value is determined by the Investigator to be a clinically 
significant change from baseline for that participant, it is considered to be an adverse event 
8.2.3 
Disease symptoms during Trial 
Symptoms of the disease under study (Tuberculosis) experienced by the participant while on the 
trial will be assessed by the investigator.  If the symptom has: 
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worsened while the participant is in the trial; and  
the investigator assesses it as clinically significant; 
it will be recorded as an adverse event.  
If there is: 
no change; and  
the investigator assesses the symptom as due to the participant’s TB; and  
not clinically significant; 
it will not be recorded as an AE and this will be noted in the participant’s source documentation.  
All TB related symptoms that meet SAE criteria will be recorded and reported as a SAE. 
8.2.4 
Overdose 
Overdose of IMP experienced by the participant while on the trial, will be assessed by the 
Investigator to determine whether the overdose led to an Adverse Event, including if the taking of 
the suspect medicine led to suicidal intention and subsequent overdose of the suspect medicine, 
or other medication. In this case it will be recorded as an adverse event. If it does not lead to an 
Adverse Event, it will not be recorded as an AE and this will be noted in the participant’s source 
documentation. 
8.2.5 
Drug Interaction 
If the Investigator becomes aware that the participant has experienced a drug interaction which 
has resulted in an adverse event, it will be recorded as an adverse event. 
8.2.6 
Pregnancy 
The Investigator will immediately notify the sponsor of any pregnancy that is discovered during 
IMP administration or which started during IMP administration.  Pregnancy forms will be 
completed for all pregnancies reported during the clinical trial, as defined below. In addition, the 
Investigator will report to the sponsor follow up information regarding the outcome of the 
pregnancy, including perinatal and neonatal outcome.  Infants will be followed for 6 months.   
All women of childbearing potential will be instructed to contact the Investigator immediately if 
they suspect they might be pregnant (for example, missed or late menses) for the following 
time-periods: 
• 
During the trial 
• 
Within 6 months after the last dose of IMP 
If pregnancy is suspected while the participant is receiving IMP, the IMP will be withheld 
immediately until the result of the pregnancy test is known.  If pregnancy is confirmed, the IMP 
will be permanently discontinued in an appropriate manner and the participant withdrawn from 
the trial. Protocol-required procedures for trial discontinuation and follow up will be performed 
unless contraindicated by the pregnancy. 
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Should the female partner of a male participant become pregnant during the trial or in 12 weeks 
after the completion of IMP and the Investigator becomes aware that this situation has occurred, 
the sponsor may request information from the female partner on her pregnancy history and on 
the current pregnancy and birth. 
Pregnancy reporting will follow the same timelines for a SAE (see above). Instructions and 
forms will be provided separately. SAE reporting will also occur if the pregnancy outcome is a 
congenital anomaly.  This will follow the reporting procedures described above for SAE reporting. 
8.3 
Monitoring for Specific Toxicities  
Monitoring for specific toxicities is based upon target organs as defined in preclinical toxicity 
studies Investigator’s Brochures[8, 15] and Package Inserts.[19, 20, 22, 40] 
AEs still ongoing at the end of treatment in the trial will be followed until satisfactory clinical 
resolution or stabilization or until the end of the follow-up period and until all queries on these AEs 
have been resolved.  Grade 3 and grade 4 laboratory abnormalities and laboratory abnormalities 
considered clinically significant should be followed until satisfactory resolution or stabilization. 
Note: For Grade 3 or 4 laboratory toxicities, participants should have a confirmatory 
measurement within 48 hours where possible. The recommendations for managing participants 
below assumes the laboratory abnormalities of concern have been confirmed. 
8.3.1 
Neurological 
Participants with co-administration of a serotonergic agent, including anti-depressants, should be 
monitored closely for signs of serotonin syndrome.  The Investigator should determine whether 
the full regimen or the concomitant agent should be discontinued for those who experience signs 
or symptoms of serotonin syndrome such as cognitive dysfunction, hyperrexia, hyperreflexia and 
incoordination. 
8.3.2 
Musculoskeletal System and Cardiac Muscle Myalgia 
Grade 2 (muscle tenderness at site other than sites of injection and/or venipuncture or with 
moderate impairment of activity) or Grade 3 (severe muscle tenderness with marked impairment 
of activity) or Grade 4 (frank myonecrosis): 
Participants with Grade 2 signs and symptoms should be followed closely. Participants with Grade 
3 or 4 signs and symptoms should be discussed with the Sponsor Medical Monitor to consider 
pausing trial medication, pending further evaluation. 
8.3.3 
Cardiac Rhythm Disturbances 
Cardiac rhythm disturbances that are Grade 3 (recurrent, persistent, symptomatic arrhythmia 
requiring treatment) or Grade 4 (unstable dysrhythmia requiring treatment): 
Participants should be monitored closely.  The Investigator should discuss with the Sponsor 
Medical Monitor to consider pausing the full regimen, pending further evaluation. 
QTc prolongation  
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If QTcF is equal to or greater than 500 msec, the ECG should be repeated and serum electrolytes 
should be evaluated. If the second ECG also has a QTcF of > 500 msec, the Sponsor Medical 
Monitor should be consulted to consider pausing the full regimen, pending further evaluation. 
New left bundle branch block (LBBB) or Mobitz type 2 or complete heart block. Recordings with 
artifacts that interfere with the interpretation of the ECG should be repeated to confirm the 
findings. If the finding is from the centralized ECG machine reading the result is to be checked 
and confirmed by the Investigator.  If this is confirmed by the Investigator, dosing is to be paused 
until the reading has been confirmed by the central cardiologist and the participant is to be treated 
per the Investigator’s clinical judgment. If it is confirmed by the central cardiologist, the participant 
is to be withdrawn from the full regimen.  Contact Sponsor Medical Monitor to review. Investigator 
should consider participants with confirmed Grade 3 or 4 elevations of lipase for temporary or 
permanent discontinuation from the full regimen. 
8.4 
Safety Monitoring by Data Monitoring Committee 
A DSMC will be appointed for the trial. The primary responsibility of the DSMC will be to act in an 
advisory capacity to the Sponsor to safeguard the interests of trial participants by monitoring 
participant safety, assess participant risk versus benefit, and assess data quality and general 
evaluation of the trial progress. Its activities will be delineated in a DSMC charter that will define 
the membership, responsibilities and the scope and frequency of data reviews. The DSMC will 
operate on a conflict-free basis independently of the Sponsor and the trial team. It will comprise 
at least 3 voting members that include at least 2 clinicians and one statistician.  The DSMC may 
have an organizational meeting prior to commencement of the trial. The DSMC will have meetings 
where it will review unblinded data during a closed session. These meetings will be planned at 
regular intervals. The Sponsor or the DSMC may convene ad hoc meetings based on rates of 
SAEs and/or to review results of the futility analysis or if safety concerns arise during the trial.  
After its assessment, the DSMC will recommend to the Sponsor continuation, modification or 
termination of the clinical trial.  
9.0 
Statistical Analysis 
The statistical analysis plan (SAP), which will contain details of the analyses specified in this 
section, will be written and signed off prior to first patient randomized. 
9.1 
Analysis Populations 
There will be three main analyses of the primary efficacy endpoint: An intent to treat (ITT) analysis; 
a modified intent to treat (mITT) analysis and a per protocol (PP) analysis 
• 
The ITT population is defined as all randomized patients excluding late screening failures. 
Late screening failures are patients withdrawn from treatment because they were found 
to be ineligible (late exclusions from the study), based on data collected prior to 
randomization. 
• 
The mITT population is defined as the ITT population with extra exclusions (described in 
the SAP). 
• 
The PP population is defined as the mITT population with extra exclusions (described in 
the SAP). 
• 
The mITT analysis will be considered primary, with consistent findings required from the 
other main analysis populations to support the primary conclusion. 
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9.2 
Sample Size 
For the primary endpoint, time-to-culture conversion at 8 weeks,150 participants per arm (DS-TB 
patients) will provide at more than 90% power (5% 2-sided significance) to detect a hazard ratio 
(HR) of at least 2 assuming 50% of control participants are culture negative by 8 weeks. If only 
25% of the control arm remain culture positive at 8 weeks, then this sample size will still retain 
more than 90% power to detect a HR of least 2.  This sample size also allows for one planned 
interim analysis of the primary endpoint (See Section 9.4.1) 
For the key secondary endpoint of clinical outcome at 12 months from randomization, 150 patients 
per arm will provide 74% power based on assumptions using data from the largest most recent 
and completed phase 3 TB treatment trial which used the same control arm.[41]  That is, assuming 
16% unfavourable (see Section 9.4.2) in the control arm and 13% unassessable (see Section 9.6) 
at 52 weeks post randomization. A 12% margin of non-inferiority was chosen to preserve at least 
75% of the estimated control arm effect against placebo (estimated to be 54%)[41, 42] which is 
considered an acceptable proportion on which to declare non-inferiority of the test regimen. 
9.3 
Interim Analyses 
There is no planned interim analysis in this trial. 
9.4 
Primary and Secondary Efficacy Endpoint Analysis 
9.4.1 
Primary Efficacy Endpoint, Time to Culture Conversion at 8 Weeks 
The primary analysis will be conducted using culture results from liquid culture (MGIT) media. 
Patients will be classified as being culture positive, culture negative, dead or unassessable at 
8 weeks.  The proportion culture negative will be those classified as being culture negative divided 
by the total considered culture negative, culture positive or have died. This proportion will be 
estimated from the Kaplan Meier estimates from the time to culture conversion to negative status 
analysis and groups compared using a hazard ratio and 95% confidence interval. 
Non-inferiority of the key secondary endpoint of clinical outcome will be assessed using the upper 
bound of the one-sided 97.5% confidence interval for the difference between the proportion of 
patients who are classified as having an unfavourable status on the intervention less the control 
regimen.  If the upper bound of the one-sided 97.5% confidence limit for this difference in 
proportions is less than 12% (the margin of inferiority) the intervention will be considered to be 
non-inferior to the control arm. 
9.4.2 
Key Secondary Efficacy Endpoint, Clinical outcome at 52 Weeks from 
Randomization  
For the key secondary endpoint of clinical outcome (bacteriologic failure or relapse or clinical 
failure), patients will be classified as having a favourable, unfavourable or unassessable outcome 
status which will be defined in detail in the SAP.  In general, participants achieving and maintaining 
culture negative status without any additional treatment will be considered favourable; participants 
who fail on treatment or relapse in follow-up will be considered unfavourable and participants who 
are not assessable (and who have not already been declared as unfavourable) will be considered 
unassessable and excluded from the analysis. 
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9.4.3 
Other Secondary Efficacy Endpoints 
The secondary efficacy endpoints and analyses are as follows are: 
• 
Clinical outcome (bacteriologic failure or relapse or clinical failure) at 104 weeks from the start 
of therapy.  
• 
Proportion of participants with sputum culture conversion to negative status in liquid culture 
(MGIT) at 4, 6, 12 and 17 weeks to be explored as a potential biomarker of outcome at 
52 weeks from start of therapy. 
• 
Change from baseline in weight will be summarised and presented. 
• 
Proportion of participants experiencing a change from baseline in TB symptoms. 
• 
Change from baseline in Patient Reported Health Status will be summarised and presented. 
9.5 
Safety and Tolerability Assessments 
• 
The incidence of all-cause mortality will be summarized. 
• 
All adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) and will be presented by Preferred Term within each MedDRA System Organ 
Class (SOC). 
• 
Treatment-emergent adverse events (TEAEs) are defined as AEs which started at or after the 
first administration of IMP and includes those events started prior to the first administration of 
IMP but which worsened after the first intake.  Adverse events starting after the last 
administration of IMP until the last scheduled visit/assessment/measurement will be regarded 
as treatment-emergent. 
• 
The incidence of the following events will be summarized for further medical analysis: 
o Incidence of TEAEs; 
o Incidence of TEAEs by Severity; 
o Incidence of TEAEs by DMID toxicity grade; 
o Incidence of Drug-Related TEAEs; 
o Incidence of Serious TEAEs; 
o Incidence of TEAEs Leading to Early Withdrawal; 
o Incidence of TEAEs leading to Death. 
 
9.6 
Pharmacokinetics 
For each analyte and each scheduled sampling time/window, the plasma concentration will be 
summarized by descriptive statistics including the mean, SD, coefficient of variation (CV), median, 
minimum, maximum, geometric mean and geometric CV (%). 
In addition, mean and/or median concentration-versus-time graphs will be provided, with error 
bars and/or scatter plots as appropriate. 
Plasma concentrations from sparse sampling will be used to update existing population PK 
models and derive exposure metrics (e.g., Cmin, Cmax, AUC) for bedaquiline and its M2 
metabolite, pretomanid, moxifloxacin, and pyrazinamide. Effects of baseline covariates on 
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exposure will be assessed; so, too, will the effects of con-medications including ART, as feasible. 
Data from other trials may be included to enhance the model-based analysis. Detailed plans for 
the PopPK analysis will be outlined in a separate modeling plan, and results will be reported in 
separate modeling report. 
9.7 
Pharmacokinetics/Pharmacodynamics 
Relationships will be explored between drug exposure and efficacy and safety endpoints. These 
exploratory PK/PD analyses may include HIV status as a covariate. Planning details and results 
will be included in the separate modeling plan and report. 
10.0 Records Management 
10.1 Data Collection 
All relevant CRF/eCRF pages will be completed for each participant who receives any amount of 
IMP, depending on visits attended.  For screening failure participants, specific eCRF pages will 
be completed as described in the eCRF Completion Guidelines. For participants who are 
prematurely withdrawn, all the visits the participant attended including withdrawal and follow-up 
visits need to be completed. 
10.2 Source Documents 
Source documents are defined as all information in original records and certified copies of original 
records of clinical findings, observations, or other activities in a clinical trial necessary for the 
reconstruction and evaluation of the trial.  Source documents will include, but are not limited to, 
progress notes, in-Patient hospital records, electronic data, screening logs, and recorded data 
from automated instruments. 
All source documents pertaining to this trial will be maintained by the Investigators.  The 
Investigator 
has 
to 
permit 
trial 
related 
monitoring, 
audits, 
Independent 
Ethics 
Committee/Institutional Review Board (EC/IRB) review and regulatory inspections providing 
authorized personnel direct access to source documents, including documents required to confirm 
inclusion/exclusion and relevant in-Patient records while participants is on trial treatment. 
10.3 File Management at the Trial Centre 
It is the responsibility of the Investigators to ensure that the trial center files are maintained in 
accordance with International Good Clinical Practice Guidelines and the ethical principles that 
have their origin in the Declaration of Helsinki. 
10.4 Records Retention at the Trial Centre 
The Investigator is obliged to retain records and data from the trial for safety reasons and for audit 
and inspection subsequent to trial completion.  The essential documents should be retained for 
not less than 2 years after the last approval of a marketing application and until there are no 
pending or contemplated marketing applications or at least 2 years have elapsed since the formal 
discontinuation of clinical development of the IMP.  Investigator should notify sponsor/designees 
prior to destroying any records pertaining to the trial. 
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11.0 Quality Control and Assurance  
11.1 Site Procedures 
The Investigator undertakes to perform the clinical trial in accordance with this protocol, local 
regulations, International GCP, and the ethical principles that have their origin in the Declaration 
of Helsinki. 
The Investigator undertakes to complete the CRFs according to the Sponsor’s requirements, in a 
timely, accurate and legible manner. CRF entries will be verifiable to source documentation other 
than the CRF. 
Site Standard Operating Procedures will be adhered to for all clinical and bioanalytical activities 
relevant to the quality of the trial.  Participant compliance will be monitored throughout the trial. 
The Investigator will sign and date any analysis results (e.g., laboratory, ECG, etc.) to verify that 
the results have been reviewed. 
The Investigator may appoint other sub-investigators to assist with the trial. However, the 
Investigator maintains responsibility for the trial and will supervise the sub-investigators. Written 
EC/IRB approval of the trial will be obtained prior to involvement in the trial. 
The Investigator will ensure that all site personnel are adequately trained in GCP, local 
regulations, the protocol, IBs/package inserts and all trial procedures and requirements. 
11.2 Monitoring 
The Investigator is responsible for the validity of all data collected at the clinical site and must 
accept the various monitoring procedures employed by the Sponsor.  The purpose of monitoring 
is to verify that the rights and well-being of human participants are protected; that trial data are 
accurate, complete and verifiable with source data; and that the trial is conducted in compliance 
with the protocol, International GCP, the ethical principles that have their origin in the Declaration 
of Helsinki and the applicable regulatory requirements.  
Monitors assigned by the Sponsor will conduct regular site visits before, during and after the trial 
for the purpose of monitoring various aspects of the trial, and to assure appropriate conduct of 
the trial in accordance with ICH GCP.  Visits will take place usually within a predetermined interval, 
but this may vary during the course of the trial.  The Investigator and site staff will allow the trial 
monitor and authorized representatives of the Sponsor to (1) inspect all CRFs, written informed 
consent documents and corresponding source documents (e.g., original medical records), patient 
records and laboratory raw data, site SOPs, training records, facilities and other trial related 
systems/processes, and (2) access clinical supplies, dispensing and storage areas.  The 
Investigator and site staff should also (1) agree to assist with monitoring activities if requested 
and (2) provide adequate time and space for monitoring visits.  
The monitor will query any missing, confusing, spurious, or otherwise ambiguous data with the 
Investigator.  All queries should be resolved in a timely manner.  A monitoring log will be 
maintained recording each visit, the reason for the visit, the monitor’s signature and Investigator 
or designee’s confirmation signature. 
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11.3 Protocol Deviations 
A protocol deviation is any noncompliance with the clinical trial protocol, GCP, or Monitoring Plan 
requirements. The noncompliance may be either on the part of the participant, the investigator, 
or the trial site staff. As a result of deviations, corrective actions are to be developed by the site 
and implemented promptly.  
It is the responsibility of the site to use continuous vigilance to identify and report deviations. All 
deviations must be addressed in trial source documents and reported to Sponsor/designee. 
Protocol deviations must be sent to the local IRB per their guidelines. The site PI/trial staff is 
responsible for knowing and adhering to their IRB requirements. 
11.4 Auditing 
For the purpose of compliance with International GCP and regulatory agency guidelines, it may 
be necessary for Sponsor-authorized Quality Assurance personnel and/or authorized personnel 
from an external regulatory agency to conduct an audit or inspection of the investigational site.  
The purpose of an audit is to assess the quality of data with regard to accuracy, adequacy and 
consistency, and to assure that trials are in accordance with the guidelines.  Having the highest 
quality data from trials is an essential aspect of drug development.  
The Investigator and site staff will be given sufficient notice to prepare for such visits, which will 
usually last between one and two days and may be conducted at any stage during the trial.  The 
audit will involve the review of all trial-related documentation required by GCP to be maintained 
by each site; drug storage, dispensing and return; all trial-related supplies; and source documents 
against the CRFs to assure the adequacy and accuracy of the information which has been 
recorded, including the verification of any AEs which have occurred. The auditors or inspectors 
may also review site SOPs, training records, site facilities and other trial related 
systems/processes. 
In the event of the site being notified of a Regulatory Inspection, the Sponsor will help with 
preparation.  It is essential that the Sponsor be notified of the inspection as soon as possible. 
12.0 Ethics and Regulatory 
12.1 Basic Principles 
This research will be carried out in accordance with International GCP, the ethical principles that 
have their origin in the Declaration of Helsinki and the applicable regulatory requirements. 
12.2 Independent Ethics Committee/Institutional Review Board (EC/IRB) Review 
The protocol and required trial related documents will be reviewed by the sites respective EC/IRB.  
The trial will not start until the EC/IRB has approved the protocol, written informed consent, any 
written information to be provided to the participant or any modification thereof, plus any other 
trial related documents required for review.  The EC/IRB shall be constituted and shall operate in 
accordance with International GCP, the ethical principles that have their origin in the Declaration 
of Helsinki. The Investigator will maintain an accurate and complete record of all submissions 
made to, and responses from the IRB/EC.  The records should be filed in the Investigator’s Trial 
File, and copies will be sent to the Sponsor. 
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12.3 Regulatory Authorities 
The Regulatory Authorities will receive the protocol, amendments, reports on SAEs, and the 
Integrated Clinical Trial Report according to national regulations.  As required by local legislation, 
written approval will be obtained from the Regulatory Authorities prior to commencement of the 
trial and implementation of e.g. amendments as applicable. 
12.4 Informed Consent 
Written informed consent will be obtained from all participants (or legally acceptable 
representative) before any trial-related procedures (including any screening or pre-treatment 
procedures) are performed.  Investigators may discuss the availability of the trial and the 
opportunity for entry with a potential participant without first obtaining consent.  However, informed 
consent must be obtained and documented prior to initiation of any procedures that are performed 
solely for the purpose of determining eligibility for research, including withdrawal from current 
medication(s).  When this is done in anticipation of, or in preparation for, the research, it is 
considered to be part of the research. 
The Investigators have both ethical and legal responsibility to ensure that each participant being 
considered for inclusion in this trial is given a full explanation of the protocol.  Participants must 
be informed that their participation is voluntary.  The investigator or his/her representative will 
explain the nature of the trial to the participant or his/her legally authorized representative and 
answer all questions regarding the trial. This shall be documented on a written informed consent 
form that shall be approved by the same EC/IRB responsible for approval of this protocol.  Each 
informed consent form shall include the elements required by the international GCP and must 
adhere to the ethical principles that have their origin in the Declaration of Helsinki.  
The trial will be included and updated in the appropriate Country registry and referenced in the 
informed consent forms (ICF). 
Once the appropriate essential information has been provided to the participant and fully 
explained by the Investigators (or qualified designees) and it is felt that the participant 
understands the implications of participating, the EC/IRB approved written informed consent form 
will be signed and dated by both the participant and the person obtaining consent (Investigators 
or designees), and by any other parties required by the EC/IRB. Ongoing participants must be re-
consented to the most current version of the ICF(s) during their participation in the trial. 
The original signed informed consent form will be kept with the trial records and a copy of signed 
informed consent form will be provided to the participant or the participant’s legally authorized 
representative.  Another copy of the signed informed consent form and a source document 
identifying the trial and recording the dates of participation will be placed in the participant’s 
medical record. 
The monitor will inspect the original completed consent form(s) for all participants. 
12.5 Confidentiality 
All site staff, the Sponsor, and any sponsor representatives will preserve the confidentiality of all 
participants taking part in the trial, in accordance with International GCP, applicable local 
legislation/regulations.  Participant to the requirement for source data verification by the trial 
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personnel by reference to the participant’s notes, confidentiality of all participant identities will be 
maintained.  Unique identifiers will be used on the CRF and in all trial correspondence, as 
permitted.  No material bearing a participant’s name will be kept on file by the Sponsor. The written 
informed consent will contain a clause granting permission for review of the participants’ source 
data by the sponsor or designees. 
 
 
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13.0 Publication Policy 
The definition of publication for this purpose is any public presentation of the data emerging from 
this trial.  
All unpublished information given to the Investigator by the Sponsor shall not be published or 
disclosed to a third party, other than to the responsible EC/IRB, within the understanding of the 
confidentiality of their nature, without the prior written consent of the Sponsor. 
Results of this research will be submitted for publication as soon as feasible upon completion of 
the trial in the form of a joint publication(s) between Sponsor and Investigator(s), including site 
clinical and laboratory investigators, as appropriate. Publication and authorship will be in accord 
with the International Association of Journal Editors.[43]  
Because the Trial is funded, in whole or in part, by the Bill and Melinda Gates Foundation (the 
“Foundation”), all peer-reviewed published research relating to the Trial must comply with the 
Foundation’s 
Open 
Access 
Policy 
as 
described 
from 
time 
to 
time 
at 
http://www.gatesfoundation.org/How-We-Work/General-Information/Open-Access-Policy. 
Specifically, (a) all peer-reviewed published research relating to the Trial must be submitted for 
publication by TB Alliance through the Chronos Open Access Publishing Service established by 
the Foundation to ensure the immediate and unrestricted access and reuse of all peer-reviewed 
published research funded, in whole or in part, by the Foundation without any embargo period, 
and (b) all data underlying the peer-reviewed published research results must be immediately 
made accessible and open to the public in accordance with the Foundation’s Open Access Policy. 
14.0 Protocol Amendment Policy 
Any change to the protocol will be effected by means of a protocol amendment.  Any changes 
which affect participant safety or welfare will be submitted to the EC/IRB and Regulatory 
Authorities prior to implementation.  The Investigator, EC/IRB, and Sponsor must agree on all 
amendments.  No amendment will be implemented until approved by the relevant Authorities 
and/or EC/IRB and signed by all required parties.  Exceptions to this are when the Investigator 
considers that the participant’s safety is compromised.  
Protocol amendments detailing minor administrative changes should be submitted by the 
Investigator to the EC/IRB and Regulatory Authorities, either for notification purposes or approval 
as appropriate. 
15.0 Sponsor, Financial Aspects, Insurance and Indemnity 
The trial sponsor is the Global Alliance for TB Drug Development (TB Alliance).  The TB Alliance 
is a not for profit, product development partnership accelerating the discovery and development 
of new TB drugs that will shorten treatment, be effective against susceptible and resistant strains, 
be compatible with antiretroviral therapies for those HIV-TB participants currently on such 
therapies, and improve treatment of latent infection. 
The TB Alliance works with public and private partners worldwide.  It is committed to ensuring 
that approved new regimens are affordable, adopted and available to those who need them. 
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The TB Alliance operates with funding mainly from the Bill & Melinda Gates Foundation, the 
Netherlands Ministry of Foreign Affairs (DGIS), the United Kingdom Department for International 
Development (DFID), and the United States Agency for International Development (USAID). 
The participants will not receive any incentives for their involvement in the trial.  The Sponsor has 
made provision to reimburse the participants for out-of-pocket expenses such as travelling to and 
from the trial site and other miscellaneous costs as a result of their trial participation. 
The Sponsor certifies that it has liability insurance coverage for itself and will provide an 
associated certificate upon request.  The insurance does not relieve the Investigators of the 
obligation to maintain their own liability insurance as required by applicable law. The Sponsor 
does not assume any obligation for the medical treatment of other injuries and illnesses.
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16.0 References 
1. 
Maggi N, Pasqualucci CR, Ballotta R, Sensi P. Rifampicin: a new orally active rifamycin. 
Chemotherapy. 1966;11(5):285-292. 
2. 
Jindani A, Aber VR, Edwards EA, Mitchison DA. The early bactericidal activity of drugs in 
patients with pulmonary tuberculosis. Am Rev Respir Dis. 1980;121(6):939-949. 
3. 
Dietze R, Teixeira L, Rocha LM, Palaci M, Johnson JL, Wells C, et al. Safety and 
bactericidal activity of rifalazil in patients with pulmonary tuberculosis. Antimicrob Agents 
Chemother. 2001;45(7):1972-1976. 
4. 
Donald PR, Sirgel FA, Venter A, Parkin DP, Seifart HI, van de Wal BW, et al. Early 
bactericidal activity of antituberculosis agents. Expert Rev Anti Infect Ther. 2003;1(1):141-
155. 
5. 
Johnson JL, Hadad DJ, Boom WH, Daley CL, Peloquin CA, Eisenach KD, et al. Early and 
extended early bactericidal activity of levofloxacin, gatifloxacin and moxifloxacin in 
pulmonary tuberculosis. Int J Tuberc Lung Dis. 2006;10(6):605-612. 
6. 
Rustomjee R, Diacon AH, Allen J, Venter A, Reddy C, Patientia RF, et al. Early bactericidal 
activity and pharmacokinetics of the diarylquinoline TMC207 in treatment of pulmonary 
tuberculosis. Antimicrob Agents Chemother. 2008;52(8):2831-2835. 
7. 
Package insert: Sirturo.  Janssen Therapeutics, September 2014 Available at: 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/204384s000lbl.pdf. 
8. 
Investigator’s Brochure: TMC207 (bedaquiline).  Edition 10. Janssen Research and 
Development, 02 Dec 2016. 
9. 
Koul A, Dendouga N, Vergauwen K, Molenberghs B, Vranckx L, Willebrords R, et al. 
Diarylquinolines target subunit c of mycobacterial ATP synthase. Nat Chem Biol. 
2007;3(6):323-324. 
10. 
Andries K, Verhasselt P, Guillemont J, Gohlmann HW, Neefs JM, Winkler H, et al. A 
diarylquinoline drug active on the ATP synthase of Mycobacterium tuberculosis. Science. 
2005;307(5707):223-227. 
11. 
Huitric E, Verhasselt P, Andries K, Hoffner SE. In vitro antimycobacterial spectrum of a 
diarylquinoline ATP synthase inhibitor. Antimicrob Agents Chemother. 2007;51(11):4202-
4204. 
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12. 
Koul A, Vranckx L, Dendouga N, Balemans W, Van den Wyngaert I, Vergauwen K, et al. 
Diarylquinolines are bactericidal for dormant mycobacteria as a result of disturbed ATP 
homeostasis. J Biol Chem. 2008;283(37):25273-25280. 
13. 
Nuermberger E, Rosenthal I, Tyagi S, Williams KN, Almeida D, Peloquin CA, et al. 
Combination chemotherapy with the nitroimidazopyran PA-824 and first-line drugs in a 
murine model of tuberculosis. Antimicrob Agents Chemother. 2006;50(8):2621-2625. 
14. 
Nuermberger E, Tyagi S, Tasneen R, Williams KN, Almeida D, Rosenthal I, et al. Powerful 
bactericidal and sterilizing activity of a regimen containing PA-824, moxifloxacin, and 
pyrazinamide in a murine model of tuberculosis. Antimicrob Agents Chemother. 
2008;52(4):1522-1524. 
15. 
Investigator's Brochure: Pretomanid (PA-824).  Global Alliance for TB Drug Development, 
22 December 2016. 
16. 
Stover CK, Warrener P, VanDevanter DR, Sherman DR, Arain TM, Langhorne MH, et al. 
A small-molecule nitroimidazopyran drug candidate for the treatment of tuberculosis. 
Nature. 2000;405(6789):962-966. 
17. 
Lenaerts AJ, Gruppo V, Marietta KS, Johnson CM, Driscoll DK, Tompkins NM, et al. 
Preclinical testing of the nitroimidazopyran PA-824 for activity against Mycobacterium 
tuberculosis in a series of in vitro and in vivo models. Antimicrob Agents Chemother. 
2005;49(6):2294-2301. 
18. 
Tyagi S, Nuermberger E, Yoshimatsu T, Williams K, Rosenthal I, Lounis N, et al. 
Bactericidal activity of the nitroimidazopyran PA-824 in a murine model of tuberculosis. 
Antimicrob Agents Chemother. 2005;49(6):2289-2293. 
19. 
Package insert: Moxifloxacin.  MacLeods Pharmaceuticals Ltd., January 2014. 
20. 
Package insert: Pyrazinamide.  MacLeods Pharmaceuticals Ltd., November 2012. 
21. 
Zhang Y, Mitchison D. The curious characteristics of pyrazinamide: a review. Int J Tuberc 
Lung Dis. 2003;7(1):6-21. 
22. 
Package insert: HRZE Combination Tablets.  MacLeods Pharmaceuticals Ltd., September 
2011. 
23. 
World Health Organization. Global tuberculosis report 2012.  2015. WHO Press, Geneva, 
Switzerland. 
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24. 
Pym AS, Diacon AH, Tang S-J, Conradie F, Danilovits M, Chuchottaworn C, et al. 
Bedaquiline safety data in a broad patient population treated for drug-resistant TB 
including XDR-TB (C209 trial). Tuberculosis. 2016;47:394-402. 
25. 
Lee M, Lee J, Carroll MW, Choi H, Min S, Song T, et al. Linezolid for treatment of chronic 
extensively drug-resistant tuberculosis. N Engl J Med. 2012;367(16):1508-1518. 
26. 
A Phase 3 Trial Assessing the Safety and Efficacy of Bedaquiline Plus PA-824 Plus 
Linezolid in Subjects With Drug Resistant Pulmonary Tuberculosis. ClinicalTrials.gov,  
Available at: https://www.clinicaltrials.gov/ct2/show/NCT02333799, Updated 28 February 
2017. 
27. 
Mdluli K, Nuermberger E. Pre-Clinical Drug Combination Trials to Identify Novel Regimens 
for TB.  2009. in Recent Advances in TB Drug Development Symposium. 40th Union World 
Conference, International Union Against TB and Lung Disease. Cancun, Mexico. 
28. 
Tasneen R, Li SY, Peloquin CA, Taylor D, Williams KN, Andries K, et al. Sterilizing activity 
of novel TMC207- and PA-824-containing regimens in a murine model of tuberculosis. 
Antimicrob Agents Chemother. 2011;55(12):5485-5492. 
29. 
Singh R, Manjunatha U, Boshoff HI, Ha YH, Niyomrattanakit P, Ledwidge R, et al. PA-824 
kills nonreplicating Mycobacterium tuberculosis by intracellular NO release. Science. 
2008;322(5906):1392-1395. 
30. 
Manjunatha U, Boshoff HI, Barry CE. The mechanism of action of PA-824: Novel insights 
from transcriptional profiling. Commun Integr Biol. 2009;2(3):215-218. 
31. 
Manjunatha UH, Boshoff H, Dowd CS, Zhang L, Albert TJ, Norton JE, et al. Identification 
of a nitroimidazo-oxazine-specific protein involved in PA-824 resistance in Mycobacterium 
tuberculosis. Proc Natl Acad Sci U S A. 2006;103(2):431-436. 
32. 
Nuermberger E, Tyagi S, Williams KN, Rosenthal I, Bishai WR, Grosset JH. Rifapentine, 
moxifloxacin, or DNA vaccine improves treatment of latent tuberculosis in a mouse model. 
Am J Respir Crit Care Med. 2005;172(11):1452-1456. 
33. 
Tasneen R, Betoudji F, Tyagi S, Li SY, Williams K, Converse PJ, et al. Contribution of 
Oxazolidinones to the Efficacy of Novel Regimens Containing Bedaquiline and 
Pretomanid in a Mouse Model of Tuberculosis. Antimicrob Agents Chemother. 
2015;60(1):270-277. 
34. 
Diacon AH, Dawson R, du Bois J, Narunsky K, Venter A, Donald PR, et al. Phase II dose-
ranging trial of the early bactericidal activity of PA-824. Antimicrob Agents Chemother. 
2012;56(6):3027-3031. 
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35. 
Burman WJ, Goldberg S, Johnson JL, Muzanye G, Engle M, Mosher AW, et al. 
Moxifloxacin versus ethambutol in the first 2 months of treatment for pulmonary 
tuberculosis. Am J Respir Crit Care Med. 2006;174(3):331-338. 
36. 
Rustomjee R, Lienhardt C, Kanyok T, Davies GR, Levin J, Mthiyane T, et al. A Phase II 
study of the sterilising activities of ofloxacin, gatifloxacin and moxifloxacin in pulmonary 
tuberculosis. Int J Tuberc Lung Dis. 2008;12(2):128-138. 
37. 
Conde MB, Efron A, Loredo C, De Souza GR, Graca NP, Cezar MC, et al. Moxifloxacin 
versus ethambutol in the initial treatment of tuberculosis: a double-blind, randomised, 
controlled phase II trial. Lancet. 2009;373(9670):1183-1189. 
38. 
Dorman SE, Johnson JL, Goldberg S, Muzanye G, Padayatchi N, Bozeman L, et al. 
Substitution of moxifloxacin for isoniazid during intensive phase treatment of pulmonary 
tuberculosis. Am J Respir Crit Care Med. 2009;180(3):273-280. 
39. 
Investigator's Brochure: Bayer HealthCare AG, moxifloxacin.  01 October 2011. 
40. 
Package insert: HR Combination Tablets.  MacLeods Pharmaceuticals Ltd., September 
2011. 
41. 
Gillespie SH, Crook AM, McHugh TD, Mendel CM, Meredith SK, Murray SR, et al. Four-
month moxifloxacin-based regimens for drug-sensitive tuberculosis. N Engl J Med. 
2014;371(17):1577-1587. 
42. 
Tiemersma EW, van der Werf MJ, Borgdorff MW, Williams BG, Nagelkerke NJ. Natural 
history of tuberculosis: duration and fatality of untreated pulmonary tuberculosis in HIV 
negative patients: a systematic review. PLoS One. 2011;6(4):e17601. 
43. 
Recommendations for the Conduct, Reporting, Editing, and Publication of Scholarly work 
in Medical Journals.  Available at: http://www.icmje.org/icmje-recommendations.pdf, 
Updated December 2016. 
 
 
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Appendices 
Appendix 1: The IUATLD Scale 
The IUATLD scale proposes five groups for reporting the results of reading smears for acid fast 
bacilli. They should be recorded as follows: 
FINDING 
RECORDING 
No acid-fast bacilli found in at least 100 fields 
negative 
1 to 9 acid-fast bacilli per 100 fields 
scanty positive 
10 to 99 acid-fast bacilli per 100 fields 
+ 
1 to 10 acid-fast bacilli per field in at least 50 
fields 
++ 
More than 10 acid-fast bacilli per field in at least 
20 fields 
+++ 
Reference: The Public Health Service National Tuberculosis Reference Laboratory and the 
National Laboratory Network. Minimum Requirements, Role and Operation in a Low-Income 
Country. International Union Against Tuberculosis and Lung Disease 1998. 
 
 
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Appendix 2: Division of Microbiology and Infectious Disease (DMID) Toxicity Table 
Source:  U.S. National Institute of Allergy and Infectious Diseases, DMID, November 2007 (Draft) 
ABBREVIATIONS:  Abbreviations utilized in the Table: 
ULN = Upper Limit of Normal 
LLN = Lower Limit of Normal 
Rx  = Therapy 
Req = Required 
Mod = Moderate 
IV  = Intravenous 
ADL = Activities of Daily Living 
Dec = Decreased 
 
ESTIMATING SEVERITY GRADE 
For abnormalities NOT found elsewhere in the Toxicity Tables use the scale below to estimate 
grade of severity: 
Grade 
Severity Rating 
Definition 
GRADE 1 
Mild 
Transient or mild discomfort (< 48 hours); no medical 
intervention/therapy required. 
GRADE 2 
Moderate 
Mild to moderate limitation in activity - some assistance may be 
needed; no or minimal medical intervention/therapy required. 
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. 
 
SERIOUS OR LIFE-THREATENING AEs 
ANY clinical event deemed by the clinician to be serious or life-threatening should be considered 
a grade 4 event. Clinical events considered to be serious or life-threatening include, but are not 
limited to: seizures, coma, tetany, diabetic ketoacidosis, disseminated intravascular coagulation, 
diffuse petechiae, paralysis, acute psychosis, severe depression. 
COMMENTS REGARDING THE USE OF THESE TABLES 
• 
Standardized and commonly used toxicity tables (Division of Acquired Immune Deficiency 
Syndrome (AIDS), NCI’s Common Toxicity Criteria (CTC), and World Health Organization 
(WHO)) have been adapted for use by the DMID and modified to better meet the needs of 
participants in DMID trials. 
• 
For parameters not included in the following Toxicity Tables, sites should refer to the “Guide 
For Estimating Severity Grade” located above. 
• 
Criteria are generally grouped by body system. 
• 
Some protocols may have additional protocol specific grading criteria, which will supersede 
the use of these tables for specified criteria. 
 
 
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Appendix 3: Who Clinical Staging of HIV/AIDS for Adults and Adolescents  
Primary HIV Infection 
Asymptomatic 
Acute retroviral syndrome 
Clinical Stage 1 
Asymptomatic 
Persistent generalized lymphadenopathy 
Clinical Stage 2 
Moderate unexplained weight loss (<10% of presumed or measured body weight) 
Recurrent respiratory infections (sinusitis, tonsillitis, otitis media, and pharyngitis) 
Herpes zoster 
Angular cheilitis 
Recurrent oral ulceration 
Papular pruritic eruptions 
Seborrheic dermatitis 
Fungal nail infections 
Clinical Stage 3 
Unexplained severe weight loss (>10% of presumed or measured body weight) 
Unexplained chronic diarrhea for >1 month 
Unexplained persistent fever for >1 month (>37.6ºC, intermittent or constant) 
Persistent oral candidiasis (thrush) 
Oral hairy leukoplakia 
Pulmonary tuberculosis (current) 
Severe presumed bacterial infections (e.g., pneumonia, empyema, pyomyositis, bone 
or joint infection, meningitis, bacteremia) 
Acute necrotizing ulcerative stomatitis, gingivitis, or periodontitis 
Unexplained anemia (hemoglobin <8 g/dL) 
Neutropenia (neutrophils <500 cells/µL) 
Chronic thrombocytopenia (platelets <50,000 cells/µL) 
Clinical Stage 4 
HIV wasting syndrome 
Pneumocystis pneumonia 
Recurrent severe bacterial pneumonia 
Chronic herpes simplex infection (orolabial, genital, or anorectal site for >1 month or 
visceral herpes at any site) 
Esophageal candidiasis (or candidiasis of trachea, bronchi, or lungs) 
Extrapulmonary tuberculosis 
Kaposi sarcoma 
Cytomegalovirus infection (retinitis or infection of other organs) 
Central nervous system toxoplasmosis 
HIV encephalopathy 
Cryptococcosis, extrapulmonary (including meningitis) 
Disseminated nontuberculosis mycobacteria infection 
Progressive multifocal leukoencephalopathy 
Candida of the trachea, bronchi, or lungs 
Chronic cryptosporidiosis (with diarrhea) 
Chronic isosporiasis 
Disseminated mycosis (e.g., histoplasmosis, coccidioidomycosis, penicilliosis) 
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Recurrent nontyphoidal Salmonella bacteremia 
Lymphoma (cerebral or B-cell non-Hodgkin) 
Invasive cervical carcinoma 
Atypical disseminated leishmaniasis 
Symptomatic HIV-associated nephropathy 
Symptomatic HIV-associated cardiomyopathy 
Reactivation of American trypanosomiasis (meningoencephalitis or myocarditis) 
 
REF: World Health Organization. WHO Case Definitions of HIV for Surveillance and Revised Clinical Staging and Immunological 
Classification of HIV-Related Disease in Adults and Children; 2007 
Vital Signs 
The following abnormalities will be defined for vital signs: 
Abnormality Code 
Vital Signs Parameter 
 
Pulse 
DBP 
SBP 
RR 
Abnormalities on actual values 
“Abnormally low” 
≤ 50 bpm 
≤ 50 mmHg 
≤ 90 mm Hg 
<12 
Breaths per minute 
“Grade 1 or mild” 
- 
> 
90 
mmHg-
<100 mmHg 
> 140 mmHg-
<160 mmHg 
17-20 
Breaths per minute 
“Grade 2 or moderate” 
- 
≥ 100 mmHg-
<110 mmHg 
≥ 160 mmHg-
<180 mmHg 
21-25 
Breaths per minute 
“Grade 3 or severe” 
- 
≥ 110 mmHg 
≥ 180 mmHg 
>25 
Breaths per minute 
“Abnormally high or Grade 
4” 
≥ 120 bpm 
- 
- 
Intubation 
 
 
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Appendix 4: Cardiovascular Safety 
CARDIOVASCULAR 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Cardiac 
Rhythm 
 
asymptomatic, 
transient signs, 
no Rx required 
recurrent/persisten
t; symptomatic Rx 
required 
unstable dysrythmia; 
hospitalization and 
treatment required 
Hypertension 
transient increase > 
20 mm/Hg; no 
treatment 
recurrent, chronic 
increase > 
20mm/Hg. 
/treatment 
required 
acute treatment 
required; 
outpatient 
treatment or 
hospitalization 
possible 
end organ damage 
or hospitalization 
required 
Hypotension 
transient orthostatic 
hypotension with 
heart rate increased 
by <20 beat/min or 
decreased by <10 
mm Hg systolic BP, 
No treatment 
required 
symptoms due to 
orthostatic 
hypotension or 
BP decreased by 
<20 mm Hg 
systolic; 
correctable with 
oral fluid 
treatment 
requires IV fluids; 
no hospitalization 
required 
mean arterial 
pressure <60mm/ 
Hg or end organ 
damage or shock;   
requires 
hospitalization and 
vasopressor 
treatment 
Pericarditis 
minimal effusion 
mild/moderate 
asymptomatic 
effusion, no 
treatment 
symptomatic 
effusion; pain; 
EKG changes 
tamponade; 
pericardiocentesis or 
surgery required 
Hemorrhage, 
Blood Loss 
microscopic/occult 
mild, no 
transfusion 
gross blood loss; 
1-2 units 
transfused 
massive blood loss; 
> 3 units transfused 
All-important abnormalities from the ECG readings will be reported. 
The percentage of participants with increases in QTc of <30, 30-60, or > 60 ms from baseline will 
also be tabulated at each time point. 
Abnormality Code 
ECG parameter 
 
HR 
PR 
QRS 
QTcorrected 
Abnormalities on actual values 
“Abnormally low” 
≤ 50 bpm 
NAP 
≤ 50 ms 
- 
“Abnormally high” 
≥ 120 bpm 
≥ 210 ms 
≥ 120 ms 
- 
“]450 ms, 480 ms] 
- 
- 
- 
450 ms < QTc ≤ 480 ms 
“]480 ms, 500 ms] 
- 
- 
- 
480 ms < QTc ≤ 500 ms 
“More than 500 ms 
- 
- 
- 
QTc > 500 ms 
Abnormalities on changes from baseline 
“[30; 60] ms” 
- 
- 
- 
[30; 60] ms 
“> 60 ms” 
- 
- 
- 
> 60 ms 
 
 
 
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Appendix 5: Karnofsky Performance Status Scale Definitions Rating (%) Criteria 
Description 
% 
Able to carry on normal activity 
and to work; no special care 
needed. 
Normal no complaints; no evidence of disease. 
100 
Able to carry on normal activity; minor signs or 
symptoms of disease. 
90 
Normal activity with effort; some signs or symptoms 
of disease.  
80 
Unable to work; able to live at 
home 
and 
care 
for 
most 
personal needs; varying amount 
of assistance needed. 
Cares for self; unable to carry on normal activity or 
to do active work. 
70 
Requires occasional assistance, but is able to care 
for most of his personal needs. 
60 
Requires considerable assistance and frequent 
medical care.  
50 
Unable to care for self; requires 
equivalent of institutional or 
hospital care; disease may be 
progressing rapidly. 
Disabled; requires special care and assistance. 
40 
Severely disabled; hospital admission is indicated 
although death not imminent. 
30 
Very sick; hospital admission necessary; active 
supportive treatment necessary. 
20 
Moribund; fatal processes progressing rapidly. 
10 
Dead 
0 
 
Ref: Oxford Textbook of Palliative Medicine, Oxford University Press.  1993; 109. 
 
 
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Appendix 6: Tuberculosis Symptoms Profile 
 
 
 
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Appendix 7: Patient Reported Health Status Questionnaire  
 
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CONFIDENTIAL  
 
 
 
Protocol Number: 
NC-008 (B-Pa-M-Z) 
Title: 
An Open-Label, Partially Randomized Trial to Evaluate the Efficacy, 
Safety and Tolerability of a 4-month Treatment of Bedaquiline plus 
Pretomanid plus Moxifloxacin plus Pyrazinamide (BPaMZ) 
Compared to a 6-month Treatment of HRZE/HR (Control) in Adult 
Participants 
with 
Drug-Sensitive 
Smear-Positive 
Pulmonary 
Tuberculosis (DS-TB) and a 6-month Treatment of BPaMZ in Adult 
Participants with Drug Resistant, Smear-Positive Pulmonary 
Tuberculosis (DR-TB). 
Drug(s)/Combination(s): 
Bedaquiline tablets (B), pretomanid tablets (Pa), moxifloxacin 
tablets (M), pyrazinamide tablets (Z), HRZE tablets [isoniazid (H), 
rifampicin (R), pyrazinamide (Z) and ethambutol (E)] and HR tablets 
[isoniazid (H) plus rifampicin (R) combination tablets] 
Protocol Amendment 
Version/Date: 
V2.0 / 21 February 2018, Incorporating Amendment 1 
Protocol Name: 
SimpliciTB 
 
 
 
 
 
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Page 2 of 106 
 
PROTOCOL SIGNATURE PAGE
Protocol Title:  An Open-Label, Partially Randomized Trial to Evaluate the Efficacy, 
Safety and Tolerability of a 4-month Treatment of Bedaquiline plus Pretomanid plus 
Moxifloxacin plus Pyrazinamide (BPaMZ) Compared to a 6-month Treatment of 
HRZE/HR (Control) in Adult Participants with Drug-Sensitive Smear-Positive Pulmonary 
Tuberculosis (DS-TB) and a 6-month Treatment of BPaMZ in Adult Participants with 
Drug Resistant, Smear-Positive Pulmonary Tuberculosis (DR-TB). 
Protocol Number:  
NC-008 (B-Pa-M-Z) 
Protocol Date: 
V2.0 / 21 February 2018, Incorporating Amendment 1 
Protocol Name:  
SimpliciTB 
 
SPONSOR:
Global Alliance for TB Drug Development 
 
I agree to the terms of this trial protocol. 
 
 
 
 
 
 
Paul Bruinenberg MD, MBA 
Signature of Senior Medical Officer  
 
 
Printed Name 
 
 
40 Wall Street, 24th Floor 
New York, NY 10005 
Phone +1 646-616-8671 / +1 646-616-
8629 
E-mail: Paul.Bruinenberg@tballiance.org 
Date 
 
 
LEAD INVESTIGATOR
I agree to the terms of this trial protocol. I will conduct the trial according to the procedures 
specified herein and in accordance to the principles of Good Clinical Practice (GCP) and 
local regulations. 
Signature  
 
 
Printed Name 
Date
 
 
 
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Page 3 of 101 
 
 
 
 
PRINCIPAL INVESTIGATOR PROTOCOL SIGNATURE PAGE 
 
An Open-Label, Partially Randomized Trial to Evaluate the Efficacy, Safety and Tolerability 
of a 4-month Treatment of Bedaquiline plus Pretomanid plus Moxifloxacin plus 
Pyrazinamide (BPaMZ) Compared to a 6-month Treatment of HRZE/HR (Control) in Adult 
Participants with Drug-Sensitive Smear-Positive Pulmonary Tuberculosis (DS-TB) and a 6-
month Treatment of BPaMZ in Adult Participants with Drug Resistant, Smear-Positive 
Pulmonary Tuberculosis (DR-TB). 
Protocol Number:  
NC-008 (B-Pa-M-Z) 
Protocol Date:  
V2.0 / 21 February 2018, Incorporating Amendment 1 
Protocol Name:  
SimpliciTB 
 
I hereby confirm that I have read the above protocol and agree to conduct this clinical trial as 
outlined in the above protocol. I will provide copies of the protocol and access to all the information 
required to conduct the clinical trial according to the above protocol to the site personnel under 
my supervision. I will discuss this material with them and ensure they are fully informed on all trial 
requirements. 
 
 
 
 
 
Signature 
 
Printed Name 
 
 
 
Date 
 
 
 
 
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Table of Contents 
Page 
List of Tables ............................................................................................................................. 8 
List of Figures ............................................................................................................................ 8 
List of Appendices ...................................................................................................................... 8 
1.0 
Synopsis ........................................................................................................................11 
1.1 
Synopsis Summary ................................................................................................11 
1.2 
Synopsis Flow Chart and Procedures .....................................................................17 
2.0 
Introduction and Rationale .............................................................................................22 
2.1 
Tuberculosis Disease .............................................................................................22 
2.2 
Tuberculosis Clinical Research ..............................................................................22 
2.3 
Trial Rationale ........................................................................................................24 
2.3.1 
Trial Design Rationale ...............................................................................24 
2.3.2 
Trial Drug Regimen Rationale ...................................................................25 
2.4 
Agents used within SimpliciTB................................................................................25 
2.5 
Background of Agents to be Studied in SimpliciTB .................................................28 
2.5.1 
Bedaquiline ...............................................................................................28 
2.5.2 
Pretomanid ................................................................................................34 
2.5.3 
Moxifloxacin (M) ........................................................................................40 
2.5.4 
Pyrazinamide (Z) .......................................................................................42 
2.6 
Overall Benefit/Risk Assessment ............................................................................43 
2.6.1 
Bedaquiline ...............................................................................................43 
2.6.2 
Pretomanid ................................................................................................44 
2.6.3 
Moxifloxacin ..............................................................................................45 
2.6.4 
Pyrazinamide ............................................................................................45 
2.6.5 
HRZE/HR Control ......................................................................................45 
3.0 
Trial Objectives ..............................................................................................................45 
3.1 
Primary Objectives .................................................................................................45 
3.2 
Secondary Objectives ............................................................................................46 
3.3 
Exploratory Objectives ...........................................................................................47 
4.0 
Trial Design ...................................................................................................................47 
4.1 
Summary of Trial Design ........................................................................................47 
4.2 
Treatment Plan: Schedule of Assessments ............................................................47 
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5.0 
Trial Population .............................................................................................................48 
5.1 
Inclusion Criteria ....................................................................................................48 
5.2 
Exclusion Criteria ...................................................................................................50 
5.3 
Restrictions ............................................................................................................53 
5.4 
Treatment Discontinuation and/or Early Withdrawal ...............................................54 
5.4.1 
Early Withdrawal .......................................................................................55 
5.4.2 
Unscheduled Visits ....................................................................................56 
5.4.3 
Lost-to-Follow-up ......................................................................................57 
5.4.4 
Early Withdrawal due to TB .......................................................................57 
5.5 
Participant Progress Definitions ..............................................................................58 
5.6 
Trial Stopping Rules ...............................................................................................58 
6.0 
Treatment ......................................................................................................................59 
6.1 
IMP Administration .................................................................................................59 
6.1.1 
Instructions for Dosing of Test Regimen (BPaMZ): ....................................59 
6.1.2 
Instructions for Dosing Control Treatment Regimen (HRZE/HR): ..............59 
6.2 
Participant Compliance ..........................................................................................59 
6.3 
Treatment Modification(s) .......................................................................................59 
6.4 
IMP Packaging and Labelling .................................................................................60 
6.5 
Blinding and Procedures for Breaking the Blind ......................................................61 
6.6 
Handling, Storage and Accountability .....................................................................61 
7.0 
Trial Variables and Procedures......................................................................................61 
7.1 
Demographic and Background Variables and Procedures ......................................61 
7.2 
Efficacy Variables and Procedures .........................................................................62 
7.3 
Safety and Tolerability Assessments ......................................................................63 
7.4 
PK Variables and Procedures.................................................................................64 
7.5 
Mycobacteriology Characterization Variable and Procedures .................................65 
8.0 
Adverse Events .............................................................................................................65 
8.1 
Definitions ..............................................................................................................65 
8.1.1 
Adverse Event (AE) ...................................................................................65 
8.1.2 
Serious Adverse Event (SAE) ...................................................................66 
8.1.3 
Attribution/Causality ..................................................................................66 
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8.1.4 
Severity .....................................................................................................67 
8.2 
Reporting ...............................................................................................................68 
8.2.1 
Follow up of Adverse Events .....................................................................68 
8.2.2 
Clinical Laboratory Adverse Events ...........................................................69 
8.2.3 
Disease symptoms during Trial .................................................................69 
8.2.4 
Overdose ..................................................................................................69 
8.2.5 
Drug Interaction.........................................................................................69 
8.2.6 
Pregnancy .................................................................................................70 
8.3 
Monitoring for Specific Toxicities ............................................................................70 
8.3.1 
Neurological ..............................................................................................70 
8.3.2 
Musculoskeletal System and Cardiac Muscle Myalgia ..............................71 
8.3.3 
Cardiac Rhythm Disturbances ...................................................................71 
8.4 
Safety Monitoring by Data Monitoring Committee ...................................................72 
9.0 
Statistical Analysis .........................................................................................................72 
9.1 
Analysis Populations ..............................................................................................72 
9.2 
Sample Size ...........................................................................................................72 
9.3 
Interim Analyses .....................................................................................................73 
9.4 
Primary and Secondary Efficacy Endpoint Analysis ................................................73 
9.4.1 
Primary Efficacy Endpoint, Time to Culture Conversion at 8 Weeks ..........73 
9.4.2 
Key Secondary Efficacy Endpoint, Clinical outcome at 52 Weeks from 
Randomization ..........................................................................................73 
9.4.3 
Other Secondary Efficacy Endpoints .........................................................73 
9.5 
Safety and Tolerability Assessments ......................................................................74 
9.6 
Pharmacokinetics ...................................................................................................74 
9.7 
Pharmacokinetics/Pharmacodynamics ...................................................................74 
10.0 
Records Management ...................................................................................................75 
10.1 
Data Collection .......................................................................................................75 
10.2 
Source Documents .................................................................................................75 
10.3 
File Management at the Trial Centre ......................................................................75 
10.4 
Records Retention at the Trial Centre ....................................................................75 
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11.0 
Quality Control and Assurance ......................................................................................75 
11.1 
Site Procedures ......................................................................................................75 
11.2 
Monitoring ..............................................................................................................76 
11.3 
Protocol Deviations ................................................................................................76 
11.4 
Auditing ..................................................................................................................77 
12.0 
Ethics and Regulatory ...................................................................................................77 
12.1 
Basic Principles ......................................................................................................77 
12.2 
Independent Ethics Committee/Institutional Review Board (EC/IRB) Review .........77 
12.3 
Regulatory Authorities ............................................................................................77 
12.4 
Informed Consent ...................................................................................................77 
12.5 
Confidentiality .........................................................................................................78 
13.0 
Publication Policy ..........................................................................................................78 
14.0 
Protocol Amendment Policy ...........................................................................................79 
15.0 
Sponsor, Financial Aspects, Insurance and Indemnity ...................................................79 
16.0 
References ....................................................................................................................81 
Appendices ...............................................................................................................................85 
 
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List of Tables 
Table 1.  Bedaquiline Adverse Drug Reactions .........................................................................32 
Table 2.  Key findings of Pretomanid in Safety and Toxicity Trials.............................................36 
Table 3.  Summary of Phase 2b trials in which moxifloxacin were administered as part of a four-
drug regimen during the intensive phase of treatment (total treatment duration: 2 months) .......41 
Table 4: Treatment Groups .......................................................................................................48 
Table 5: Follow-up visits required for Early Withdrawal Participants ..........................................56 
Table 6: Adverse Events Attribution/Causality Ratings ..............................................................67 
Table 7: Definitions for Adverse Event Severity Gradings .........................................................67 
 
List of Figures 
Figure 1.  Unified Drug Sensitive/Drug Resistant Regimen Development Path .........................23 
Figure 2.  Log10 CFU Counts in Lungs .....................................................................................35 
Figure 3.  Mean log Colony Forming Unit Values over Time Trial CL-010 .................................38 
 
 
List of Appendices 
Appendix 1: The IUATLD Scale ................................................................................................85 
Appendix 2: Division of Microbiology and Infectious Disease (DMID) Toxicity Table .................86 
Appendix 3: Who Clinical Staging of HIV/AIDS for Adults and Adolescents ..............................93 
Appendix 4: Cardiovascular Safety ...........................................................................................95 
Appendix 5: Karnofsky Performance Status Scale Definitions Rating (%) Criteria .....................96 
Appendix 6: Tuberculosis Symptoms Profile .............................................................................97 
Appendix 7: Patient Reported Health Status Questionnaire ......................................................98 
 
 
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Abbreviations and Definition of Terms 
 
3TC 
Lamivudine 
ABC 
Abacavir 
AE  
Adverse Event  
AFB 
Acid-fast bacilli 
AIDS 
Acquired Immune Deficiency Syndrome 
ALP 
Alkaline Phosphatase 
ALT 
Alanine aminotransferase 
AREDS2 
Age Related Eye Disease Scale 2 
ART 
Anti-Retroviral Therapy 
AST 
Aspartate aminotransferase 
AUCτ 
Area Under Curve over a dosing interval 
B 
Bedaquiline 
BA 
Bacterial activity 
BMI 
Body Mass Index 
BPaMZ 
Combination of bedaquiline plus pretomanid plus moxifloxacin plus 
pyrazinamide 
C 
Clofazimine 
CFU 
Colony Forming Units 
C(max), (min) 
plasma Concentration (maximum), (minimum) 
CO2 
Carbon dioxide 
CPK 
Creatine Phosphokinase 
CYP3A4 
Cytochrome P450 3A4 
DMID 
Division of Microbiology and Infection Disease 
DNA 
Deoxyribonucleic Acid 
DR-TB 
Drug-resistant tuberculosis 
For this particular protocol defined as TB participants with  
1. mono-resistance to rifampicin or isoniazid, OR 
2. resistance to both rifampicin and isoniazid (MDR-TB) 
(participants with fluoroquinolone resistance are excluded) 
DS-TB 
Drug-sensitive tuberculosis 
DSMC 
Data Safety and Monitoring Committee 
E 
Ethambutol 
EBA 
Early Bactericidal Activity 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
EFV 
Efavirenz 
(e)CRF 
(electronic) Case Report Form 
EMS 
Early Morning Sputum 
EWD 
Early Withdrawal 
FTC 
Emtricitabine 
FSH 
Follicle-stimulating hormone 
GCP  
Good Clinical Practice 
GMR 
Geometric Mean Ratio 
H 
Isoniazid 
hERG 
Human Ether-à-go-go Related Gene 
HIV  
Human Immunodeficiency Virus 
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HRZE 
Isoniazid, Rifampicin, Pyrazinamide, Ethambutol 
HR 
Isoniazid plus rifampicin combination tablet 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IMP 
Investigational Medicinal Product 
IRB 
Institutional Review Board 
ITT 
Intent to Treat 
IUATLD 
International Union Against Tuberculosis and Lung Disease 
IWRS 
Interactive Web Randomization System 
kg 
Kilogram 
L 
Linezolid 
LH 
Luteinizing hormone 
LLN 
Lower Limit of Normal 
LPV 
Lopinavir 
LTFU 
Long term follow-up  
M 
Moxifloxacin 
MBD 
Minimum Bactericidal Dose 
MIC 
Minimum Inhibitory Concentration 
MTB 
Mycobacterium tuberculosis 
MDR-TB 
Multi Drug Resistant Tuberculosis 
MGIT 
Mycobacterial Growth Inhibiting Tube 
mITT 
Modified Intent to Treat 
ms 
millisecond 
NVP 
Nevirapine 
NO 
Nitric Oxide 
NOAEL 
No Observed Adverse Effect Level 
NRTI 
(Triple) Nucleosidase Reverse Transcriptase Inhibitor 
Pa 
Pretomanid 
PD 
Pharmacodynamic 
PP 
Per Protocol 
PK 
Pharmacokinetic 
PR 
PR interval 
R 
Rifampicin 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SSCC 
Serial sputum colony counting 
TB 
Tuberculosis 
TDF 
Tenofovir 
TEAE 
Treatment Emergent Adverse Events 
TTP 
Time to Positivity  
ULN 
Upper Limit of Normal 
WHO 
World Health Organization 
XDR-TB 
Extensively Drug Resistant Tuberculosis 
μg(/ml) 
micrograms (per millilitre) 
Z 
Pyrazinamide (tablets) 
 
 
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1.0 
Synopsis 
1.1 
Synopsis Summary 
Synopsis 
Description  
Name of 
Sponsor/Company 
Global Alliance for TB Drug Development 
Name of Finished 
Products 
Bedaquiline tablets (B), pretomanid tablets (Pa), moxifloxacin 
tablets (M), pyrazinamide tablets (Z), HRZE tablets [isoniazid (H), 
rifampicin (R), pyrazinamide (Z) and ethambutol (E)] and HR 
tablets [isoniazid (H) plus rifampicin (R) combination tablets] 
Protocol Number/Title 
NC-008 / (B-Pa-M-Z)/ An Open-Label, Partially Randomized Trial 
to Evaluate the Efficacy, Safety and Tolerability of a 4-month 
Treatment of Bedaquiline plus Pretomanid plus Moxifloxacin plus 
Pyrazinamide (BPaMZ) Compared to a 6-month Treatment of 
HRZE/HR (Control) in Adult Participants with Drug-Sensitive 
Smear-Positive Pulmonary Tuberculosis (DS-TB) and a 6-month 
Treatment of BPaMZ in Adult Participants with Drug Resistant, 
Smear-Positive Pulmonary Tuberculosis (DR-TB) 
Treatment Indication 
Pulmonary Tuberculosis (TB) 
Trial Objective(s) 
To evaluate the efficacy, safety and tolerability at 8 weeks (2-
months), 52 weeks (12-months), and 104 Weeks (24-months) 
post the start of the following treatment regimens in participants 
with: 
 
Drug Sensitive TB (DS-TB) 
– 
BPaMZ given for 17 Weeks (4 months), or 
– 
Standard HRZE/HR treatment given for 26 weeks (6 
 
months) 
 
Drug Resistant TB (DR-TB)  
– 
BPaMZ given for 26 Weeks (6 months) 
 
DR-TB Defined as participants with  
1. mono-resistance to rifampicin or isoniazid, OR 
2. resistance to both rifampicin and isoniazid (MDR-TB) 
Trial Design 
Phase 2c multi-centre, open-label, partially randomized clinical 
trial in DS-TB and DR-TB participants.  
 
All participants will enter post-treatment follow-up which continues 
until Week 104 (24 months) after start of treatment / 
randomisation. 
 
Participants with Drug Sensitive TB (DS-TB): 
 
Participants with DS-TB will be randomized to one of two 
treatment arms. These participants will receive either BPaMZ daily 
for 17 weeks (4 months), or HRZE/HR tablets daily for 26 weeks 
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Synopsis 
Description  
(6 months). Participants will be stratified for co-infection with 
human immunodeficiency virus (HIV) and cavitation. 
 
Participants with Drug Resistant TB (DR-TB): 
 
Participants with DR-TB will be assigned to receive BPaMZ daily 
for 26 weeks (6 months). 
Patient Population 
A total of up to 450 male and female participants, diagnosed with 
DS-TB or DR-TB, aged 18 years and over with a target of up to 
50% being HIV positive. 
 
300 DS-TB participants (150 per treatment arm) will be 
randomized and stratified for co-infection with HIV and cavitation. 
 
Up to 150 DR-TB participants will be enrolled. 
Test product, Dose and 
Mode of Administration 
The Test Treatment Regimen (BPaMZ) consists of a combination 
of the following products and will be supplied as: 
 
Product 
Tablet Strength 
Abbreviation  
Bedaquiline 
100 mg  
(B) 
Pretomanid 
200 mg  
(Pa) 
Moxifloxacin 
400 mg 
(M) 
Pyrazinamide 
500 mg 
(Z) 
 
Instructions for Dosing of Test Regimen (BPaMZ):  
Treatment will be administered orally once daily, to be taken 
during breakfast, with a full glass of water (approximately 240 ml), 
for 17 weeks (4 months) or 26 weeks (6 months) in the following 
dosing schemes: 
 
Participants with Drug Sensitive TB: (DS-TB) 
Bedaquiline 200 mg daily for 8 weeks then 100 mg daily for 9 
weeks, together with pretomanid 200 mg + moxifloxacin 400 mg + 
pyrazinamide 1500 mg daily for 17 weeks (Total treatment 
duration 4 months)  
 
OR 
 
Participants with Drug Resistant TB: (DR-TB) 
Bedaquiline 200 mg daily for 8 weeks then 100 mg daily for 18 
weeks, together with pretomanid 200 mg + moxifloxacin 400 mg + 
pyrazinamide 1500 mg daily for 26 weeks (Total treatment 
duration 6 months) 
Positive Control 
Product, Dose and 
Mode of Administration 
The Control Treatment Regimen (HRZE/HR) will be supplied as:  
 
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Synopsis 
Description  
HRZE Tablets: (isoniazid 75 mg plus rifampicin 150 mg plus 
pyrazinamide 400 mg plus ethambutol 275 mg combination 
tablets). This combination will be given for the first 8 weeks. 
 
AND 
 
HR Tablets: (isoniazid 75 mg plus rifampicin 150 mg combination 
tablets). This combination will be given from Weeks 9 to 26. 
 
Instructions 
for 
Dosing 
Control 
Treatment 
Regimen 
(HRZE/HR): 
 
To be taken with a glass of water (approximately 240 ml).  HRZE 
or HR should not be taken with a meal (generally, no closer to 
meals than 1 hour before or 2 hours after a meal) in the following 
dosing schemes: 
 
Treatment will be administered orally once daily to the HRZE/HR 
randomized DS-TB participants as follows: 
 
 
Weeks 1-26: HRZE/HR tablets daily dose per the 
 
participant’s weight as follows:  
 
 
Weight Band 
Weight Range 
Number of 
tablets  
1 
30-39 kg 
2 
2 
40-54 kg 
3 
3 
55-70 kg 
4 
4 
≥ 71 kg 
5 
 
Vitamin B6 daily supplement to be taken with the HRZE/HR 
treatment, per each country’s TB Treatment Guidelines.  
Treatment 
Interruptions/Pauses 
For All Trial Regimens:  
The trial treatment regimens may require interruptions/pauses due 
to toxicities. All dose interruptions/pauses should be discussed 
with the Sponsor’s Medical monitor prior to implementation, unless 
an interruption/pause is required urgently for a safety concern.   
Action required for participants missing the following number of 
doses within the trial treatment regimens:  
• 
Up to 7 consecutive doses: restart treatment, no extension 
of treatment required 
• 
Greater than 7 and to ≤ 35 consecutive doses: restart 
treatment, extend the treatment by the number of 
consecutive doses missed, before the end of the treatment 
period (week 17/26). In this case, the last visit of the 
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Synopsis 
Description  
treatment period should also be pushed out to the date of 
the last dose 
• 
Greater than 35 consecutive doses: discontinue treatment 
and withdraw participant from the trial  
• 
If the participant misses a total (sum of) of 56 cumulative 
missed doses, discontinue IMP and withdraw participant 
from the trial. 
 
Any participant for whom the trial medication is discontinued 
(including for non-adherence) will be discussed with the Sponsor 
Medical Monitor and, if applicable, the participant will be restarted 
on trial medication as soon as possible. 
Statistical Methods: 
A general description of the statistical methods planned to be used to analyse efficacy data is 
outlined below. Specific details will be provided in the statistical analysis plan (SAP,) which 
will be written and signed off prior to the first participant enrolled in the trial. 
 
The primary analysis will be conducted using culture results from liquid culture (in the 
Mycobacterial Growth Indicator Tube (MGIT) system). 
 
Criteria for Evaluation: 
 
The primary efficacy endpoint will be time to culture negativity over 8 weeks. The 
primary hypothesis to be evaluated is:  
 
In the participants with DS-TB in the experimental BPaMZ treatment regimen, the time to 
culture negativity by 8 weeks will be superior, compared to the participants who are 
treated with the standard HRZE regimen. 
 
There will be three main analyses.  A modified Intent to Treat (mITT) analysis will be primary. 
A per-protocol (PP) analysis and an ITT analysis will also be performed for the secondary 
endpoint. These will be examined for consistency with the mITT analysis.  
 
Note:  Culture conversion requires at least 2 consecutive culture negative samples, at least 7 
days apart (after positive baseline confirmation).  Participants who are documented at a visit 
as unable to produce sputum and who are clinically considered to be responding well to 
treatment will be considered culture negative at that visit.  
 
Secondary Endpoints 
 
A key secondary endpoint will be the proportion of participants experiencing bacteriologic 
failure or relapse or clinical failure (unfavourable outcome) at 52 weeks (12 months). The 
hypothesis to be evaluated for this endpoint is: 
 
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Synopsis 
Description  
In the participants with DS-TB in the experimental BPaMZ treatment regimen, the 
proportion experiencing an unfavourable outcome will be non-inferior compared to the 
participants who are treated with the standard HRZE regimen. 
 
Other Secondary Endpoints 
 
Efficacy: 
• 
Incidence of bacteriologic failure or relapse or clinical failure at 104 weeks from the 
start of therapy.  
• 
Proportion of participants with sputum culture conversion to negative status in liquid 
culture (MGIT) at 4, 6, 12 and 17 weeks to be explored as a potential biomarker of 
outcome at 52 weeks from start of therapy. 
• 
Change from baseline in weight. 
• 
Change from baseline in TB symptoms. 
• 
Change from baseline in Participant Reported Health Status. 
 
Safety and Tolerability: 
• 
Incidence of Treatment Emergent Adverse Events (TEAEs) presented by incidence, 
severity, drug relatedness, seriousness, leading to early withdrawal, and leading to 
death.  
o Quantitative and qualitative clinical safety laboratory measurements, including 
observed and change from baseline. 
o Quantitative and qualitative electrocardiogram (ECG) results (heart rate, RR 
interval, PR interval, QRS interval, QT interval and QTc interval), including 
observed. QT/QTc intervals, change from baseline, will be categorized as 
these will be centrally read. 
• 
Changes in male reproductive hormones and lens opacities. 
 
These data will be presented as descriptive analyses, and no inferential tests will be carried 
out. 
 
Pharmacokinetics (PK) and Pharmacokinetics/Pharmacodynamics (PK/PD): 
Plasma concentrations from sparse sampling will be used to update existing population PK 
models and derive exposure metrics (e.g., minimum plasma concentration [Cmin], maximum 
plasma concentration [Cmax], area under curve over a dosing interval [AUC]) for bedaquiline 
and its M2 metabolite, pretomanid, moxifloxacin, and pyrazinamide. Effects of baseline 
covariates on exposure will be assessed; so too, will the effects of con-medications, including 
antiretroviral therapy (ART), where feasible. Data from other trials may be included to 
enhance the model-based analysis. Relationships will be explored between drug exposure 
and efficacy and safety endpoints. These exploratory PK/PD analyses may include HIV status 
as a covariate. 
 
Exploratory: 
Evaluate whether any of the secondary endpoints predict relapse free cure. Subgroup 
analysis of populations by HIV status will be performed. 
 
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Synopsis 
Description  
No formal statistical comparisons will be made for the participants enrolled with DR-TB. 
 
Sample Size 
Primary endpoint: 150 participants per arm (DS-TB patients) will provide at least 90% power 
(5% 2-sided significance) to detect a hazard ratio (HR) of at least 2 assuming 50% of control 
participants are culture negative by 8 weeks.  
 
Additional efficacy parameters will be evaluated including the incidence of bacteriologic failure 
or relapse or clinical failure (unfavourable outcome) at 52 weeks and 104 weeks from the start 
of treatment. Time to unfavourable outcome from assignment of trial treatment through follow-
up as a function of time will be analysed using Kaplan-Meier analysis. 
 
Trial Duration: 
Approximately 4 years (18-month enrolment period for DS-TB participants, up to 26 week-
treatment, and follow-up until week 104 from start of treatment. Depending on the DR-TB 
recruitment rate, enrolment into this arm may continue after enrolment into the DS-TB arms is 
complete.  
 
There will be 3 database locks, data analyses and trial reports generated for this trial:  
 
1. When all participants have completed 8 weeks (2 months) of treatment from baseline.  
2. When all participants have completed 52 weeks (12 months) follow-up from start of 
therapy. 
3. When all participants have completed 104 weeks (24 months) follow-up from start of 
therapy.  
 
 
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1.2 
Synopsis Flow Chart and Procedures 
Period 
Screen-
inga 
Treatment 
Follow-Upc 
Visitb 
Day -9 to -1 
Day 1 
(Baseline)d 
Day 7 (Week 1) 
Week 2 
Week 3 
Week 4 
Week 5 
Week 6 
Week 7 
Week 8  
Week 12 
Week 17 
4-mth treatmente 
Week 17  
6-mth treatmente 
Week 22  
Week 26  
4-mth treatmente 
Week 26  
6-mth treatmente 
Week 39 
Week 52 
Week 65 
Week 78 
Week 104 
Early 
Withdrawalc 
Visit Windowv 
N/A 
+/- 3 Days 
+/- 5 Days 
+/- 14 Days 
Written Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/Treatment/ Smoking History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sputum Samplingf,g 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HIV Statush and CD4 Counti 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Karnofsky Score 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Drug Screenj 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Pregnancy Testk 
X 
X 
 
 
 
 
 
 
 
X 
 
X 
X 
 
X 
X 
 
 
 
 
 
X 
Laboratory Safety Testl 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
 
 
 
 
X 
Male Reproductive Hormone Testsm 
X 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
 
 
 
 
12-lead ECGn 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
X 
 
 
 
 
X 
Chest X-Rayo 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TB Symptoms Profile 
X 
X 
 
X 
 
X 
 
 
 
X 
 
X 
X 
 
X 
X 
 
X 
 
 
X 
X 
Patient Reported Health Status  
X 
X 
 
X 
 
X 
 
 
 
X 
 
X 
X 
 
X 
X 
 
X 
 
 
X 
X 
Vital Signs and weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Ophthalmic Examinationp 
X 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
X 
X 
X 
 
 
 
 
X 
Physical Examination – fullq 
X 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
Physical Examination – limitedr 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
Pharmacokinetic Samplings 
 
X 
 
X 
 
 
 
 
 
X 
X 
X 
X 
 
 
 
X 
 
X 
X 
X 
 
IMP Randomization/ Assignmentt 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IMP Compliance Checku 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 Xe 
 
X 
 
 
 
 
 
Xt 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Investigator Assessmentv 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
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GENERAL: Vital signs, ECGs and blood draws are to be performed pre-dosing unless 
otherwise specified. Vital signs and/or ECGs should be done prior to blood draws 
(safety and PK) on days with those assessments. 
 
a. Screening: Screening assessments can occur on different days within nine days prior to 
Day 1 dosing (randomisation).  
b. Visit Schedule (due to unforeseen circumstances): If the duration of treatment is 
extended due to dose interruptions / pauses, the last visit of the treatment period should 
also be pushed out to the date of last dose. It is not necessary to have an unscheduled 
visit at the time that the last visit of the treatment period would have been.   
c. Follow-up Visits for Early Withdrawal Participants: Once a participant has been 
permanently withdrawn from the trial, they will be required to attend Early Withdrawal, 
Week 52 (if not already performed) and Week 104 follow-up visits. The Week 52 and Week 
104 visits will be to collect Serious Adverse Event (SAE) information (including verification 
of survival) and participant reported TB outcome information only and may be telephonic, 
a home or a site visit. Visits will occur at Week 52 and/or Week 104 after the participant’s 
start of treatment date.  Refer to Table 5 for additional guidance. 
d. Day 1 (Baseline): All procedures are to be completed prior to dosing.  
e. Last Visit of the Treatment Period: Investigational Medicinal Product (IMP) Compliance 
Check is not performed at the Week 22 visit for participants who have completed treatment 
at Week 17. 
f. Sputum Sampling: The sputum sampling methodology/requirements and tests will be 
described in a separate document, the Mycobacteria Laboratory Manual. 
• 
Days -9 to -1 (Screening). Two spot sputum samples taken 30 minutes apart will be 
collected at the research site under the coaching and observation of the trial staff. The 
following analyses will be performed on the first of these samples: 
o Smear microscopy for acid-fast bacilli (AFB); 
o Rapid molecular tests for fluoroquinolones, isoniazid and rifampicin resistance;  
o Liquid Culture (MGIT) for Mycobacterium tuberculosis (MTB), followed by a 
speciation test to detect presence or absence of MTB and obtain time to 
positivity (TTP) when positive. 
o The second sample is collected as a back-up sample to the first sample in case 
it is technically not possible to obtain a result/s from the first sample. If the Day 
-9 to -1 (Screening) spot sputum smear shows an indeterminate result or is 
AFB negative, the test may be repeated on the back-up sample or on a freshly 
collected spot sputum/s and that result will be used.  
• 
Baseline to Week 104, including any unscheduled visits:  
o Two sputum samples (ideally one early morning brought from home and one 
spot at the research site under the coaching and observation of the trial staff. 
If the participant forgets to bring in the Early Morning Sputum (EMS), then two 
spots are to be collected at the site, at least 30 min apart, and this altered 
sample collection is captured within case report form [CRF]).   
o If both sputum samples at Weeks 8, 17 (4-month treatment arm), 26 (6-month 
treatment arm), 52 or 104 are contaminated, the participant should return for 
an unscheduled visit(s) to give additional samples or to document that the 
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participant is not able to produce sputum. If there is a MTB confirmed positive 
culture at or after the last visit of the treatment period (Week 17 for the 4-month 
treatment arms and Week 26 for the 6-month treatment arms), the participant 
should return for an unscheduled visit(s) to give additional sputum samples a 
minimum of 7 days after the previous sample, or to document that the 
participant is not able to produce sputum.  
•
Additional samples may be required to define a participants’ primary outcome status
as described in Section 7.2.
•
Liquid Culture (MGIT) for MTB, followed by a speciation test to detect presence or
absence of MTB and obtain TTP when positive, will be performed on all samples.
g. Mycobacteriology Characterisation Tests performed:
•
Day 1 (baseline) sputum sample (or any positive sample from screening out to Week
4 if the baseline cultures are contaminated or negative);
•
MTB confirmed positive cultures at or after Week 17 (4-month treatment arms) or
Week 26 (6-month treatment arms).
Refer to Mycobacteria Laboratory Manual for full details. 
Mycobacterial Characterization - MTB isolates will be processed for: 
o
Minimum Inhibitory Concentration (MIC) against bedaquiline, pretomanid, and
moxifloxacin;
o
Drug Susceptibility Testing for streptomycin, rifampicin, isoniazid, ethambutol,
moxifloxacin, pyrazinamide and second line TB drugs including, but not limited
to fluoroquinolones, and injectables using an indirect susceptibility test in liquid
culture;
o
Extraction of organismal (MTB) DNA for whole genome sequencing, and
comparison of sequences from baseline and relapse isolates.
h. HIV Testing: If HIV status is a confirmed known positive, a repeated HIV test is not needed
provided that a documented HIV test result is available. If HIV status is unknown or
suspected negative, a HIV test will be requested. If an ELISA and/or Western Blot and/or
Electro-Chemiluminescence based HIV test was performed within 4 weeks prior to
screening, it should not be repeated if documentation of testing method and negative HIV
results can be provided. Repeated HIV testing, during the Screening period is permitted
for indeterminate HIV results.
i.
CD4 Count: Required for all HIV-positive participants.
j.
Urine Drug Screen: Cannabinoids, cocaine, amphetamines, opiates, benzodiazepines,
barbiturates, at Screening only. Investigator to utilize this result to determine whether
participant meets Exclusion criteria 2. Positive results will not automatically exclude a
participant from the trial.
k.
Urine Pregnancy Test: Women of childbearing potential only, whether they are sexually
active or not.
l.
Safety Laboratory Assessments: The Safety Laboratory sampling methodology and
requirements will be described in a separate document, the Safety Laboratory Manual,
which will be provided prior to the trial start. The following analyses will be performed:
•
Full Blood Count (haemoglobin, haematocrit, red blood cell count, white blood cell
count with differential, platelet count).
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• 
Clinical Chemistry (albumin, serum urea, creatinine, direct, indirect and total bilirubin, 
uric acid, total protein, alkaline phosphatase [ALP], aspartate aminotransferase [AST], 
alanine aminotransferase [ALT], lipase, phosphate, sodium, potassium, calcium 
(corrected for albumin), chloride, magnesium, glucose, bicarbonate/carbon dioxide 
[CO2], creatine phosphokinase [CPK]). GGT is only routinely included at the Screening 
visit (Day -9 to -1).  
• 
Urinalysis (pH, specific gravity, protein, glucose, micro-albumin, ketones, bilirubin, 
creatinine, nitrite, sodium, urobilinogen, blood, leukocytes). Microscopy will be 
completed as follow-up to abnormal urinalysis per discretion of Investigator.  
• 
When managing participants with elevated liver enzymes at an Unscheduled visit, the 
investigator can request additional tests, in addition to the repeat LFT [e.g. Gamma 
Glutamyl Transferase (GGT), screening for Hepatitis A, B, C; to assist in ruling out 
other causes of a dysfunctional liver test (e.g. alcohol induced hepatic cell injury, 
hepatobiliary disease, hepatic viral infection)]. 
m. Male Reproductive Hormone Tests: Testosterone, follicle-stimulating hormone (FSH), 
luteinizing hormone (LH) and Inhibin B to be done on male participants in ALL treatment 
groups. 
n. Single 12-Lead ECG: To every extent possible, this should be performed at 
approximately the same time of day as the trial procedures (+/-1 hour). Central ECG 
analysis will be performed. Results from central reading of Day -9 to -1 (Screening) ECG 
must be used to determine eligibility.  
o. Chest X-Ray: A chest x-ray (digital image only) within 6 months prior to or at the Screening 
visit, will be obtained and read locally by the Investigator or designee. Digital images will 
be provided to the Sponsor and this process will be described in a separate document, 
the Radiology Manual. 
p. Slit Lamp Ophthalmic Examination: Slit lamp examination will be done at the Screening 
visit, the last visit of the treatment period, Week 17 or 26, and at Week 39 (9 months) for 
both treatment groups.  An additional slit lamp at 6 months will be done for the 4-month 
treatment group. Slit lamp ophthalmology examination will be performed by an 
Ophthalmologist with AREDS2 training. Ophthalmology examinations may occur at any 
time within the window period for the applicable visit i.e. they do not have to be performed 
on the same day as the trial procedures. 
q. Physical Examination – Full: Height (m) will only be collected at Day -9 to -1 (Screening).  
r. Physical Exam – Limited: Limited physical exams will include weight and gross 
neurological, pulmonary, cardiovascular and abdominal exam(s). 
s. Pharmacokinetic (PK) Sampling: This process will be described in a separate 
document, the PK Sampling Manual. No PK samples will be collected for the HRZE-HR 
treatment arm.  Blood draws for PK samples collected pre-dose must be done after the 
ECG is performed.  The dates and times of the two doses of IMP taken prior to all pre-
dose PK samples will be collected.  Specific PK blood draws will be obtained as follows: 
• 
Day 1: pre-dose (within 2 hours prior to dosing) 
• 
Week 2: pre-dose (within 2 hours prior to dosing), 1.5–3 hours post-dose and 4-6 hours 
post-dose 
• 
Week 8: pre-dose (within 2 hours prior to dosing), 1.5–3 hours post-dose and 4-6 hours 
post-dose 
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• 
Week 12: pre-dose (within 2 hours prior to dosing)  
• 
Week 17 or at early withdrawal if prior to week 17: pre-dose (within 2 hours prior to 
dosing) and 1.5–3 hours post-dose 
• 
Weeks 39, 65, 78 and 104: PK samples are to be obtained at any time on the day of 
the scheduled visit 
t. Investigational Medicinal Product (IMP) Randomization/Assignment: Randomization 
may occur once all the Screening results are available and the Investigator has 
determined that the participant is eligible for the trial. 
u. IMP/Compliance Check: IMP administration will be supervised per local site practice to 
assure compliance to regimen. Performed at all visits and Early Withdrawal (EWD), if 
during the treatment period.  
v. Investigator Assessment: Investigator to review participant status and assess whether 
IMP or TB treatment at current visit is considered a “success” or “failure”.  If considered a 
failure, the Investigator should specify if based on bacteriology and/or clinical deterioration 
and/or radiological deterioration. Investigator Assessment to be completed, as shown on 
the flowchart, and at any time Investigator determines that participant fulfils criteria for 
outcome of treatment failure. 
w. Visit Windows: The windows noted on the flowchart for timing of visit also apply to timing 
within a visit.  Procedures should be performed within +/- 3 days of scheduled visit from 
Day 1 to Week 8 or +/- 5 Days of scheduled visit from Week 12 to Week 26 or +/- 14 days 
of scheduled visit at or after Week 39.  Sites should make every effort to ensure all 
procedures are done on the same day, when possible. 
 
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2.0 
Introduction and Rationale 
2.1 
Tuberculosis Disease 
Although some progress has been made in recent years in controlling tuberculosis (TB) globally, 
TB has remained a persistent problem in the developing countries of Africa, Asia and South 
America.  TB is currently one of the top three killer infectious diseases, and there is more TB in 
the world today than at any other time in history.  The current first-line anti-tuberculosis agents 
have been in use for over 40 years and are relatively ineffective in controlling TB as a public health 
problem.  Although the current regimens and drugs have been very successful in controlled 
clinical trials resulting in the permanent cure of more than 95% of trial participants, treatment takes 
6 months or more to complete. This, long duration treatment plus side effects, result in poor 
adherence which particularly occurs after the second month of treatment.  
The current TB treatment regimens and treatments for drug-sensitive TB are decades old. The 
available treatments have a lengthy duration of treatment, involve multi-drug therapy, and require 
large commitments of resources and infrastructure. High rates of noncompliance are common, 
which often results in increased mortality and chronic, infectious, drug-resistant cases. The 
present TB epidemic and the challenge of current treatment options demonstrate the clear need 
for effective novel TB drugs and drug regimens that are safe for drug sensitive and drug resistant 
TB disease and that are well-tolerated and will shorten the current treatment duration for patients. 
The full application of the Directly Observed Treatment, Short-Course strategy is becoming more 
and more difficult in the developing countries of the world that are also battling to control the HIV-
epidemic.  Because of poor treatment adherence, drug resistance is becoming more common 
and fears of an epidemic with virtually untreatable strains of TB are growing.  Since the discovery 
of the rifamycins,[1] and their introduction into standard antituberculosis regimens, very few new 
classes of drugs have been evaluated with a view to their registration as antituberculosis agents.  
On December 28, 2012 the U.S. Food and Drug Administration approved bedaquiline (B) as part 
of combination therapy to treat adults with multi-drug resistant (MDR) pulmonary tuberculosis (TB) 
when other alternatives are not available. Following the declaration of TB as a global emergency 
by the World Health Organization (WHO) in 1993, there has been a resurgence of efforts to 
develop improved TB therapies and several promising new agents are presently in or approaching 
clinical evaluation.   
New combination regimens are desperately needed for two reasons: to shorten treatment to a 
duration more easily manageable by patients and public health services, and to provide more 
efficacious, safer and better tolerated, affordable treatments for the growing number of patients 
suffering from multidrug-resistant and extensively drug-resistant tuberculosis. 
2.2 
Tuberculosis Clinical Research 
TB currently must be treated with multiple drugs to achieve maximal efficacy and prevent 
resistance. To transform treatment, novel TB regimens are needed. To telescope the time, it takes 
to develop novel, tolerable multi-drug treatments, it is necessary to use the regimen development 
paradigm. This approach tests promising combinations of drugs together to find the most 
impactful treatment once the individual drug candidates have been tested in a robust pre-clinical 
program and the establishment of the individual drug candidates’ safety and efficacy have been 
evaluated.  It evaluates novel combinations of TB drugs — instead of single drugs — as part of a 
single development program, enabling the development of novel TB drug regimens that have 
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potential to transform treatment for drug-sensitive and drug-resistant tuberculosis. This approach 
offers the potential to reduce the time previously needed to develop a novel treatment regimen 
by up to 75%, shortening the clinical development from decades to years. The steps followed in 
this development model are shown in Figure 1 Between each step on the unified development 
pathway a decision is made as to whether to proceed. 
Figure 1.  Unified Drug Sensitive/Drug Resistant Regimen Development Path 
 
Early Bactericidal Activity (EBA) Trials 
EBA trials are the backbone clinical trials to quantify the bactericidal action of anti-tuberculosis 
agents alone or in combination by either trialling the fall in the number of colony forming units 
(CFU) or measuring the TTP in liquid culture of M. tuberculosis (MTB) present in the sputum of 
participants with microscopy smear-positive pulmonary TB. EBA trials have been conducted over 
2, 5, 7 and 14 days.[2]. A review of EBA trials conducted on the key anti-TB drugs has shown the 
value these trials offer to demonstrate the early anti-TB effect that a new therapeutic agent may 
have and to explore the relationships between dose, pharmacokinetics and bactericidal activity in 
participants.[3] 
8-week Bactericidal Activity (BA) Trials 
EBA methodology of quantitative colony counting on solid medium has been adapted to Phase 2, 
8-week TB treatment trials based on serial sputum colony counting (SSCC) or measurement of 
TTP liquid culture to provide a more sensitive efficacy endpoint than the previously used binary 
endpoint of rate of sputum conversion measured after 8 weeks of treatment.[4-6] Such trials are 
conducted to provide data on which to base the selection of treatment-shortening regimens.  
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2.3 
Trial Rationale 
This trial (SimpliciTB) will evaluate and support that, in additional to previous studies evaluated 
with BPaMZ, this drug regimen (BPaMZ) will be safe and effective, is well-tolerated and could 
potentially shorten the current treatment duration compared to Standard HRZE/HR treatment for 
patients with drug sensitive TB disease. This trial will also evaluate if this drug regimen (BPaMZ) 
given for 6 months will be safe and effective in drug resistant TB disease. 
Therefore, the trial design addresses the need to find and evaluate a potentially effective and 
shorter regimen compared to regimens (Standard HRZE/HR) that are currently being used. 
2.3.1 
Trial Design Rationale 
NC-008 (B-Pa-M-Z) trial - [SimpliciTB] - is a Phase 2c multi-centre, open-label, partially 
randomized clinical trial in DS-TB and DR-TB participants. This trial is to evaluate the combination 
regimen of Bedaquiline (B) plus Pretomanid (Pa) plus Moxifloxacin (M) plus Pyrazinamide 
(Z), (BPaMZ) in participants with pulmonary TB. 
All participants will enter post-treatment follow-up which continues until Week 104 (24 months) 
after start of treatment / randomisation. 
 
Participants with Drug Sensitive TB (DS-TB): 
Participants with DS-TB will be randomized to one of two treatment arms. These participants 
will receive either BPaMZ daily for 17 weeks (4 months),  
 
or  
HRZE/HR combination tablets daily for 26 weeks (6 months). Participants will be stratified for 
co-infection with HIV and cavitation. 
Participants with Drug Resistant TB (DR-TB) are defined as: 
1. mono-resistance to rifampicin or isoniazid, OR 
2. resistance to both rifampicin and isoniazid (multi-drug resistant tuberculosis [MDR-TB]) 
Up to 150 participants with DR-TB will be assigned to receive BPaMZ daily for 26 weeks (6 
months).  Approximately 300 DS-TB participants (150 per treatment arm) will be randomized and 
stratified for co-infection with HIV and cavitation to either BPaMZ for 4 months or HRZE/HR for 6 
months.  
 
The trial is sufficiently statistically powered to not only show superiority of 2 months’ culture 
conversion, but should also demonstrate non-inferiority for cure at 12 months. (This is in the 
participants with DS-TB in the experimental BPaMZ treatment regimen, the proportion 
experiencing an unfavourable outcome will be non-inferior compared to the participants who are 
treated with the standard HRZE regimen). 
 
As previously described in the background information, in order to telescope the time it takes to 
develop novel, tolerable multi-drug treatments, it is necessary to use the regimen development 
paradigm and utilize data generated in non-clinical and clinical studies regarding combining of 
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anti-tuberculosis agents which could contribute significantly to the sterilization of lesions and thus 
treatment shortening. Therefore, the trial design and proposed trial regimen (BPaMZ) which is 
supported with previous non-clinical and clinical studies outlined below should address the need 
and manner of evaluating an effective shorter regimen compared to regimes that are currently 
being used. 
2.3.2 
Trial Drug Regimen Rationale 
The BPaMZ regimen has been studied singularly and in different combinations as outlined above. 
Moxifloxacin has been added to the B-Pa-Z regimen because of the high rate of pyrazinamide 
resistance seen in MDR-TB participants in the NC-002 trial. It essentially provides protection 
against the development of new resistance to the B-Pa-Z drugs. Based on the exciting and 
promising results seen in NC-005, this regimen can be initiated in drug sensitive and drug resistant 
TB participants whom are sensitive to the individual drugs in the regimen (excluding extensively 
drug-resistant tuberculosis [XDR-TB]) and has the potential to shorten TB treatment to less than 
4 months in drug sensitive TB. These are also oral regimens, removing the need for injectables 
as part of MDR-TB treatment and also project to be markedly less expensive than current MDR-
TB therapy. Additionally, these regimens can be administered in a fixed dose for all patients, and 
will therefore be simpler for health systems to deliver and patients to use. 
2.4 
Agents used within SimpliciTB 
Bedaquiline (TMC207; SirturoTM package insert)[7]  is a novel agent approved for TB treatment. 
As detailed in the Investigator’s Brochure,[8] bedaquiline is a diarylquinoline that offers a novel 
mechanism of anti-tuberculosis action by specifically inhibiting mycobacterial adenosine 
triphosphate synthase.[9, 10]) In vitro, bedaquiline potently inhibits both drug-sensitive and drug-
resistant M. Tb isolates,[10, 11], and is also bactericidal against non-replicating M. Tb.[12] In the 
murine model of TB, bedaquiline was as active as the triple combination of isoniazid (H), rifampin 
(R), and pyrazinamide (Z). Addition of bedaquiline to HRZ results in accelerated clearance of M. 
Tb.[3, 4] There appears to be a synergistic interaction with pyrazinamide: 100% of mice were 
culture negative after 8 weeks of treatment with bedaquiline and pyrazinamide compared to 0% 
of mice treated with the standard regimen of rifampicin, isoniazid and pyrazinamide.[13] 
Collectively, these findings in the mouse model have led to the suggestion that regimens 
containing bedaquiline and pyrazinamide could be effective in the treatment of both DS- and 
MDR-TB and shorten treatment duration in patients. While the combination of bedaquiline and 
pretomanid in the murine model of TB appeared somewhat antagonistic relative to bedaquiline 
alone, it was as active as the triple combination of HRZ[13] and in a subsequent trial it was more 
active in the mouse model than HRZ.[14] Thus, a novel regimen with a bedaquiline plus pretomanid 
core could be effective in the treatment of MDR-TB by providing two novel drugs for which there 
is no known pre-existing resistance.  
Pretomanid, (Pa)[15]  is a new chemical entity being developed by TB Alliance for the treatment 
of TB.  It is a member of a class of compounds known as nitroimidazo-oxazines, which possess 
significant anti-tuberculosis activity and a unique mechanism of action.[16] PRETOMANID has 
been under development for several years, and entered clinical trials in 2005. Several trials of 
pretomanid have also been conducted previously in healthy volunteers.  Collectively, these trials 
in participants with active TB and healthy participants have defined the efficacy, safety and 
pharmacokinetic features of the drug.  Overall, pretomanid has mycobactericidal activity in 
participants and is well tolerated and bioavailable after oral dosing.  Pretomanid demonstrated in 
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vitro activity against both drug-sensitive (DS) and MDR-TB,[17] and in vivo activity in a mouse 
model of TB[17, 18] with a significant promise for shortening treatment of active TB. 
Moxifloxacin (M)[19]  is a microbial compound, approved in most countries around the world for 
the treatment of acute bacterial sinusitis, acute bacterial exacerbation of chronic bronchitis, 
community-acquired pneumonia, skin and soft tissue infections.  Clinical studies have been 
carried out for many additional indications (urinary tract infections, pelvic infections, 
pharyngitis/tonsillitis, and tuberculosis). Moxifloxacin is an 8-methoxyquinolone whose oral 
formulation (which will be used in this trial) has enhanced activity against Gram-positive 
pathogens, and anaerobes while retaining useful activity against Gram-negative organisms. 
Moxifloxacin is not metabolized by or induces the cytochrome P450 system, thus the risk of 
clinically relevant drug interactions is reduced. It has a positive safety profile within the 
fluoroquinolone class at the approved daily dose of 400 mg. Moxifloxacin while not approved for 
TB by most regulatory authorities, it is regularly used in second line MDR-TB treatment. The WHO 
TB Treatment Guidelines place moxifloxacin in the category of Group 3 drugs and notes that “all 
patients [with MDR-TB] should receive a Group 3 medication if the MTB strain is susceptible or if 
the agent is thought to have efficacy. One of the higher generation fluoroquinolones, such as 
levofloxacin or moxifloxacin, is the fluoroquinolone of choice.[5]” It is currently in late stage clinical 
development for first-line TB treatment in combination with other TB drugs, including 
pyrazinamide in two different four-month long regimens.  
Pyrazinamide (Z)[20] is a pyrazine analogue of nicotinamide and an approved anti-tuberculosis 
agent which is indicated for the initial treatment of active tuberculosis in adults and children when 
combined with other anti-tuberculosis agents and contributes significantly to the sterilization of 
lesions and thus treatment shortening.[21]   
Control Group: HRZE/HR 
The HRZE/HR combination [HRZE tablets [isoniazid (H), rifampicin (R), pyrazinamide (Z) and 
ethambutol (E)] and HR tablets [isoniazid (H) plus rifampicin (R) combination tablets] is approved 
indicated and commonly used as a 6-month treatment for drug-sensitive TB patients.  Participants 
with DS-TB that are randomized to the HRZE/HR control arm in this trial will be given standard 
weight-adjusted doses of HRZE.  Please see the HRZE package insert for more information.[22]   
Additional background data supporting the combined use of new novel agents in this 
BPaMZ regimen for the treatment of TB: 
Data from preclinical studies suggest that a regimen consisting of moxifloxacin plus pretomanid 
plus pyrazinamide may not only be appropriate for treating both DS and MDR-TB but may also 
shorten duration of therapy.  Results from an 8-week Phase 2b SSCC trial, NC-002-(M-Pa-Z), 
showed that this combination regimen was effective as measured by time dependent decline of 
viable bacteria in participants with DS pulmonary TB.  The combination was also shown to be 
safe and well tolerated supporting the evaluation of this combination in a Phase 3 trial. In this NC-
002 trial 71.4% of participants with DS-TB treated with PaMZ at the 100-mg daily dose of 
pretomanid converted sputum to negative for MTB growth in liquid culture in comparison with only 
37.8 % of participants treated with the HRZE control (p<0.05).  
Studies in mice infected with MTB demonstrated reductions in cultured colony counts from lungs 
over an 8-week period when treated with the PaMZ regimen that were substantially, and 
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statistically significantly greater, than the reductions in mice treated with an HRZ control.  
Experiments in mice found that mice did not relapse with MTB infection when treated with PaMZ 
for 4 months and followed for 3 months off treatment, in comparison to mice that required 6 
months of treatment with HRZ to prevent relapse.[14]   
Drug Resistant TB Background: 
Although some progress has been made in recent years in controlling tuberculosis (TB) globally, 
TB has remained a persistent problem in many countries. TB is the world’s leading cause for 
mortality from infectious disease and is responsible for more deaths than HIV.[23] It is the leading 
cause of death among HIV-infected individuals, and there is more TB in the world today than at 
any other time in history. Because of poor treatment adherence, in addition to primary 
transmission, drug resistance is becoming more common and fears of an epidemic with strains 
of extensively drug-resistant TB (XDR-TB) that is very difficult to treat are growing.  Novel drugs 
and regimens for TB are needed for the growing number of patients with drug resistant-TB.  
The regulatory approvals of bedaquiline and delamanid have given hope that outcomes for 
patients with drug resistant TB might be improved when added to background regimens. 
Experience recently published from the C209 uncontrolled trial of bedaquiline given on a 
background of multiple drugs notes that the subset of 38 participants with XDR-TB had rates of 
sputum culture conversion to negative of 62.2%.[24] However, in this trial only one participant with 
XDR-TB was co-infected with HIV. All participants were required to have Mycobacterium 
tuberculosis (MTB) isolates susceptible to at least 3 drugs at enrolment and participants had a 
median of only 5.4 months of treatment-free follow-up. This trial added bedaquiline for 6 months 
to a background regimen of many drugs given for 18 months or longer. While treatment success 
for MDR-TB is better than for XDR-TB, overall success in treating MDR-TB is still 
approximately 50% according to the World Health Organization 2015 Global TB Report.[23]  This 
report presented that overall, the proportion of MDR-TB patients in the 2012 cohort who 
successfully completed treatment (i.e. cured or treatment completed) was 50%; 16% died, 16% 
were lost to follow-up, 10% failed treatment, and for 8% there was no outcome information.   
With such poor historical outcomes for patients with drug resistant-TB and with the complexity, 
expense and toxicity of treatments for all forms of drug resistant TB, novel drug combinations 
are desperately needed to improve treatment outcomes. Linezolid was identified in a small 
trial as a potentially efficacious drug in patients with XDR-TB when added to a failing regimen[25] 
and this drug has increasingly been added to complex regimens to treat patients with MDR-TB. 
With the current availability of the following three drugs for which there is little, if any, pre-existing 
resistance among strains of MTB (pretomanid [Pa], bedaquiline [B], and linezolid [L]). Mice 
infected with MTB had relapse-free cures with 3 months of treatment with a B-Pa-L regimen. 
While it is not known whether that treatment duration will translate to humans, the ongoing Nix-
TB clinical trial hypothesizes patients with pulmonary XDR-TB or MDR-TB not responsive to or 
intolerant to therapy may have relapse-free cure after as little as 6 months’ treatment with the B-
Pa-L regimen.[26]  Moxifloxacin has been added to the B-Pa-Z regimen because of the high rate of 
pyrazinamide resistance seen in MDR-TB participants in the NC-002 trial. The proposed trial 
[SimpliciTB] allows the opportunity to assess the efficacy, safety and tolerability of BPaMZ, a new 
6 months regimen that may be administered orally once daily to treat patients with drug resistant 
-TB (excluding participants with XDR-TB). 
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Therefore, the overall purpose of the present proposed trial [SimpliciTB] is to assess the 
efficacy, safety and tolerability of the BPaMZ regime after 4 months of treatment in adult 
participants with drug sensitive TB and after 6 months of treatment in participants with multi drug-
resistant TB. The trial will also generate data of the potential for a shorted treatment duration with 
the BPaMZ regime after 4 months compared to a 6-month HRZE/HR (control) treatment regime 
in adult participants with drug sensitive TB. 
This trial will be conducted in accordance with the Protocol, ICH Guidelines for Good Clinical 
Practice (GCP), the ethical principles that have their origin in the Declaration of Helsinki and the 
applicable regulatory requirement(s). 
2.5 
Background of Agents to be Studied in SimpliciTB 
2.5.1 
Bedaquiline (B) 
Bedaquiline (formerly known as TMC-207; SirturoTM package insert[7]) is approved agent for TB 
treatment. As detailed in the Investigator’s Brochure,[8] bedaquiline is a diarylquinoline that offers 
a novel mechanism of anti-tuberculosis action by specifically inhibiting mycobacterial adenosine 
triphosphate  synthase.[11] In vitro, bedaquiline potently inhibits both drug-sensitive and 
drug-resistant MTB isolates,[11, 12] and is also bactericidal against non-replicating MTB[12] In the 
murine model of TB, bedaquiline was as active as the triple combination of isoniazid (H), 
rifampicin (R), and pyrazinamide (Z). Addition of bedaquiline to HRZ results in accelerated 
clearance of MTB.[1, 2]. There appears to be a synergistic interaction with pyrazinamide: 100% of 
mice were culture negative after 8 weeks of treatment with bedaquiline and pyrazinamide 
compared to 0% of mice treated with the standard regimen of rifampicin, isoniazid and 
pyrazinamide.[27].Collectively, these findings in the mouse model have led to the suggestion that 
regimens containing bedaquiline and pyrazinamide could be effective in the treatment of both 
drug sensitive and drug resistant TB and shorten treatment duration in patients. While the 
combination of bedaquiline and pretomanid in the murine model of TB appeared somewhat 
antagonistic relative to bedaquiline alone, it was as active as the triple combination of HRZ[27] and 
in a subsequent trial it was more active in the mouse model than HRZ.[28]. Thus, a novel regimen 
with a bedaquiline plus pretomanid core could be effective in the treatment of MDR-TB/XDR-TB 
by providing two novel drugs for which there is no known pre-existing resistance. 
Bedaquiline is currently registered in many countries to be administered to patients with 
pulmonary tuberculosis by the following scheme: 400mg once daily for Days 1-14 followed by 
200mg three times per week for the remainder of treatment. In this trial bedaquiline will be 
administered as 200 mg daily for 8 weeks, followed by 100 mg daily for the remaining 17 weeks 
or 30 weeks if treatment is extended.  This daily dosing scheme will allow more convenient dosing 
that should ultimately enhance patient adherence and may allow the formulation of fixed dose 
combinations with other drugs.  This daily dosing regimen is supported by safety and efficacy 
demonstrated in the NC-005 trial that administered bedaquiline 200 mg daily over 8 weeks, and 
by pharmacokinetic modelling and simulation of the daily dosing scheme.  This supportive 
information is detailed below. 
2.5.1.1 
Bedaquiline Non-Clinical Studies 
Full details of the preclinical studies are provided in the current bedaquiline Investigator’s 
Brochure,[8] and Sirturo 
TM label.[7] In vitro studies have demonstrated that the range of minimum 
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inhibitory concentrations (MICs) for MTB H37Rv, the international reference strain, and 6 fully 
drug-susceptible clinical isolates, was 0.030 to 0.120 μg/ml. The activity of bedaquiline appears 
to be specific for mycobacteria, as the MICs for non- mycobacteria were at least 500-fold higher. 
The activity of the main metabolite of bedaquiline, M2, was determined against MTB.  H37Rv in 
both solid and liquid media and its MIC was found to be 0.1 μg/ml. This MIC shows that M2 is 
active against MTB but 3-6 times less active than the parent compound bedaquiline. Bedaquiline 
demonstrated similar in vitro efficacy against MTB clinical isolates resistant to the known anti-TB 
drugs (isoniazid, rifampicin, pyrazinamide, streptomycin, ethambutol, or fluoroquinolones). As 
expected, from the lack of cross-resistance with currently used anti-tuberculosis agents, 
bedaquiline retained activity against MDR-TB isolates. 
The non-clinical safety evaluation of bedaquiline includes pharmacology, pharmacokinetics, 
toxicology and metabolism studies that were conducted in accordance with current International 
Council for Harmonisation (ICH) guidelines. Repeated dose toxicity studies were performed with 
dosing durations up to 3 months in mice and up to 6 months in rats and in dogs. Recovery was 
studied in rats and dogs. In repeated dose toxicity studies, up to 3 months in mice, up to 6 months 
in the rat and up to 9 months in dogs, bedaquiline was associated with target organ changes in 
the mononuclear phagocytic system (indicative of phospholipidosis), stomach, liver, pancreas, 
and muscle. Toxicity was often associated with an increased presence of neutrophils in some 
tissues such as the female genital tract and this was preceded by a peripheral neutrophilia. For 
more detailed information please refer to the bedaquiline IB.[8] 
Respiratory parameters in rats were unaffected by treatment. There were no effects suggestive 
of neurological impairment or delayed neurotoxicity in rats. In single dose toxicity studies, there 
were no mortalities following oral doses of up to 200 mg/kg in mice and rats. No mutagenicity or 
clastogenic effects were seen in a series of in vitro and in vivo genotoxicity tests. Bedaquiline 
was evaluated for possible developmental toxicity effects in the rat and the rabbit. No teratogenic 
effects were found. In vitro, bedaquiline slightly to moderately inhibited the delayed rectifier 
potassium current (IKr) in the human ether-à-go-go-related gene (hERG) model. Bedaquiline and 
M2 had no notable effects on IKr at 0.01 μM (0.006 and 0.005 μg/mL, respectively). However, at 
higher concentrations (0.03 to 3 μM), both compounds had a slight to strong concentration-
dependent effect with a 50% inhibitory concentration (IC50) of 0.37 μM (0.2 μg/mL) for bedaquiline 
and up to 0.45 μM (0.24 μg/mL) for M2. However, this effect did not manifest as a prolongation of 
repolarization in subsequent in vivo studies. 
There were no relevant effects on the isolated right atrium of guinea pigs in vitro, or in the isolated 
Langendorff-perfused rabbit heart. In vivo, positive chronotropic effects were seen in the 
anesthetized guinea pig after IV administration, but not in the conscious dog. In conscious, 
telemetered dogs, oral bedaquiline had no relevant effects on cardio-hemodynamic and ECG 
parameters. 
Prior to the use of pretomanid in combination with bedaquiline in clinical trial NC-001, a preclinical 
cardiovascular safety pharmacology trial was conducted in unrestrained beagle dogs with both 
drugs to explore the potential for additive effects on QT prolongation induced by the combination. 
Results indicate that administration of 100 mg/kg bedaquiline daily, for 7 days, causes a small 
increase in QTc interval by Day 6 in some animals that is not influenced by the addition of 
100 mg/kg pretomanid on Day 7.[28] 
 The effect of pretomanid dosing alone on QT interval 
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appeared to be due to discomfort related to the SC route of administration and not related to the 
plasma exposure (please see the pretomanid) Investigators Brochure for more detail. 
2.5.1.2 
Bedaquiline Clinical Studies 
In the clinical studies conducted to date, a total of approximately 645 participants (including 
265 healthy volunteers) have been exposed to bedaquiline in the Phase 1 and 2 clinical trials 
conducted as a part of the development program for the treatment of MDR-TB. An additional 45 
participants received bedaquiline, either as monotherapy (B) or in combination with other agents 
(B-Pa or B-Z) in trial NC-001, and 45 more in trial NC-003 (B-Pa-Z, B-Pa-C, B-Pa-Z-C). Four 
short-term Phase 2a trials enrolled treatment-naïve participants (C202, TMC207-CL001, NC-001 
and NC-003). One long-term, open-label, Phase 2 trial, in MDR-TB participants (bedaquiline- 
TiDP13-C209) and one long-term, Phase 2b trial, consisting of 2 different stages in participants 
infected with newly diagnosed sputum smear-positive pulmonary MDR-TB (bedaquiline-TiDP13-
C208), have been completed. The principal findings of these trials are summarized below. Full 
details of the completed clinical studies are provided in the current bedaquiline IB,[8] and Sirturo
TM 
label.[7]. 
The Phase 1 trials have provided a basic understanding of bedaquiline’s pharmacokinetic 
characteristics, drug- drug interaction potential, and short-term safety/tolerability profile in healthy 
participants. Bedaquiline was well absorbed with time to reach the maximum plasma 
concentration at approximately 5 hours post-dose. The maximum plasma concentration and AUC 
increased proportionally up to the highest doses studied (up to 700 mg in a single dose-ranging 
trial, 800 mg single dose in trial bedaquiline-TBC1003 and 400 mg q.d. multiple doses). 
Accumulation from Days 1 to 14 was approximately 2-fold expressed as increase in AUC, while 
trough concentrations increased up to 3.5-fold. The pharmacokinetics of bedaquiline were 
comparable between healthy participants and participants with pulmonary TB. The apparently 
close to steady-state concentrations in plasma after 14 days of daily treatment is ascribed to the 
important amount of the drug that is eliminated from the circulation during the ἀ and β phases of 
the plasma concentration-time curve. The average terminal elimination half-life of bedaquiline and 
metabolite M2 noted on extended follow-up after repeat dosing of participants with TB infection is 
about 5.5 months. 
Administration of bedaquiline as the tablet formulation with food, increased the relative 
bioavailability (by 95%) compared to administration without food, and drug-drug interaction trials 
confirmed the role of cytochrome P450 3A4 (CYP3A4) in the metabolism of bedaquiline to M2. A 
recently completed trial (DMID 10-0043) demonstrated that when given in combination, rifampicin, 
and to a lesser degree rifabutin, decreased exposure to bedaquiline presumptively due to 
induction of P450 enzymes. The clinical significance of these findings is unknown, however the 
current trial (NC-005) will not permit the concomitant use of bedaquiline with any rifamycin. 
The efficacy of bedaquiline was initially demonstrated in two monotherapy EBA studies C202 and 
TMC207- CL001. Trial C202 was a 7-day trial of three daily doses of bedaquiline (25, 100 and 
400mg) in treatment-naïve participants with MDR-TB. In this trial, the 400mg dose group 
demonstrated positive EBA and was numerically superior to the 25 and 100mg doses. In trial 
TMC207-CL001, doses of 100, 200, 300 and 400mg daily (following a 2-day loading dose) were 
studied in participants with newly-diagnosed pulmonary TB for 14 days. There were no statistically 
significant differences between the treatment groups, although there was a numerical trend 
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suggesting a positive dose-response relationship. Taken together, these studies establish that 
bedaquiline monotherapy has EBA in participants with TB and that higher doses appear to have 
greater efficacy. 
A 14-day EBA regimen trial (TB Alliance Trial NC-001-(B-M-Pa-Z)) evaluated bedaquiline 
administered as monotherapy at 400 mg/d or in combination at that dose with either pretomanid 
administered at 200 mg/d or weight-adjusted pyrazinamide, to participants with pulmonary TB at 
2 clinical sites in South Africa. The results indicate that over 14 days, the mean logCFU decreased 
by 1.3 from baseline in the 15 participants given bedaquiline 400 mg/d after a 2-day loading dose. 
In the cohort of 15 participants given bedaquiline 400 mg/d after a loading dose plus weight-
adjusted daily doses of pyrazinamide (Z), the mean logCFU decreased by 2.0 logs from baseline, 
indicating that Z potentiates the early bactericidal effect of bedaquiline. In the cohort with 15 
participants given bedaquiline 400 mg/d after a loading dose plus 200 mg/d pretomanid, the mean 
logCFU decreased by 1.9. While it appeared that the addition of pretomanid potentiated the anti-
tuberculosis activity of bedaquiline, the mean logCFU decrease of the combination was similar to 
that of two previous EBA studies using pretomanid monotherapy at 200 mg/day. 
The second 14-day EBA combination trial (NC-003) included a number of bedaquiline-containing 
arms: bedaquiline, pyrazinamide and clofazimine (B-Z-C), bedaquiline, pretomanid and 
clofazimine (B-Pa-C), bedaquiline, pretomanid, and pyrazinamide (B-Pa-Z) and bedaquiline, 
pretomanid, pyrazinamide and clofazimine (B-Pa-Z-C). Among these, B-Pa-Z had the best activity 
which was at least as good as the HRZE control (Daily Log CFU – 0.167 vs 0.151, respectively). 
The long-term efficacy of bedaquiline in participants with MDR-TB has been studied in a placebo-
controlled, randomized Phase 2b trial (C208) and an open-label, uncontrolled, Phase 2b trial 
(C209). In the Phase 2b placebo-controlled trial, C208, the addition of bedaquiline to a 5-drug 
MDR-TB regimen resulted in significantly faster time to culture conversion compared to placebo. 
During the 8-week treatment in Stage 1, 47.6% of participants in the bedaquiline group became 
MGIT culture negative compared to 8.7% of participants in the placebo group. At Week 24 in Stage 
1, after 8 weeks of investigational treatment and 24 weeks of background treatment, 81.0% of 
participants in the bedaquiline group and 65.2% of participants in the placebo group showed 
treatment success, (i.e., completed week 24 and were liquid culture negative, at this time point). 
For C208 Stage 2, in the interim analysis as well as in the primary efficacy analysis, a statistically 
significant difference in time to culture conversion between the treatment groups (p < 0.0001) in 
favour of bedaquiline was shown. In both analyses, an identical number of participants with culture 
conversion at week 24 (i.e., 24-week responders [missing = failure]) was observed: 78.8% in the 
bedaquiline group and 57.6% in the placebo group, which was statistically significantly different 
(p =   0.008) based on a logistic regression model with only treatment as covariate. Microbiological 
response at Week 24 was durable in C208 Stage 2: the percentage of responders (missing = 
failure) at week 72 was 71.2% in the bedaquiline group and 56.1% in the placebo group. 
In the Phase 2b uncontrolled trial, C209, treatment with bedaquiline in combination with an 
individualized MDR- TB treatment regimen was effective against pulmonary MDR-TB both in 
newly diagnosed and in non-newly diagnosed participants. Culture conversion rates after 2 weeks 
of treatment with bedaquiline as part of an individualized anti-tuberculosis regimen were higher in 
participants with lower extent of resistance of the M. Tb strain and in participants with no lung 
cavitation compared to participants with cavitations (in one or both lungs). 
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2.5.1.3 
Bedaquiline Clinical Safety 
In the clinical trials conducted to date, a total of approximately 645 participants (including 
265 healthy volunteers) have been exposed to bedaquiline in the Phase 1 and 2 clinical trials 
conducted as a part of the development program for the treatment of MDR-TB. An additional 60 
participants received bedaquiline in a monotherapy EBA trial of 14 days (trial TMC207-CL001) 45 
participants received bedaquiline, either as monotherapy (B) or in combination with other agents 
(B-Pa or B-Z) in trial NC-001 and 45 more in trial NC- 003 (B-Pa-Z, B-Pa-C, B-Pa-Z-C). In these 
trials, bedaquiline has been shown to be an effective treatment for participants with both DS and 
MDR-TB. Specifically, the regimen B-Pa-Z was demonstrated to have efficacy at least as good 
as the HRZE control in trial NC-003. Furthermore, bedaquiline is a novel agent with no pre-existing 
resistance and, based on mouse model data, may result in shortened treatment durations when 
included in novel regimens to treat both DS- and MDR-TB. Based on the combined experience in 
these clinical trials, the following known and potential risks have been identified. 
Adverse Drug Reactions for bedaquiline 
During the Investigational Treatment phase in the controlled trials, the most frequently reported 
Adverse Drug Reactions in the any bedaquiline group (> 10.0% of participants) were nausea, 
arthralgia, headache, vomiting, and dizziness. Details of Adverse Events, none of which were 
Serious, that were considered Adverse Drug Reactions are in the table below: 
Table 1.  Bedaquiline Adverse Drug Reactions 
 
 
 
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Mortality 
Overall, there was an imbalance in the number of deaths in the pooled Stage 1 and Stage 2 C208 
trial. In the pooled analysis (Stage 1 and Stage 2), 12 participants in the Any bedaquiline group 
and 5 participants in the Any Placebo group experienced a SAE leading to death; causes of death 
were varied with only death due to TB reported more than once, and none of these participants 
had a treatment-emergent QTcF ≥ 500 ms. The imbalance in deaths is primarily driven by the 
C208 Stage 2 results in which the imbalance was 10 bedaquiline participants (12.7%) compared 
to 3 placebo participants (3.7%). Based on the pooled results (Stage 1 and 2) while being followed 
in the placebo- controlled trial, 7 participants in the Any bedaquiline group and 1 Participant in the 
Any Placebo group died. Of these deaths, 1 occurred during the Investigational Treatment phase 
with bedaquiline/placebo, the remaining deaths occurred afterwards. In the Any bedaquiline 
group, causes of death were myocardial infarction, TB (2 cases), alcohol poisoning, hepatitis and 
hepatic cirrhosis (1 case), septic shock and peritonitis (1 case), and cerebrovascular accident. In 
the Any Placebo group, cause of death was haemoptysis. The Investigator considered the SAEs 
leading to death not related to bedaquiline intake in the Any bedaquiline group and doubtfully 
related to investigational medication in the Any Placebo group. The analysis of long-term follow-
up for survival outcomes in participants who prematurely discontinued in trial C208 (Stage 1 and 
2), based on data collection every 24 weeks (6 months) after withdrawal (up to LSLV in the rollover 
arm [16 Oct 2012] in Stage 2), included 9 deaths. One Participant in the bedaquiline group 
(pulmonary TB) and 2 participants in the Placebo group (TB-related illness and pulmonary TB) in 
Stage 1 died, and 4 participants in the bedaquiline group (3 participants with TB-related illness, 1 
Participant motor vehicle accident) and 2 participants in the Placebo group (both TB-related 
illness) died after they discontinued Stage 2 of the trial. None of these participants had a 
treatment-emergent QTcF ≥ 500 ms. The imbalance in deaths is unexplained.  In addition, no 
discernible pattern between  death  and  sputum  culture  conversion,  relapse, sensitivity to other 
drugs used to treat TB, human immunodeficiency virus (HIV) status, or severity of disease was 
observed. 
In the uncontrolled Phase 2b trial, C209, the most frequently reported AEs during the 
investigational phase were hyperuricemia, arthralgia, nausea, vomiting, headache, diarrhoea, 
blood uric acid increased, hypokalaemia, pruritus, injection site pain, insomnia, and tinnitus. From 
start of the trial up to the final analysis, 12 participants died during the C209 trial due to SAEs that 
included TB (5 cases), congestive cardiac failure, renal impairment, lung infection, cardiac arrest 
(underlying cause pneumonia), haemoptysis, hypertension, and pyopneumothorax/respiratory 
failure. These SAEs leading to death were considered not related to bedaquiline by the 
Investigator, except for renal impairment that was judged doubtfully related to bedaquiline. 
The analysis of long-term follow-up for survival outcomes for participants who prematurely 
discontinued in trial C209, based on data collection every 24 weeks (6 months) after withdrawal, 
included 4 deaths (all described as TB-related). In total, since the start of the C209 trial, 16 
participants (6.9%) have died (12 participants during the trial and 4 participants during the survival 
follow-up phase after premature discontinuation). None of the fatal SAEs were considered related 
to bedaquiline by the Investigator and none of these participants has a treatment- emergent 
adverse event. 
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Cardiovascular safety 
During clinical trials with bedaquiline a prolongation of QTc interval was observed. The US 
Product Label for bedaquiline[7] notes that treatment initiation is not recommended in patients with: 
• 
Heart failure; 
• 
QTcF interval > 500 ms (confirmed by repeat electrocardiogram); 
• 
A personal or family history of congenital QT prolongation; 
• 
Concomitant administration of fluoroquinolone antibiotics that have a greater potential 
for significant QT prolongation (i.e., gatifloxacin, moxifloxacin and sparfloxacin). 
• 
Hypokalaemia 
The US Product Label recommends that bedaquiline treatment must be discontinued if the patient 
develops clinically significant ventricular arrhythmia. An additive or synergistic effect on QT 
prolongation of bedaquiline when co-administered with other medicinal products that prolong the 
QT interval cannot be excluded. Caution is recommended when using bedaquiline concomitantly 
with medicinal products with a known risk of QT prolongation. If co-administration of such 
medicinal products with bedaquiline is necessary, clinical monitoring including frequent ECG 
assessment is recommended. 
Hepatic safety 
The US product label notes increases in transaminases were seen in clinical trials during 
administration of bedaquiline with the background regimen. participants should be monitored 
during treatment. Other hepatotoxic medicinal products and alcohol should be avoided while 
taking bedaquiline, especially in those participants with diminished hepatic reserve.[7]  
Additional safety information from a recently completed trial 
In a recently completed phase I trial not yet included in the bedaquiline Investigators Brochure 
that evaluated drug-drug interactions between bedaquiline and either rifampin or rifabutin, 7 
participants experienced SAEs. Of those participants, 5 experienced SAEs of lymphocytopenia 
(all received rifabutin), which did not appear to be related to the AUC or Cmax of TMC207 or 
rifabutin. One participant experienced an SAE of elevated Creatine Kinase (rifampicin arm) and 
one experienced a grade 4 Total Bilirubin SAE (rifampicin arm). Lymphopenia was previously 
noted to be an infrequent toxicity associated with rifabutin, but not previously seen with 
bedaquiline. 
The bedaquiline/rifabutin regimen demonstrated significant reversible lymphopenia, which did not 
appear to be related to the AUC or Cmax of TMC-207 or rifabutin. 
2.5.2 
Pretomanid (P) 
As detailed in the Investigator’s Brochure,[15] pretomanid is a new chemical entity and a member 
of a class of compounds known as nitroimidazo-oxazines, which possess significant anti-
tuberculosis activity and a unique mechanism of action.[16] Pretomanid demonstrated in vitro 
activity against both DS- and MDR-TB,[17] and in vivo activity in a mouse model of tuberculosis.[16, 
17]  
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2.5.2.1 
Pharmacology 
Key in Vitro Evaluation of Pretomanid Bactericidal Activity 
Non-clinical in vitro trials demonstrated that pretomanid was active against actively growing drug- 
sensitive and drug-resistant MTB strains as well as against non-replicating MTB. The minimum 
inhibitory concentration (MIC) of pretomanid against a variety of drug-sensitive MTB isolates in 
vitro was shown to be like the MIC of isoniazid (MIC of pretomanid, ≤0.015 to 0.25 µg/mL; MIC of 
isoniazid, 0.03 to 0.06 µg/mL). Pretomanid was efficacious in vitro against drug-resistant clinical 
isolates of MTB with MIC values ranging from 0.03 to 0.53 µg/mL. The Investigator’s Brochure 
contains further information on in vitro bactericidal activity.[16] 
Although not thoroughly elucidated at this time, pretomanid has a novel mechanism of action that 
appears to involve inhibition of the synthesis of cell wall lipids under aerobic conditions and 
generation of reactive nitrogen species under anaerobic conditions. Reduction of pretomanid by 
a deazaflavin (F420)-dependent nitroreductase has been shown to be associated with generation 
of reactive nitrogen species, including nitric oxide (NO),[29] although the exact target(s) of the 
reactive nitrogen species are not known. Transcriptional profiling trials also suggest that 
pretomanid affects both cell wall biosynthesis and the respiratory complex of MTB.[30, 31] 
2.5.2.2 
Key Non-Clinical Trials of Pretomanid 
The activity of pretomanid as a single agent or as part of a multi-drug combination regimen has 
been examined in a number of mouse trials.[13, 14, 18, 32, 33] In a mouse model of established TB, the 
activity of various doses of pretomanid (given once daily, 5 days/week, for 1 month), initiated 22 
days after inhalation infection with H37Rv MTB is shown in Figure 2. In this model, the minimum 
effective dose (MED) for pretomanid, defined as the lowest dose able to prevent the development 
of gross lung lesions and splenomegaly, was 12.5 mg/kg/day, while the minimum bactericidal 
dose (MBD), defined as the lowest dose able to reduce lung colony forming units (CFU) by 99%, 
was 100 mg/kg/day. Moreover, in these experiments, the activity of pretomanid at 100 mg/kg was 
comparable to the activity of isoniazid at 25 mg/kg. 
Figure 2.  Log10 CFU Counts in Lungs  
After One Month of Daily Treatment with the Indicated Dose (in mg/kg) of Pretomanid 
 
Arrows denote the minimum effective dose (MED) and minimum bactericidal dose (MBD). 
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2.5.2.3 
Non-Clinical Toxicology and Safety 
Pretomanid has been evaluated in an ICH recommended battery of safety pharmacology trials, in 
repeat-dose toxicity trials in rats (2 to 26 weeks) and cynomolgus monkeys (7 days to 9 months), 
in 8 genotoxicity trials, and in fertility and teratology trials in rats and rabbits.  
In the repeat-dose toxicity trials, the lowest no-observed adverse effect level (NOAELs) was 
10 mg/kg/day in a 26-week trial in rats, 50 mg/kg/day in a 13-week trial in monkeys and 
<25 mg/kg/day (based on findings of thickening of the gastrointestinal tract at all doses) in a 9-
month trial in monkeys. The major findings in safety and toxicity trials are listed below in Table 2 
and are detailed in the Investigator’s Brochure.[15] 
Table 2.  Key findings of Pretomanid in Safety and Toxicity Trials 
Nervous system-related effects.  
Rats given single oral pretomanid doses had decreased body tone, touch responses and 
decreased grooming behaviour at ≥150 mg/kg, which resolved within 24 hours. Rats given 
repeated daily doses of pretomanid had convulsions, ataxia, hypoactivity, recumbency, 
hyperactivity and sensitivity to touch, and squinting at ≥100 mg/kg/day, and early deaths 
occurred at doses ≥500 mg/kg/day. Monkeys given repeated daily doses of pretomanid had 
hypoactivity, ataxia, tremors, and convulsions at ≥450/300 mg/kg/day. These effects were 
reversible when dosing stopped and were absent at ≤30 mg/kg/day in rats and ≤150 mg/kg/day 
in monkeys. 
Testicular toxicity 
Although rat and rabbit embryonic development trials indicate no effects of pretomanid on foetal 
development, testicular atrophy in rats was observed in 3-month and 6-month repeat-dose 
toxicology trials and a Segment I fertility trial. In this fertility trial, testicular atrophy was 
associated with infertility; an approximate 30% reduction in fertility was also observed at a lower 
dose not associated with testicular atrophy. A detailed trial in sexually mature male monkeys 
demonstrated no effects on testicular histology or function in adult cynomolgus monkeys after 
3 months’ dosing.  
Cataracts 
Cataracts developed in rats with prolonged daily administration of pretomanid at doses 
≥100 mg/kg/day. In one 13-week trial in monkeys, cataracts did develop at 450/300 mg/kg/day, 
but only by the end of a 13-week recovery period. In a second 13-week trial in monkeys that 
included extensive ophthalmic examinations, cataracts did not develop at the high-dose level 
of 300 mg/kg/day. 
hERG inhibition and QT prolongation 
Altered ventricular repolarisation due to inhibition of hERG-mediated potassium current and 
manifested on the ECG as a prolonged QT interval corrected for heart rate (QTc). Pretomanid 
inhibited hERG current with IC50 values of approximately 6.2 µg/mL. Following a single 
pretomanid dose of 450 mg/kg in monkeys, QTc interval prolongation ranged from 21 to 
36 msec using Fridericia’s formula (QTcF) to correct for heart rate. Co-administration of 
pretomanid with moxifloxacin in the monkey or with bedaquiline in the dog did not result in any 
greater effect on the QT interval than with either agent alone. After repeated daily doses, the 
QTc interval in the monkey was prolonged at pretomanid doses of ≥150 mg/kg/day. 
 
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2.5.2.4 
Clinical Background Information 
Pretomanid has been evaluated in 8 single- and multi-dose Phase 1 trials with healthy adult male 
and female participants, with 163 participants receiving single oral doses ranging from 50 to 
1500 mg and multiple oral doses ranging from 50 to 1000 mg/day given for up to 7 days. These 
Phase 1 trials have evaluated the safety, tolerability, and pharmacokinetics (PK) of pretomanid. 
Two additional Phase 1 trials Sponsored by the NIH included a Thorough QT trial and a trial of 
drug interactions among pretomanid, efavirenz and ritonavir/lopinavir.  Further details of the trials 
are in the Investigator’s Brochure.[15] 
2.5.2.5 
Pharmacokinetics 
Several Phase 1 trials have evaluated the safety, tolerability, and pharmacokinetics (PK) of 
pretomanid and have demonstrated that pretomanid has a half-life of approximately 18 hours, 
which supports daily dosing, and an effect of food with the 200-mg dose that increases total 
exposure by 88%. Interaction trials with midazolam, efavirenz and ritonavir/lopinavir demonstrate 
effects that are not likely to be clinically significant. 
Drug interaction with midazolam: Trial CL-006 was an open-label, fixed-sequence drug-drug 
interaction trial to evaluate the effects of multiple-dose administration of pretomanid on the PK of 
midazolam, a sensitive probe substrate and representative compound for drugs metabolised by 
CYP3A enzymes. Dosing with pretomanid at 400 mg/day for 14 days (to steady state) had minimal 
effect on the PK of midazolam and its 1-hydroxy metabolite as assessed by measurement of the 
Day 17: Day 1 ratios of maximum concentration (Cmax, AUC0-t, and AUC0-inf. The Cmax and AUC 
values for midazolam after co-administration with pretomanid were approximately 85% of those 
observed after treatment with midazolam alone. Furthermore, midazolam and 1-hydroxy 
midazolam time to maximum concentration (Tmax) and half-life (t1/2) values were not different in 
the presence or absence of pretomanid. Therefore, 14 days’ dosing with 400 mg/day pretomanid 
does not appear to significantly inhibit CYP3A4 in humans. 
Drug interaction with efavirenz, ritonavir/lopinavir, and rifampicin: The US NIH Sponsored this 
drug interaction trial with rifampicin, a known hepatic enzyme inducer, and with the antiretroviral 
drugs efavirenz and ritonavir/lopinavir (LPV/r) in healthy participants. Participants in Arm 1 were 
randomised to Sequence 1 (pretomanid 200 mg once daily for 7 days, two-week washout period, 
efavirenz (EFV) 600 mg once daily for 14 days, then both drugs for 7 days) or Sequence 2 
(Treatment 1B: EFV, then EFV + pretomanid, washout, and pretomanid). Results indicate that 
comparing pretomanid given with EFV versus pretomanid alone in 16 participants, the geometric 
mean ratio (GMR) for Cmax was 0.71, the GMR for AUC0-24h was 0.65, and the GMR for Cmin was 
0.54. Concentrations of EFV when given with pretomanid versus given alone were similar. 
Participants in Arm 2 were randomised to Sequence 1 (pretomanid 200 mg once daily for 7 days, 
then a 2-week washout period, then LPV/r 400/100 mg twice daily for 14 days, then LPV/r + 
pretomanid together for 7 days) or Sequence 2 (LPV/r, then LPV/r + pretomanid, washout, then 
pretomanid alone). Comparing pretomanid + LPV/r versus pretomanid- alone from 16 PK-
evaluable participants, the GMR for Cmax was 0.87, for AUC0-24h was 0.83, and for Cmin was 0.78. 
In Arm 3, participants received pretomanid for 7 days, then rifampicin 600 mg for 7 days, then 
pretomanid + rifampicin together for 7 days. Comparing pretomanid + rifampicin versus 
pretomanid alone from 16 PK-evaluable participants, the GMR for Cmax, AUC0-24h, and Cmin were 
0.47, 0.34, and 0.15, respectively.  
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In conclusion, compared to pretomanid alone, plasma pretomanid values (based on geometric 
mean ratios) for Cmax, AUC0-24h, and Cmin were reduced 28%, 35%, and 46% with efavirenz; 13%, 
17%, and 21% with LPV/r; and 53%, 66%, and 85% with rifampicin, respectively. 
2.5.2.6 
Pretomanid Clinical Efficacy 
The first two Phase 2 trials to evaluate the early bactericidal effect (EBA) of pretomanid oral 
monotherapy (50 to 1200 mg/day for 14 days) examined the dose-response for pretomanid in 
participants with newly diagnosed pulmonary TB infection. The first trial (CL-007) demonstrated 
good EBA, but all doses in this trial (200 to 1200 mg/day) had the same activity. The second trial 
(CL-010) evaluated a lower dose range (50 to 200 mg/day) and the maximum effect on EBA was 
seen at a dose of 100 mg/day over 14 days (Figure 3).[34] 
Figure 3.  Mean log Colony Forming Unit Values over Time Trial CL-010 
 
CFU = colony-forming unit; PRETOMANID = pretomanid 
* Day 0 = (Day -2 + Day -1)/2 = baseline measurement 
Pretomanid has been evaluated in patients with TB as monotherapy for a maximum duration of 
14 days, the longest considered acceptable for a TB patient to be treated in a clinical trial with a 
single drug.  Trials of pretomanid for both 14 days and for up to 6 months, in combination with 
either bedaquiline and/or linezolid, are described below.  
2.5.2.7 
Pretomanid Clinical Safety 
The pretomanid Investigator’s Brochure[15] provides detailed safety information. 
4
4.5
5
5.5
6
logCFU
0
2
4
6
8
10
12
14
Day
 PA-824 50mg
 PA-824 100mg
 PA-824 150mg
 PA-824 200mg
 Rifafour e275 
Bi-linear regression of logCFU vs day over treatment
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Across the 16 clinical trials with pretomanid completed to date, a total of 649 participants have 
been exposed to pretomanid, including 289 healthy participants across the 10 Phase 1 trials and 
360 participants with newly diagnosed smear positive pulmonary TB across 5 Phase 2 
trials.  Among the 289 healthy participants, 174 received exposure to a single dose of pretomanid 
ranging from 50 to 1500 mg and 115 received exposures to repeated daily doses of pretomanid 
(50 to 1000 mg) for up to 14 days. The 360 participants with newly diagnosed smear positive 
pulmonary TB were exposed to pretomanid either as a single agent at daily doses of 50 to 
1200 mg for 14 days or in combination with other anti-TB agents (bedaquiline, moxifloxacin, 
pyrazinamide, linezolid and/or clofazimine) at a dose of 100 mg or 200 mg for up to 26 weeks.  The 
overall safety profile determined from the clinical trials completed to date indicates pretomanid is 
well tolerated in healthy adults and in TB patients when administered alone and in combination 
with moxifloxacin, pyrazinamide, bedaquiline and clofazimine.   
Pretomanid is an investigational drug and there is limited experience in humans; the safety 
database is being developed and Investigators should be vigilant to any adverse events noted in 
clinical trials.  Across these trials, the most common side effects or AEs associated with 
pretomanid exposure include: 
• 
Headache 
• 
Stomach discomfort (nausea, vomiting, flatulence, and/or diarrhoea) 
• 
Skin and subcutaneous tissue disorders 
The only adverse drug reaction identified in clinical trials completed to date as likely caused by 
pretomanid is blood creatinine increased.  A trial of the effects of repeat doses of pretomanid in 
healthy volunteers determined that the drug does not adversely affect glomerular filtration rate, 
effective renal plasma flow or filtration fraction and the elevations in serum creatinine reverse.  
The following parameters will be followed with particular care in the Phase 3 development 
program: 
• 
Hepatic Safety – Specific guidelines are included in the protocol to assure close surveillance 
and careful management of participants who have elevations in aminotransferases and/or 
bilirubin. Serious liver injury, including death in 3 participants taking a combination of 
pretomanid, pyrazinamide and moxifloxacin, has occurred during clinical trials and the risk of 
liver injury may be higher for participants taking a combination of pretomanid and 
pyrazinamide than it is for the standard HRZE treatment. Therefore, close monitoring of liver 
function is required for participants who are administered pretomanid, especially when 
combined with pyrazinamide.  Administration of the regimen of PaMZ has been associated 
with death in 3 participants associated with hepatic injury. Furthermore, the HRZE control 
regimen, and both pyrazinamide and moxifloxacin, has been associated with drug induced 
liver injury and in rare cases hepatic necrosis.  Consequently, hepatic safety will be under 
close surveillance in all clinical trials. 
• 
Ophthalmologic Evaluations – while the detailed examinations in Phase 2 have not raised 
concern for humans, ophthalmologic examinations, with slit lamp exam and grading of lens 
opacities, will continue in all human trials that involve exposure to pretomanid longer than 
14 days.  These examinations will be conducted at baseline, near the end of the dosing period 
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and 3 months after the end of trial drug exposure.  These examinations are to follow up on 
the finding of cataracts in rats exposed to pretomanid in clinical trials. 
• 
Cardiovascular Safety – All participants will have ECGs taken at baseline and at multiple time 
points during the trial.  Although the Thorough QT Trial in healthy participants found that 
pretomanid did not increase corrected QT intervals in a clinically meaningful way and did not 
add to the known effect of moxifloxacin, the ECGs will be carefully monitored during Phase 3.  
All ECGs will be interpreted and conduction intervals will be confirmed by a central cardiology 
service. 
• 
Central Nervous System Safety –While pretomanid alone or combined in various regimens 
has been well tolerated overall, one participant in Trial NC-002 of the Pa-M-Z regimen had a 
seizure without any prior seizure history, and some animals in toxicology trials have had 
seizures at high drug exposures.  Consequently, close surveillance will be made of 
participants in the Phase 3 trial for seizures or any central nervous system adverse events of 
potential concern. 
Of note, preclinical toxicology trials found that rats, but not primates, had testicular toxicity when 
treated with pretomanid. Clinical evaluations of potential testicular toxicity in Phase 2 trials have 
evaluated over 300 participants exposed to pretomanid over 2-6 months with evaluations of 
testosterone, LH, or Inhibin B (2 trials) or FSH values (3 trials) at baseline and after daily dosing 
of regimens containing pretomanid in various combinations with moxifloxacin, pyrazinamide and 
bedaquiline.  A review of data from the 3 trials by an independent reproductive endocrine expert 
concluded that, based on the hormone evaluations to date, there is no evidence that pretomanid 
is a testicular toxicant in men at the doses and exposure times evaluated. 
2.5.3 
Moxifloxacin (M) 
Moxifloxacin (M)[19]  is an 8-methoxyquinolone whose oral formulation (which will be used in 
this trial) has enhanced activity against Gram-positive pathogens, and anaerobes while retaining 
useful activity against Gram-negative organisms. Moxifloxacin is not metabolized by nor induces 
the cytochrome P450 system, thus the risk of clinically relevant drug interactions is reduced. It 
has a positive safety profile within the fluoroquinolone class at the approved daily dose of 400 mg. 
Moxifloxacin while not approved for TB by most regulatory authorities, it is regularly used in 
second line MDR-TB treatment. The WHO TB Treatment Guidelines place moxifloxacin in the 
category of Group 3 drugs and notes that “all patients [with MDR-TB] should receive a Group 3 
medication if the strain of MTB is susceptible or if the agent is thought to have efficacy. One of 
the higher generation fluoroquinolones, such as levofloxacin or moxifloxacin, is the fluoroquinolo-
ne of choice.[5]” It is currently in late stage clinical development for first-line TB treatment in 
combination with other TB drugs, including pyrazinamide in two different four-month long 
regimens.  
2.2.3.1. 
Moxifloxacin Clinical Trials 
Moxifloxacin is commonly used as second line therapy for TB (e.g. MDR- TB), and has also been 
evaluated in several clinical studies of participants with TB, including four 8-week treatment period 
Phase 2b studies (see Table 3 below).  
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Table 3.  Summary of Phase 2b trials in which moxifloxacin were administered as 
part of a four-drug regimen during the intensive phase of treatment (total treatment 
duration: 2 months) 
Trial 
Design 
Objective 
Participants 
(N) 
Status 
Trial 27 
Randomized, 
double-blind, 
controlled 
To compare the sputum culture-
conversion rate at the end of the 4-drug 
(intensive) phase of therapy using the 
standard 4-drug regimen HRZE with a 
standard regimen with M replacing E.  
336 
Completed 
OFLOTUB 
Trial 
Randomized, 
Open label, 
Controlled 
To compare the bactericidal activities of 
regimens where gatifloxacin, M, and 
ofloxacin were substituted for E in the 2-
month initial phase of standard TB 
treatment with HRZE.  
 
217 
Completed 
Johns 
Hopkins 
(FDA 
orphan 
drug) Trial 
Randomized, 
double-blind, 
Controlled 
To compare the sputum culture 
conversion rate at the end of the 4-drug 
(intensive) phase of therapy using a 
standard 4-drug regimen (HRZE) with a 
regimen with M replacing E (HRZM). 
170 
Completed 
Trial 28 
Randomized, 
double-blind, 
Controlled 
To compare the culture-conversion rate 
at the end of the 4-drug (intensive) 
phase of therapy using a standard 4-
drug regimen (HRZE 5 days per week) 
with a regimen with M replacing H 
(MRZE 5 days per week). 
 
433 
Completed 
 
2.5.3.1 
Moxifloxacin Clinical Safety 
In Trial 27,[35] the moxifloxacin-containing TB regimens (HRZM) were shown to be safe and well 
tolerated. There was no difference in SAEs between the HRZM and HRZE treatment arms, and 
most SAEs were hospitalizations thought to be unrelated to the trial treatment.  Participants 
treated with the moxifloxacin-containing regimen were more likely to report nausea (22% vs. 9%, 
p = 0.002), but this was generally mild and did not lead to treatment discontinuation as similar 
proportions of participants in both groups completed trial drug treatment (88% HRZM-treated vs. 
89% HRZE-treated).  The one death during the first 2 months of treatment was thought to be 
caused by a pulmonary embolism unrelated to tuberculosis therapy.   
In the OFLOTUB trial,[36] AEs and SAEs occurred with equal frequency in the four treatment arms.  
The most frequent AEs were raised amylase (in 41% of participants due to HIV infection), raised 
transaminase (10%), arthralgia (9%), anaemia (7%), hypokalaemia (6%) and vomiting (5%).  No 
Participant was withdrawn from the trial due to an adverse event.  There were 4 deaths in the 
trial: 2 in the control group, 1 each in the moxifloxacin and ofloxacin arms.  Importantly, 
participants in this trial who received moxifloxacin and pyrazinamide in addition to isoniazid and 
rifampin had more rapid sputum clearance than participants on the four standard first line drugs 
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(isoniazid, rifampin, pyrazinamide and ethambutol). This difference was evident 14 days after 
initiation of treatment. 
In the JHU trial,[37] AEs did not differ by treatment group. There were 16 SAEs (8 in each group) 
in 12 participants. Only 1 event was judged related to trial drug (grade 3 cutaneous reaction in 
the ethambutol group). Eight participants died during the trial, including 1 in each group still 
receiving trial phase treatment. No death was attributed to trial treatment. Only 5 participants 
discontinued treatment because of toxic effects; 2 participants in the moxifloxacin group stopped 
because of grade 2 nausea and vomiting and 1 because of grade 2 paraesthesia’s and ataxia. 
Two participants in the E group stopped because of grade 2 rash and pruritus and 1 because of 
grade 3 peripheral neuropathy.  There was no change in the QTc interval on serial 
electrocardiograms taken during the trial. 
In Trial 28,[38] the proportions of participants with SAEs during the intensive phase treatment were 
similar between arms (isoniazid 3.9% vs. moxifloxacin 4.2%; P = 0.88). Three SAEs attributed to 
trial treatment during the first 2 months occurred among the moxifloxacin group and two in the 
isoniazid group.  Seven participants died during the trial including 3 participants receiving the 
moxifloxacin treatment regimen and 4 participants receiving the isoniazid treatment regimen. The 
3 moxifloxacin participants died during the intensive phase of TB treatment. Two participants died 
from advanced pulmonary TB judged not related to trial treatment and 1 Participant (who 
developed diabetic ketoacidosis considered possibly related to trial treatment) died from possible 
acute pulmonary embolus unrelated to trial treatment. The 4 isoniazid deaths occurred during the 
continuation phase, and all 4 were considered unrelated to trial treatment.  Nausea was more 
common among participants in the moxifloxacin arm than in the isoniazid arm (19.6% vs. 11.7%, 
respectively; P = 0.03) although similar proportions reported vomiting.  However, the proportions 
of participants with hepatitis, defined as serum AST 3 times or greater than the upper limit of 
normal, were similar between treatment arms during intensive phase (isoniazid 3.4% vs. 
moxifloxacin 3.3%; P = 0.93).  Moxifloxacin has also been evaluated in combination with 
pretomanid for two weeks in participants with TB (Trial NC-001) and for 8 weeks in NC002 as 
reviewed above in Section 2.2.3 (Trial NC-001). 
For additional information on moxifloxacin, refer to the IB[39] and the manufacturer’s package 
insert.[19] 
2.5.4 
Pyrazinamide (Z) 
Pyrazinamide (Z) is a standard drug used as part of the four drug HRZE regimen used for the first 
two months of intensive therapy for drug-sensitive TB as recommended by the WHO and many 
National TB programs.  Please see the Package Insert[20] for more detail.  Z is active against TB 
in vitro and it potentiates the bactericidal and sterilizing activity of both bedaquiline and  
pretomanid in mouse models of TB infection.[8, 15]  Pyrazinamide enhanced the bactericidal activity 
of both bedaquiline and  pretomanid in Trial NC-001-(J-M-Pa-Z) as noted by decreases over 14 
days in the CFU counts in sputum among participants. 
The pyrazinamide product label notes that pyrazinamide is contraindicated in persons with severe 
hepatic damage, who have shown hypersensitivity to it, and with acute gout.  The most serious 
side effect is hepatotoxicity. Its frequency appears to be dose-related and thus liver function 
should be assessed before and regularly during treatment with pyrazinamide.  Hyperuricemia 
commonly occurs and is occasionally accompanied by arthralgia and may lead to attacks of gout. 
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Photosensitivity and skin rash have been reported less frequently. Other side effects that have 
been reported are anorexia, nausea and vomiting, malaise, fever, sideroblastic anaemia and 
dysuria.  
Pyrazinamide may decrease the efficacy of gout therapy (e.g. allopurinol, colchicine, probenecid 
or sulphinpyrazone) and dosage adjustments of these medications may be necessary.  For 
additional information on pyrazinamide, refer to the manufacturer’s package insert. [20] 
2.6 
Overall Benefit/Risk Assessment 
Some participants with pulmonary TB in this trial will be given a regimen of BPaMZ. These drugs 
individually and in combination are known to have anti-tuberculosis activity and is not expected 
to have an adverse impact on the ultimate cure of TB in these participants. Based on NC-005 and 
other regimens using each of the regimen drugs in different combinations there is good evidence 
that this may be a highly effective therapy for both DS-TB and DR-TB.  
For DS-TB the potential for a shorter regimen than 6 months is expected to be successful based 
on preclinical and clinical information as listed before.  Participants in this trial will have their TB 
infection carefully characterized, with drug sensitivity profiles established, and they will receive 
treatment with trial drugs that have demonstrated activity against MTB.   
Participants will receive individualized medical attention; this will allow a continuous monitoring of 
the health conditions of each participant, any of whom can be withdrawn at any stage of the trial 
and removed from trial treatment should his/her condition suggest to the Investigator that this 
would be in his/her best interest.  Multiple blood samples will be taken for safety laboratory 
studies, and ECGs will be taken at multiple time points.  
One concern in particular, the combination of two agents with known QT-prolonging effects 
(bedaquiline and moxifloxacin), has been addressed specifically by carefully identifying and 
excluding participants with risk factors that might predispose them to cardiac arrhythmias, 
screening all participants for evidence of existing cardiac disease and monitoring all participants 
with ECGs throughout the trial.  
The trial drugs in the proposed regimens to be tested in this trial have all demonstrated safety 
and efficacy in the treatment of pulmonary tuberculosis in non-clinical and clinical studies. 
Specifically, the regimen B-Pa-Z was generally well-tolerated and demonstrated bactericidal 
activity in a 14-day EBA trial. The potential risks associated with the trial drugs and regimens has 
been identified as outlined below and will be monitored carefully throughout the conduct of the 
trial. 
The BPaMZ regimen is a novel regimen treatment expected to be effective, safe and well-
tolerated and might even shorten the current treatment duration for patients with TB. Based on 
data from previous trial evaluations of key monitoring and safety information as outlined before 
suggests a favourable benefit-to-risk ratio trials.  
Key Monitoring and Safety Information Regarding Regimen Agents 
2.6.1 
Bedaquiline (B) 
2.6.1.1 
Adverse Drug Reactions for bedaquiline  
Participants in the Any bedaquiline group compared to the Any Placebo group (difference > 5.0%) 
had headache (23.5% versus 11.4%, respectively), nausea (35.3% versus 25.7%, respectively), 
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arthralgia (29.4% versus 20.0%, respectively), and transaminases increased (6.9% versus 1.0%, 
respectively).and diarrhoea (11.4% versus 5.9%, respectively). 
2.6.1.2 
Cardiovascular safety 
During clinical studies with bedaquiline a prolongation of QTc interval was observed. An ECG 
should be obtained prior to and after initiation of therapy with bedaquiline to monitor the QTc 
interval. 
Bedaquiline treatment initiation is not recommended in patients with: 
• 
Heart failure 
• 
QTcF interval > 450 ms (confirmed by repeat electrocardiogram) 
• 
A personal or family history of congenital QT prolongation 
• 
Concomitant administration of fluoroquinolone antibiotics that have a greater potential for 
significant QT prolongation (i.e., gatifloxacin, moxifloxacin and sparfloxacin) 
• 
Hypokalemia 
 
Bedaquiline treatment must be discontinued if the patient develops clinically significant ventricular 
arrhythmia. An additive or synergistic effect on QT prolongation of bedaquiline when co-
administered with other medicinal products that prolong the QT interval cannot be excluded. 
Caution is recommended when using bedaquiline concomitantly with medicinal products with a 
known risk of QT prolongation. If co-administration of such medicinal products with bedaquiline is 
necessary, clinical monitoring including frequent ECG assessment is recommended. 
In the DR-TB treatment arm of the present trial, moxifloxacin will be co-administered with 
bedaquiline. This is to prevent the development of resistance to the other drugs in the regimen in 
case the participant’s strain of MTB is resistant to pyrazinamide. ECG assessments will be 
performed on all participants at screening, baseline, and at treatment visits specified in the flow 
chart.   
2.6.1.3 
Hepatic safety 
Increases in transaminases were seen in clinical studies during administration of bedaquiline with 
the background regimen. Participants should be monitored during treatment. 
Other hepatotoxic medicinal products and alcohol should be avoided while taking bedaquiline, 
especially in participants with diminished hepatic reserve. 
2.6.2 
Pretomanid (P) 
The most common side effects or AEs associated with pretomanid exposure include: 
• 
Headache 
• 
Benign, isolated and reversible elevations of serum creatinine 
• 
Stomach discomfort (nausea, vomiting, flatulence, and/or diarrhoea) 
• 
Skin and subcutaneous tissue disorders 
2.6.2.1 
Hepatic Safety 
Hepatic enzyme increases have been seen in participants treated with pretomanid in 
combinations with various other medications during the clinical development program. It is difficult 
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to assign specific causality to any one drug within a regimen; nonetheless, the NC-008 trial will 
include specific monitoring of hepatic enzymes. 
For additional information refer to  pretomanid IB.[15] 
2.6.3 
Moxifloxacin (M) 
In the usual daily doses of 400 mg/day, moxifloxacin is well tolerated.  As stated in the Package 
Insert[19]  the most frequent individual drug related AEs observed in clinical trials with 400 mg oral 
moxifloxacin therapy were nausea (7.5%) and diarrhoea (5.8%).  Fluoroquinolones, including 
moxifloxacin, are associated with an increased risk of tendinitis and tendon rupture in all ages.   
A known but rare side effect of fluoroquinolones, including moxifloxacin is exacerbation of 
myasthenia gravis. In addition, moxifloxacin has been shown to prolong the QT interval of the 
electrocardiogram in some participants.  It should be used with caution in participants being 
treated concomitantly with other drugs where an additive effect on the QT interval cannot be 
excluded.  
Serious and sometimes fatal hypersensitivity reactions, including anaphylactic reactions, as well 
as peripheral neuropathy may occur after the first or subsequent doses of moxifloxacin. For 
additional information, refer to the moxifloxacin package insert.[19] 
2.6.4 
Pyrazinamide (Z) 
The dose of pyrazinamide that will be used in this trial is an approved dosage for the treatment of 
TB. The most serious side-effect of pyrazinamide is hepatotoxicity and its frequency appears to 
be dose-related. Hyperuricemia commonly occurs, occasionally accompanied by arthralgia and 
may lead to attacks of gout.  Photosensitivity and skin rash have been reported less frequently.  
Other side-effects that have been reported are anorexia, nausea and vomiting, malaise, fever, 
sideroblastic anaemia and dysuria.  Pyrazinamide may decrease the efficacy of gout therapy (e.g. 
allopurinol, colchicine, probenecid or sulphinpyrazone) and dosage adjustments of these 
medications may be necessary.  For additional information on pyrazinamide, refer to the 
manufacturer’s package insert.[20] 
2.6.5 
HRZE/HR Control 
The HRZE (isoniazid 75 mg plus rifampicin 150 mg plus pyrazinamide 400 mg plus ethambutol 
275 mg combination tablets) combination will be given the first 8 weeks and the HR (isoniazid 75 
mg plus rifampicin 150 mg combination tablets) combination will be given from Weeks 9 to 26. 
Participants with DS-TB that are randomized to the HRZE/HR control arm in this trial will be 
given standard weight-adjusted doses of HRZE.   
Please see the HRZE and HR Package Inserts[22, 40] for known and potential risks and benefits. 
3.0 
Trial Objectives 
3.1 
Primary Objectives 
To evaluate the efficacy, safety and tolerability at 8 weeks (2-months), 52 weeks (12-months), 
and 104 Weeks (24-months) post the start of the following treatment regimens in participants with: 
Drug Sensitive TB (DS-TB) 
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–  BPaMZ given for 17 Weeks (4 months) 
– Standard HRZE/HR treatment given for 26 weeks (6 months) 
 
Drug Resistant TB (DR-TB)  
– BPaMZ given for 26 Weeks (6 months) 
 
DR-TB are defined as participants with: 
1. mono-resistance to rifampicin or isoniazid, OR 
2. resistance to both rifampicin and isoniazid (DR-TB) 
3.2 
Secondary Objectives 
Efficacy: 
 
• 
Incidence of bacteriologic failure or relapse or clinical failure at 52 weeks (or 12 months) and 
104 weeks (or 24 months) weeks from the start of therapy.  
• 
Proportion of participants with sputum culture conversion to negative status in liquid culture 
(MGIT) at 4, 6, 12 and 17 weeks to be explored as a potential biomarker of outcome at 52 
weeks from start of therapy. 
• 
Change from baseline in weight. 
• 
Change from baseline in TB symptoms. 
• 
Change from baseline in Participant Reported Health Status. 
 
Safety and Tolerability: 
 
• 
Incidence of Treatment Emergent Adverse Events (TEAEs) presented by incidence, severity, 
drug relatedness, seriousness, leading to early withdrawal, and leading to death.  
 
Quantitative and qualitative clinical safety laboratory measurements, including observed 
and change from baseline. 
 
Quantitative and qualitative ECG results (heart rate, RR interval, PR interval, QRS 
interval, QT interval and QTc interval), including observed. QT/QTc intervals, change 
from baseline, will be categorized as these will be centrally read. 
• 
Changes in male reproductive hormones and lens opacities. 
 
These data will be presented as descriptive analyses, and no inferential tests will be carried out. 
Pharmacokinetics (PK) and Pharmacokinetics/Pharmacodynamics (PK/PD): 
 
Plasma concentrations from sparse sampling will be used to update existing population PK 
models and derive exposure metrics (e.g., Cmin, Cmax, AUC) for bedaquiline and its M2 
metabolite, pretomanid, moxifloxacin, and pyrazinamide. Effects of baseline covariates on 
exposure will be assessed; so too, will the effects of con-medications including antiretroviral 
therapy (ART), as feasible.  
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Data from other trials may be included to enhance the model-based analysis. Relationships will 
be explored between drug exposure and efficacy and safety endpoints. These exploratory PK/PD 
analyses may include HIV status as a covariate. 
3.3 
Exploratory Objectives 
• 
Evaluate whether any of the secondary endpoints predicts relapse free cure. 
• 
Subgroup analysis of populations by HIV status.  
No formal statistical comparisons will be made for the participants enrolled with DR-TB. 
 
4.0 
Trial Design 
4.1 
Summary of Trial Design 
This is a Phase 2c, multi-centre, open-label, partially randomized clinical trial conducted in 3 
treatment groups.  Participants, trial Investigators and staff, including laboratory staff, will not be 
blinded to treatment allocation during the treatment phase of the trial. 
The trial will be performed globally at multiple centres located throughout all regions of the world.    
A total of 300 DS-TB participants (150 per treatment arm) will be randomized and stratified for co-
infection with HIV and cavitation.  Up to 150 DR-TB participants will be enrolled and assigned to 
the treatment arm described in Table 4 below.   
Participants with Drug Sensitive TB (DS-TB): 
 
Participants with DS-TB will be randomized to one of two treatment arms. These participants will 
receive either BPaMZ daily for 17 weeks (4 months), or HRZE/HR combination tablets daily for 
26 weeks (6 months).  Participants will be stratified for co-infection with human immunodeficiency 
virus (HIV) and cavitation. 
 
Participants with Drug Resistant TB (DR-TB): 
 
Participants with DR-TB will be assigned to receive BPaMZ daily for 26 weeks (6 months). 
Eligible participants who meet all the inclusion criteria and none of the exclusion criteria, aged 18 
and over, male or female will be assigned to one of the 3 treatment groups with a target of 50% 
of the participants being HIV positive. An interactive web response system (IWRS) will be used 
which will utilize a dynamic randomization system using cavitation with a random element to 
allocate participants evenly across the arms by HIV status and type of TB (DS versus DR) after 
they have given written, informed consent during the Screening Visit (Days -9 to -1) and met all 
eligibility criteria. 
4.2 
Treatment Plan: Schedule of Assessments 
• 
Screening Period (Day -9 to Day -1) 
• 
Treatment Period (Day 1 to Week 17 (4-month treatment); or Week 26 (6-month treatment))  
• 
Follow-Up Period (Week 39 to Week 104) 
 
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Refer to: 
• 
Synopsis Flow Chart and Procedures (Section 1.2; flow chart) for the timing of all procedures 
and laboratory samples to done at each visit.   
• 
Trial Procedures (Section 7.0, Trial Variables and Procedures) for details regarding specific 
procedures or laboratory tests. 
Each participant will receive up to 26 weeks of treatment.  The trial treatment regimens may 
require interruptions/pauses due to toxicities. All dose interruptions/pauses should be discussed 
with the Sponsor’s Medical Monitor prior to implementation unless an interruption/pause is 
required urgently for a safety concern.  
 
All participants will enter post-treatment follow-up which continues until Week 104 (24 months) 
after start of treatment / randomisation. 
 
Participants will receive daily dosing, orally. They will be randomized to one of the following arms: 
Table 4: Treatment Groups 
 
Treatment Group 
Treatment 
Duration 
No of 
Participants 
1 Bedaquiline 200 mg daily for 8 weeks  
then 100 mg daily for 9 weeks, together with pretomanid 
200 mg + moxifloxacin 400 mg + pyrazinamide 1500 mg 
daily 
17 weeks 
(4 months) 
150 DS-TB 
2 HRZE Tablets (Weeks 1-8): (isoniazid 75 mg plus 
rifampicin 150 mg plus pyrazinamide 400 mg plus 
ethambutol 275 mg combination tablets).  
 
Followed by 
 
HR Tablets (Weeks 9-26): (isoniazid 75 mg plus 
rifampicin 150 mg combination tablets).   
First 8 weeks  
(2 months) 
 
 
then 
 
17 weeks  
(4 months) 
 
Total 6 months 
150 DS-TB 
3 Bedaquiline 200 mg daily for 8 weeks  
then 100 mg daily for 18 weeks, together with pretomanid 
200 mg + moxifloxacin 400 mg + pyrazinamide 1500 mg 
daily. 
26 weeks 
(6 months) 
Up to 150 
DR-TB 
5.0 
Trial Population 
The participant must meet all inclusion and no exclusion criteria within the screening period.  
Retesting for any laboratory or ECG parameters is allowed within the screening period.  Sponsor 
may consider replacement of late exclusions. 
5.1 
Inclusion Criteria 
Participants are required to meet all the following inclusion criteria during the screening period to 
be randomized. 
1. Signed written consent prior to undertaking any trial-related procedures. 
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2. Male or female, aged 18 years or over. 
3. Body weight (in light clothing and no shoes) ≥ 30 kg. 
4. Sputum positive for tubercule bacilli (at least 1+ on the International Union Against 
Tuberculosis and Lung Disease [IUATLD]/WHO scale (Appendix 1) on smear microscopy) at 
the trial laboratory. 
5. Disease Characteristics: 
• 
Participants with one of the following pulmonary TB conditions: 
DS-TB treatment arm participants should be: 
a. sensitive to rifampicin and isoniazid by rapid sputum based test AND 
b. either newly diagnosed for TB or have a history of being untreated for at least 3 
years after cure from a previous episode of TB. 
If they are randomised into the trial due to being sensitive to rifampicin and isoniazid 
by rapid molecular sputum based test, however on receipt of the rifampicin and/or 
isoniazid phenotypic resistance testing in liquid culture this shows they are rifampicin 
or isoniazid resistant, they will be: 
a. Excluded as late exclusions; 
b. Possibly replaced as determined by the Sponsor.  
DR-TB treatment arm participants should be: 
a. Resistant to rifampicin and/or isoniazid.  
b. Should not have had previous treatment for DR-TB/MDR-TB, although may have 
been on a DR-TB/MDR-TB treatment regimen for no longer than 7 days at start of 
screening. 
6. A chest x-ray, within 6 months prior to or during the Screening visit, which in the opinion 
of the Investigator is compatible with pulmonary TB.  
7. Contraception: 
 
Be of non-childbearing potential or using effective methods of birth control, as defined 
 
below: 
Non-childbearing potential: 
a. Participant - not heterosexually active or practice sexual abstinence; or  
b. Female participant or male participants female sexual partner - bilateral 
oophorectomy, 
bilateral 
tubal 
ligation 
and/or 
hysterectomy 
or has 
been 
postmenopausal with a history of no menses for at least 12 consecutive months; or  
c. Male participant or female participants male sexual partner - vasectomised or has had 
a bilateral orchidectomy at least three months prior to screening; 
 
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Effective birth control methods: 
a. Double barrier method which can include a male condom, diaphragm, cervical cap, or 
female condom; or  
b. Female participant: Barrier method combined with hormone-based contraceptives or 
an intra-uterine device for the female participant.  
c. Male participants’ female sexual partner: Double barrier method or hormone-based 
contraceptives or an intra-uterine device for the female partner.  
Both male and female participants must be willing to continue practicing birth control 
methods and are not planning to conceive throughout treatment and for 12 weeks after 
the last dose of trial medication or discontinuation from trial medication in case of 
premature discontinuation.  
Note: Hormone-based contraception alone may not be reliable when taking IMP; therefore, 
hormone-based contraceptives alone cannot be used by female participants to prevent 
pregnancy. 
 
5.2 
Exclusion Criteria 
Participants will be excluded from participation if they meet any of the following criteria: 
Medical History and Concurrent Conditions: 
1. Any non-TB related condition where participation in the trial, as judged by the Investigator, 
could compromise the well-being of the participant or prevent, limit or confound protocol 
specified assessments. 
2. Abuse of alcohol or illegal drugs that in the opinion of the Investigator would compromise 
the participants’ safety or ability to follow through with all protocol-specified restrictions, 
visits and evaluations. 
3. Being, or about to be, treated for malaria. 
4. Is critically ill and, in the judgment of the Investigator, has a diagnosis likely to result in 
death during the trial or the follow-up period. 
5. TB meningitis or other forms of extrapulmonary tuberculosis with high risk of a poor 
outcome, or likely to require a longer course of therapy (such as TB of the bone or joint), 
as judged by the Investigator. 
6. History of allergy or hypersensitivity to any of the trial IMP or related substances, including 
known allergy to any fluoroquinolone antibiotic, history of tendinopathy associated with 
quinolones or suspected hypersensitivity to any rifampicin antibiotics. 
7. For HIV infected participants any of the following: 
 
a. CD4+ count <100 cells/µL  
b. Karnofsky score <60% (Appendix 5)   
c. Received intravenous antifungal medication within the last 90 days 
d. WHO Clinical Stage 4 HIV disease (Appendix 3) 
 
8. Participants who recently started or expected to need to start ART within 1 month after 
randomization. Participants who have been on ARTs for more than 30 days prior to start 
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of the Screening visit, or expected to start ART greater than 30 days after randomization 
may be included.  
9. Resistant to fluoroquinolones (rapid, sputum-based molecular screening tests)  
 
a. If they are randomised into the trial due to being sensitive to fluoroquinolones by 
rapid sputum based test, however on receipt of the moxifloxacin phenotypic 
resistance testing in liquid culture they are found to be fluoroquinolones resistant, 
they will be excluded as late exclusions. 
 
10. Having participated in other clinical trials with investigational agents within 8 weeks prior 
to start of trial medication or currently enrolled in an investigational trial. 
11. Participants with any of the following at the Screening visit (per measurements and 
reading done by ECG): 
 
a. QTcF interval on ECG >500 msec.  Participants with QTcF > 450 must be 
discussed with the Sponsor Medical Monitor before enrolment. 
b. Heart failure 
c. A personal or family history of congenital QT prolongation 
d. A history of or known, untreated, ongoing hypothyroidism 
e. A history of or ongoing bradyarrhythmia 
f. 
A history of Torsade de Pointe 
 
12. Unstable Diabetes Mellitus which required hospitalization for hyper- or hypo-glycaemia 
within the past year prior to start of screening. 
13. Females who have a positive pregnancy test at the Screening visit or already known to be 
pregnant, breast-feeding, or planning to conceive a child during the trial or within 6 months 
of stopping treatment.  Males planning to conceive a child during the trial or within 6 
months of stopping treatment. 
Previous and Concomitant Therapy 
14. Previous treatment with pretomanid or bedaquiline. 
15. Previous treatment for TB which includes, but is not limited to, gatifloxacin, amikacin, 
cycloserine, rifabutin, kanamycin, para-aminosalicylic acid, rifapentine, thioacetazone, 
capreomycin, quinolones, thioamides, and metronidazole. 
16. For DS-TB participants: Previous treatment for tuberculosis within 3 years prior to the 
Screening visit. Participants who have previously received isoniazid prophylactically may 
be included in the trial if that treatment is/was discontinued at least 7 days prior to 
randomization. 
17. For the DR-TB participants: Previous treatment for DR-TB/MDR-TB, although may have 
been on a DR/MDR-TB treatment regimen for no longer than 7 days at start of screening. 
18. Any diseases or conditions in which the use of the standard TB drugs or any of their 
components is contra-indicated, including but not limited to drug allergy. 
19. Use of any drug within 30 days prior to randomisation known to prolong QTc interval 
(including, but not limited to, amiodarone, amitriptyline, bepridil, chloroquine, 
chlorpromazine, cisapride, clarithromycin, disopyramide dofetilide, domperidone, 
droperidol, erythromycin, halofantrine, haloperidol, ibutilide, levomethadyl, mesoridazine, 
methadone, pentamidine, pimozide, procainamide, quinacrine, quinidine, sotalol, 
sparfloxacin, thioridazine). 
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20. Use of systemic glucocorticoids within one year of start of screening (topical, inhaled or 
intranasal glucocorticoids are allowed) due to visual opacities or cataracts. 
21. For HIV infected participants, only the following types of ART are permissible:  
 
a. Lopinavir/ritonavir based regimen consisting of lopinavir/ritonavir in combination 
with any two NRTI. TDF/ABC and FTC/3TC. 
b. Integrase inhibitor (e.g., dolutegravir) in combination with TDF/ABC and FTC/3TC. 
c. In participants who have viral load suppressed on efavirenz at the time of 
screening, their ART can be changed to rilpivirine in combination with TDF/ABC 
and FTC/3TC. If possible, the same nucleoside backbone should be used. 
d. Nevirapine (NVP) based regimen consisting of NVP in combination with any two 
nucleosidase reverse transcriptase inhibitors (NRTIs) tenofovir (TDF)/abacavir 
(ABC) and emtricitabine (FTC)/lamivudine (3TC). 
 
22. In the case where participants are randomized to a rifampicin containing regime: 
 
a. EFV can be used with rifampicin.  
b. LPV needs to be double dosed.  
c. Rilpivirine cannot be given with rifampicin  
 
Diagnostic and Laboratory Abnormalities 
23. Participants with the following toxicities at screening as defined by the enhanced Division 
of Microbiology and Infectious Disease (DMID) adult toxicity table (Draft November 2007) 
(Appendix 2) where applicable: 
 
a. platelets grade 2 or greater (<100,000/mm3) 
b. creatinine grade 2 or greater (>1.5 times upper limit of normal [ULN])  
c. eGFR ≤ 60 mL/min/m2 
d. haemoglobin grade 2 or greater (≤8.0 g/dL) 
e. serum potassium less than the lower limit of normal for the laboratory. This may 
be repeated once 
f. GGT: greater than 3 x ULN 
g. AST: 
• 
grade 3 or greater (≥3.0 x ULN) to be excluded; 
• 
results between 1.5 x ULN and 3 x ULN must be discussed with and 
approved by the Sponsor Medical Monitor 
h. ALT: 
• 
grade 3 or greater (≥3.0 x ULN) to be excluded 
• 
greater than ULN must be discussed with and approved by the Sponsor 
Medical Monitor 
i. 
 ALP: 
• 
grade 3 or greater (≥3.0 x ULN) to be excluded 
• 
grade 2 (2.0 – <3.0 x ULN) must be discussed with and approved by the 
Sponsor Medical Monitor 
j. 
Total bilirubin: 
• 
>1.5 x ULN to be excluded; 
• 
1 – 1.5 x ULN must be discussed with and approved by the Sponsor 
Medical Monitor 
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k. Direct bilirubin: 
• 
greater than 1x ULN to be excluded 
All the inclusion and none of the exclusion criteria must be met. If no single variable/value is 
outside of the ranges of acceptability, but when multiple values are close to the limits and/or 
whenever the Investigator has reason to suspect that there might be a health problem (other than 
TB), enrolment should only be considered after discussing the case with the Sponsor Medical 
monitor. 
 No protocol waivers will be granted by the TB Alliance. 
 
5.3 
Restrictions 
Concomitant medications should be kept to a minimum during the trial. However, if concomitant 
medications are necessary for the participant’s welfare and are unlikely to interfere with the IMP, 
they may be given at the discretion of the Investigator. For any concomitant medications given as 
a treatment for a new condition or a worsening of an existing condition occurring after signing of 
the informed consent form, the condition must be documented on the Adverse Event pages of the 
electronic Case Report Form (eCRF). 
The prescribing information for all concomitant medication should be reviewed carefully. The 
determinations listed in the respective contraindicated, warning, and precaution sections must be 
respected to prevent any potentially serious and/or life-threatening drug interactions. 
The following recommendations should be followed with regards to concomitant medication to 
avoid possible drug interaction with the IMP: 
Participants on a moxifloxacin containing treatment arm: The IMP should be taken either 
4 hours before or 8 hours after taking the following products: 
• 
An antacid, multivitamin, or other product that has magnesium, aluminium, iron or 
zinc 
• 
Sucralfate 
• 
Didanosine 
Participants on the HRZE/HR treatment arm: 
• 
Any aluminium-containing antacids should be taken at least one hour after the IMP 
dose. 
The following medicinal products are prohibited from Day -9 to Day -1 (Screening) and during the 
treatment period: 
• 
Quinolone antimalarial (e.g., chloroquine and quinacrine). Participants who have 
malaria at screening are to be excluded. However, if a participant develops malaria 
during the trial, the Investigator is advised to consult the Malaria Treatment Guidance 
document regarding the interaction between moxifloxacin and bedaquiline with anti-
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malarial drugs. Investigators may also contact the Sponsor Medical Monitor for further 
guidance. 
• 
Chronic systemic glucocorticoids (topical, inhaled or intranasal glucocorticoids are 
allowed) due to their potential to cause visual opacities. Short term systemic 
glucocorticoids are allowed for emergency situations (e.g. for treatment of pulmonary 
exacerbation when Inhaled glucocorticoids is inadequate). 
• 
Medicinal products used to treat pulmonary TB: including but not limited to gatifloxacin, 
amikacin, cycloserine, rifabutin, kanamycin, para-aminosalicylic acid, rifapentine, 
thioacetazone, capreomycin, other quinolones, thioamides, and metronidazole. 
The following medicinal products should be avoided from Day 1 (Baseline visit) and during the 
treatment period as much as possible unless discussed with the Sponsor Medical Monitor: 
• 
Any drug known to prolong QTc interval (including but not limited to amiodarone, 
bepridil, chloroquine, chlorpromazine, cisapride, clarithromycin, disopyramide 
dofetilide, domperidone, droperidol, erythromycin, halofantrine, haloperidol, ibutilide, 
levomethadyl, mesoridazine, methadone, pentamidine, pimozide, procainamide, 
quinidine, sotalol, sparfloxacin, thioridazine). The exception is moxifloxacin and 
bedaquiline administered as part of the trial IMP, with ECG monitoring, to help ensure 
participant safety. 
• 
Any 
drug 
known 
to 
be 
hepatotoxic 
(including 
but 
not 
limited 
to 
acetaminophen/paracetamol, acetazolamide, allopurinol, amiodarone, amitriptyline, 
amoxicillin, amprenavir, atorvastatin, augmentin/co-amoxiclav, azathioprine, baclofen, 
bumetanide, captopril, carbamazepine, celecoxib, chlorpromazine, chlorpromazine, 
clindamycin, clopidogrel, contraceptive pill, co-trimoxazole, darunavir, delavirdine, 
diclofenac, doxycycline, enalapril, fluconazole, fluoxetine, fosamprenavir, furosemide, 
gliclazide, glimeperide, glipizide, ibuprofen, irbesartan, ketoconazole, lisinopril, 
loperamide, 
losartan, 
methotrexate, 
metolazone, 
mirtazepine, nitrofurantoin, 
omeprazole, other non-steroidal anti-inflammatory drugs, paroxetine, phenobarbital, 
phenothiazines, phenytoin, pravastatin, probenecid, prochlorperazine, risperidone, 
rosuvastatin, 
sertraline, 
simeprevir, 
simvastatin, 
sodium 
valproate, 
sotalol, 
sulfasalazine, sumatriptan, tamsulosin, terbinafine, tetracycline, theophyllin/uniphyllin, 
tipranavir, tolazamide, tolbutamide, topiramate, trazodone, tricyclic antidepressants, 
trimethoprim, verapamil).  
 
5.4 
Treatment Discontinuation and/or Early Withdrawal  
Any participant for whom the Investigator decides to temporarily discontinue their IMP is to be 
discussed with the Sponsor Medical Monitor and, if applicable, be restarted on IMP as soon as 
possible.  
A participant must be prematurely withdrawn from the trial (during the trial treatment or follow-up 
periods) because of the following: 
• 
Withdrawal of informed consent 
• 
Investigator considers that for safety reasons it is in the best interest of the participant that 
he/she be withdrawn, including a concern that the participant has symptomatic TB and/or 
bacteriological failure/relapse and requires a change in TB treatment. 
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• 
Pregnancy 
• 
At the specific request of the Sponsor or termination of the trial by the Sponsor. 
• 
Lost to follow-up 
• 
Drug-Sensitive TB treatment arms: participants, who have been randomised onto the trial as 
a rifampicin sensitive participant on the rapid sputum based test result, who on receipt of the 
rifampicin resistance testing using an indirect susceptibility test in liquid culture, shows a 
rifampicin resistant result. 
• 
Participants, who have been randomised onto the trial as fluoroquinolone sensitive on the 
rapid sputum based test result, who on receipt of the fluoroquinolone resistance testing using 
an indirect susceptibility test in liquid culture; this shows a fluoroquinolone resistant result. 
• 
Early withdrawal due to TB (see Section 5.4.4) 
A participant may withdraw from the trial at any time at his/her request (withdrawal of consent), 
or may be withdrawn at any time at the discretion of the Investigator for safety, behavioural, 
compliance or administrative issues. When a participant withdraws consent from the trial, no 
additional follow-up visits will be performed. 
Participants who withdraw from the trial after having received IMP will not be replaced.  
All participants withdrawn from trial and who received at least one dose of IMP will be requested 
to return for an Early Withdrawal visit and the applicable safety Follow-Up visits, as per the 
Synopsis Flow Chart and Procedures (Section 1.2 footnote c), as well as Table 5. 
5.4.1 
Early Withdrawal 
In case of early withdrawal during the treatment or follow-up period, all efforts shall be made to 
complete the Early Withdrawal assessments.  At the Early Withdrawal visit the following 
information will be collected and procedures performed: 
• 
Sputum sample collection x 2 (one early morning brought from home and one spot at the 
research site under the coaching and observation of the trial staff).  If no early morning 
sputum sample was provided by the participant, 2 samples may be collected at the site, at 
least 30 minutes apart. 
• 
Urine pregnancy test (women of child bearing potential, whether they are sexually active or 
not) 
• 
Laboratory safety sampling (including male reproductive hormone tests); 
• 
Single 12-lead ECG 
• 
TB Symptoms Profile 
• 
Patient Reported Health Status Questionnaire 
• 
Vital signs 
• 
Full physical examination, including weight 
• 
Ophthalmology examination, if required as described in Table 5 
• 
IMP compliance check (if participant on IMP) 
• 
Concomitant medications 
• 
Adverse events 
Once a participant has been withdrawn early from the trial, they will be requested to attend follow-
up visits as described in Table 5: 
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Table 5: Follow-up Visits Required for Early Withdrawal Participants 
Treatment 
Duration at 
EWD visit 
Ophthalmology 
Examination at 
EWDa 
Ophthalmology 
Examination  
 
Visit 3 months 
after EWD Visita 
Week 52  
(Month12) 
Follow-up 
Visit 
Week 104 
(Month 24) 
Follow-up 
Visit 
≤ 14 days 
Not required 
Not required 
Required 
Required 
15 days to      ≤ 
12 weeks 
Not required 
Required 
Required 
Required 
> 12 weeks  
Required 
Required 
Required, if not 
already 
performed 
Required 
a. If an additional visit is required for an ophthalmology examination after EWD, only the 
ophthalmology examination will be performed at this visit, and it will occur 3 months after the 
EWD visit date. 
The Weeks 52 and 104 (Month 12 and 24) visits will be performed to collect SAE information 
(including verification of survival) and participant reported TB outcome information.  This visit may 
be telephonic, a home or a site visit at Weeks 52 (Month 12) and/or Week 104 (Month 24) after 
the participants’ start of treatment date. 
5.4.2 
Unscheduled Visits 
Any visit which is conducted in addition to those required by the Synopsis Flow Chart and 
Procedures, should be considered unscheduled regardless of the reason for the visit. The 
assessments which are undertaken as part of a Unscheduled visit should be as clinically 
indicated.  
The following situation/s would require an unscheduled visit/s: 
• 
If both sputum samples (Early Morning and Spot) at Week 8 or later are contaminated, the 
participant should return for an unscheduled visit(s) to give additional sputum samples x 
2 (one early morning and one spot at the research site under the coaching and observation 
of the trial staff) or to document that the participant is not able to produce sputum. 
• 
If there is a MTB confirmed positive culture at or after the end of treatment at Week 17 (4-
month treatment) or Week 26 (6-month treatment), the participant should return for an 
Unscheduled visit(s) to give additional sputum samples x 2 (one early morning and one 
spot at the research site under the coaching and observation of the trial staff) or to 
document that the participant is not able to produce sputum. If no early morning sputum 
sample was provided by the participant, 2 samples may be collected at the site, at least 
30 minutes apart. 
To be able to define a participant’s primary outcome status it may be necessary in certain 
situations to contact a participant and request they visit the site to collect additional sputum 
samples at unscheduled visits, as follows: 
• 
To be assessed on sputum culture results from: 
o End of Treatment Period (Week 17 or 26) 
o End of Follow-up Period (Month 12 and 24) 
o Early Withdrawal, if applicable 
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• 
To confirm whether the participant has: 
o two sequential negative sputum culture results; or  
o two sequential positive sputum culture results; or  
o has been unable to produce sputum after documentation of two negative 
sputum cultures with no intervening positive and are clinically asymptomatic 
If they do not fall into one of these categories, two sputum samples x 2 (one early morning and 
one spot at the research site under the coaching and observation of the trial staff) should be taken 
at least 7 days apart until they fall into one of the above categories.  If no early morning sputum 
sample was provided by the participant, 2 samples may be collected on site at least 30 minutes 
apart. 
If the Investigator is unsure of the outcome in any of the above scenarios the Investigator is to 
contact the Sponsor Medical Monitor and discuss and agree on how the participant is to be 
managed. 
5.4.3 
Lost-to-Follow-up 
Every reasonable attempt must be made to minimise Lost-to-Follow-up (LTFU) participants.  A 
minimum of three contact attempts (telephonic/home visit) will be made for participants who do 
not arrive for their scheduled trial visits. If these attempts are unsuccessful the participant will be 
considered LTFU.  All attempts to contact the participant must be clearly documented in the 
participant’s source documents. 
5.4.4 
Early Withdrawal due to TB 
Ultimately it is the Investigator’s decision whether a participant requires early withdrawal from the 
trial due to a concern that the participant has symptomatic worsening of TB and/or bacteriological 
failure/relapse.  
Early withdrawal is usually not indicated for a single positive culture.  Should a participant have a 
single positive culture result after being negative, the Investigator is to evaluate whether the 
participant has signs and symptoms suggestive of active inadequately treated TB and whether it 
is in the participants best interest that he/she be withdrawn. Prior to early withdrawal of a 
participant due to TB, the Investigator must discuss the participant with the Sponsor Medical 
Monitor, unless the Investigator cannot contact the Sponsor Medical Monitor and considers that 
early withdrawal must occur immediately due to immediate safety concerns with respect to the 
participant. 
If the Investigator decides to withdraw a participant due to TB, additional sputum samples may 
need to be collected to ensure the participant’s outcome status as determined in Section 5.5. 
All early withdrawn participants who are confirmed sputum positive (two sequential sputum 
positive cultures) and/or have symptomatic TB will require further TB treatment. These 
participants will be referred to their applicable DS/DR local community TB clinics for standard anti-
tuberculosis chemotherapy according to National TB Treatment Guidelines. The participants will 
be provided with a referral letter from the Investigator to take with them to the TB clinic.  A follow-
up call will be made by the trial site staff to the clinic to ensure the participant attended the clinic.  
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5.5 
Participant Progress Definitions 
Status 
Treatment 
Follow-Up 
Screen Failure 
Participants from whom informed consent is obtained and is 
documented in writing (i.e., participant signs an informed consent form) 
but who are not randomized 
Completed 
Treatment / 
Completed 
Follow-Up* 
Participants who complete 
the full course of IMP 
Participants who complete all follow-up 
visits 
Completed 
Treatment / 
Discontinued 
Follow-Up 
Participants who complete 
the full course of IMP 
Participants who do not complete all 
applicable follow-up visits, regardless of 
the reason (excluding LTFU) 
Completed 
Treatment / Lost 
to Follow-Up 
Participants who complete 
the full course of IMP 
Participants who are unable to be 
contacted on or before their final visit 
Discontinued 
Treatment / 
Completed FU 
Participants who discontinue 
treatment prior to completion 
of the protocol-defined 
treatment course 
Participants who complete all applicable 
follow-up visits 
Discontinued 
Treatment / 
Discontinued 
Follow-Up** 
Participants who discontinue 
treatment prior to completion 
of the protocol-defined 
treatment course 
Participants who do not complete all 
applicable follow-up visits, regardless of 
the reason (excluding LTFU) 
Lost to Follow-Up 
Participants who are unable to be contacted on or before their final 
treatment visit and it cannot be confirmed whether treatment was 
completed 
* 
Note that this includes treatment failures who complete all applicable follow-up visits 
** 
Early Withdrawal 
5.6 
Trial Stopping Rules 
There are no trial specific stopping rules.  
The trial or parts of the trial can be stopped by the Sponsor on advice from the Data Safety and 
Monitoring Committee (DSMC) after their review of applicable trial data.  In addition, the Sponsor 
has the right to stop the trial or a specific trial site at any time, although this should only occur 
after consultation between the involved parties.  Should this occur, the local and central Ethics 
Committee/Institutional Review Board (EC/IRB) and Regulatory Authorities will be informed.   
Should a trial site be closed prematurely, all trial materials (except documentation that must 
remain at the site) will be returned to the Sponsor or vendor.   The Investigator will retain all other 
documents until notification given by the Sponsor for destruction.  Participants currently on 
treatment will receive an appropriate regimen and all participants will be referred to their 
applicable DS-TB/DR-TB National Treatment Program. 
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6.0 
Treatment 
6.1 
IMP Administration  
6.1.1 
Instructions for Dosing of Test Regimen (BPaMZ):  
• 
Treatment will be orally administered once daily, to be taken during breakfast, with a full 
glass of water (approximately 240 ml), for 17 weeks (4 months) or 26 weeks (6 months). 
 
6.1.2 
Instructions for Dosing Control Treatment Regimen (HRZE/HR): 
• 
To be taken with a glass of water (approximately 240 ml). 
• 
HRZE or HR should not be taken with a meal (generally, no closer to meals than 1 hour 
before or 2 hours after a meal) in the following dosing schemes. 
HRZE/HR treatment will be administered orally once daily to DS-TB participants as follows: 
Weight Band 
Weight Range 
Number of tablets 
per weight band 
1 
30-39 kg 
2 
2 
40-54 kg 
3 
3 
55-70 kg 
4 
4 
≥ 71 kg 
5 
 
A daily supplement of Vitamin B6 will be provided by the trial site to participants randomised to 
the HRZE/HR treatment arm, per each country’s National TB Treatment Guideline.   
6.2 
Participant Compliance 
During site clinic visits, the IMP will be administered by the Investigator(s)/designated site 
personnel and when possible, the check for IMP compliance via the hand-and-mouth procedure 
(both the hand and the mouth of the participant will be checked to ensure that the participant has 
swallowed the IMP). During the trial, sites will be responsible for ensuring participants are taking 
IMP correctly and are fully trained on how the IMP is to be taken as well as check cards for unused 
tablets in the containers at each visit during the treatment phase.  
6.3 
Treatment Modification(s) 
The importance of adherence to the treatment schedule will be reinforced at each visit.  Non-
adherence should prompt the Investigator to identify and address the cause(s) (e.g. side effects).  
 
Participants that do not take: 
 
• 
Up to 7 consecutive doses of IMP doses: restart IMP, no extension of IMP required. 
• 
Greater than 7 to ≤ 35 consecutive doses of IMP: restart IMP and extend the IMP 
treatment by the number of consecutive doses missed. The final treatment visit should 
also be pushed out to the date of last dose. It is not necessary to have an unscheduled 
visit at the time when the end of treatment visit would have been.   
• 
Greater than 35 consecutive doses of IMP, discontinue IMP and withdraw participant 
from the trial. 
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• 
If the participant misses a total (sum) of 56 cumulative missed doses, discontinue IMP 
and withdraw participant from the trial. 
Any participant for whom the trial medication is discontinued (including for non-adherence) will be 
discussed with the Sponsor Medical Monitor and, if applicable, the participant will be restarted on 
trial medication as soon as possible.  
6.4 
IMP Packaging and Labelling 
The complete formulations of the IMP, bedaquiline and pretomanid, are found in the respective 
Investigator Brochures.[8, 15] The complete formulations of moxifloxacin, pyrazinamide, HRZE/HR 
are found in the Package Inserts.[19, 20, 22, 40]  
The IMP will be packaged in weekly or bi-weekly cards as follows: 
Week 1 to 8 Cards: Dispensed Weekly 
IMP 
Strength 
Number of tablets 
Abbreviation 
Bedaquiline 
100 mg 
14 
B 
Pretomanid 
200 mg 
7 
Pa 
Moxifloxacin 
400 mg 
7 
M 
Pyrazinamide 
500 mg 
21 
Z 
 
Week 9 to 17/26 Cards: Dispensed Weekly 
IMP 
Strength 
Number of tablets 
Abbreviation 
Bedaquiline 
100 mg 
7 
B 
Pretomanid 
200 mg 
7 
Pa 
Moxifloxacin 
400 mg 
7 
M 
Pyrazinamide 
500 mg 
21 
Z 
 
Control (HRZE/HR) Group: Dispensed Bi-weekly 
Weight Band 
Weight Range 
Number of tablets 
per weight band 
Number of tablets 
in each card 
1 
30-39 kg 
2 
28 
2 
40-54 kg 
3 
42 
3 
55-70 kg 
4 
56 
4 
≥71 kg 
5 
70 
 
A daily supplement of Vitamin B6 will be provided by the trial site to participants randomised to 
the HRZE/HR treatment arm, per each country’s National TB Treatment Guideline. 
The packaging of each weekly and biweekly cards will be labelled with, at a minimum, the 
following information: 
• 
Name of Sponsor 
• 
Name of medication 
• 
Dosage, quantity and method of administration  
• 
Reference/lot number 
• 
The statement “For Clinical Trial Use Only” 
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• 
Space for completion of name of Investigator and site number 
• 
MedID: medication identification number 
• 
Storage conditions 
• 
Period of use 
• 
The statement “Keep out of reach of children” 
• 
Expiry date 
• 
Directions for use 
• 
Space for completion of participant number and visit/date dispensed 
6.5 
Blinding and Procedures for Breaking the Blind 
As this is an open label trial there is no need for blinding or procedures to break the blind. The 
trial participants, the site staff, Sponsor, and CROs will not be blinded to treatment assignment.  
6.6 
Handling, Storage and Accountability  
The Investigator or designee must confirm that the appropriate temperature conditions as per 
details on IMP labelling, have been maintained during transit for all trial treatment received and 
any discrepancies are reported and resolved before use of the trial treatment. 
Only participants randomised in the trial may receive trial treatment and only authorized site staff 
may supply or administer trial treatment. All trial treatments must be stored in a secure, 
environmentally controlled, and monitored (manual or automated) area in accordance with the 
labelled storage conditions with access limited to the Investigator and authorized site staff. 
The Investigator, institution, or the head of the medical institution (where applicable) is responsible 
for trial treatment accountability, reconciliation, and record maintenance (i.e., receipt, 
reconciliation, and final disposition records).  Upon completion or termination of the trial, all 
unused and/or partially used IMPs must either be returned to Sponsor (or designated vendor: who 
will arrange for destruction) or destroyed at site as agreed by Sponsor, after final accountability 
has been confirmed. 
The Investigator/designee will immediately inform the Sponsor of any quality issues arising with 
respect to the trial medication. The Sponsor will take whatever action is required should such a 
situation arise. 
Further guidance and information for the handling, storage, accountability and final disposition of 
unused trial treatment are provided in the pharmacy manual. 
7.0 
Trial Variables and Procedures 
The Synopsis Flowchart and Procedures in Section 1.2  should be referenced for timing, 
sequence of assessments, and specific procedures. 
7.1 
Demographic and Background Variables and Procedures 
The following demographic and background variables will be collected: 
• 
Written Informed Consent 
• 
Visit dates 
• 
Participant disposition 
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• 
Demography (date of birth, race and gender) 
• 
Inclusion and exclusion criteria 
• 
Clinically significant medical and TB treatment history (including past and current TB 
diagnosis, smoking and alcohol use) 
• 
Screening coached spot sputum samples: 
o Smear microscopy for acid-fast bacilli 
o Gene Xpert, Hain Assay MTBDRplus or equivalent to determine MTB complex and 
rifamycin resistance 
• 
Urine pregnancy test: women of childbearing potential only, whether they are sexually 
active or not (Non-childbearing potential for a female participant is defined as having 
bilateral oophorectomy, bilateral tubal ligation and/or hysterectomy or has been 
postmenopausal with a history of no menses for at least 12 consecutive months). 
• 
Serology: HIV and CD4 count.  Where required by regulatory authorities or ethics 
committees, a separate (EC/IRB approved) HIV informed consent form will be obtained 
from participants: 
o Prior to HIV testing and on receipt of the results, participants will be counselled on HIV 
by trained counsellors if they have indicated as such on the HIV consent form. If 
requested by the participant, HIV counselling that is provided to the participant by the 
trial site should be clearly documented in the participant’s medical records/source.  
Participants have the right to decline to know or receive their HIV test results. This 
decision should be clearly documented in the participant’s medical records/source.   
• 
Karnofsky Score (Appendix 4) 
• 
Chest X-Ray: A chest X-ray digital image within 6 months prior to or during the Screening 
visit, will be obtained and read locally by the Investigator or designee.  Digital images will 
be provided to the Sponsor; this process will be documented in the Radiology Manual.  The 
investigator is responsible for review and analysis of the chest X-ray for participant’s 
inclusion. 
• 
Method of birth control: male and female participants and their partners 
• 
IMP details: randomization 
• 
IMP compliance and actual dosing 
• 
Concomitant medications 
7.2 
Efficacy Variables and Procedures 
Two spot sputum samples are collected, one early morning brought from home or collected in the 
hospital ward (only if the participant is hospitalised) and one spot sputum sample collected at the 
research site under the coaching and observation of the trial staff or, if no early morning sputum 
sample was provided by the participant, 2 samples may be collected on site at least 30 minutes 
apart. The mycobacteriology sampling methodology and requirements will be described in a 
separate document, the Mycobacteriology Laboratory Manual, which will be provided prior to the 
trial start. Sputum samples may not be obtained by induction. 
The following analyses will be performed: 
• 
Liquid culture (MGIT), to detect presence or absence of MTB and obtain the TTP followed 
by a speciation test when applicable, to confirm MTB. 
 
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Using these observed variables, the following derived variables will be assessed for evaluation of 
the efficacy endpoints: 
• 
Bacteriologic failure/relapse 
• 
Time to sputum culture conversion 
• 
Number of participants with sputum culture conversion 
 
Every effort must be made to collect sputum samples. However, in general, the inability to produce 
sputum is treated as being equivalent to having a negative culture (favourable) result.  A 
participant who never achieves culture negative status due to the inability to produce sputum, but 
has completed Week 26 (6 months) post treatment completion follow-up and is without clinical or 
biological evidence of relapse, will be considered to have a favourable outcome. 
TB Symptoms Profile:  
• 
The TB Symptoms Profile (Appendix 6) will record participants’ ratings of the severity of 
common TB symptoms.  
 
Patient Reported Health Status Variables and Procedures:  
• 
The Patient Reported Health Status variables will be collected at the time points described 
in the Synopsis Flow Chart and Procedures (Section 1.2). Patient Reported Health Status 
will be collected using the EQ-5D-5L Health Questionnaire (Appendix 7). This descriptive 
system consists of five health-related quality of life dimensions, each of which will be 
recorded using five levels of severity.  
 
Methodology: The Patient Reported Health Status methodology and requirements will be 
described in a separate document/guideline which will be provided prior to the trial start. 
7.3 
Safety and Tolerability Assessments 
The following safety and tolerability variables will be collected at the time points described in the 
Synopsis Flow Chart and Procedures and assessed for evaluation of the safety endpoints: 
• 
Laboratory parameters. The safety laboratory sampling methodology and requirements will 
be described in a separate document, the Safety Laboratory Manual, which will be provided 
prior to the trial start. The following analyses will be performed: 
 
o Full Blood Count (haemoglobin, haematocrit, red blood cell count, white blood cell 
count with differential, platelet count) 
o Clinical Chemistry (albumin, serum urea, creatinine, direct, indirect and total bilirubin, 
uric acid, total protein, ALP, AST, ALT, lipase, phosphate, sodium, potassium, calcium 
(corrected for albumin), chloride, magnesium, glucose, bicarbonate/CO2, creatine 
phosphokinase (CPK). GGT is only routinely included at the Screening visit (Day -9 to 
-1).  
o When managing participants with elevated liver enzymes at an Unscheduled visit, the 
investigator can request additional tests, in addition to the repeat LFT [e.g. Gamma 
Glutamyl Transferase (GGT), screening for Hepatitis A, B, C; to assist in ruling out 
other causes of a dysfunctional liver test (e.g. alcohol induced hepatic cell injury, 
hepatobiliary disease, hepatic viral infection)]. 
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o Urinalysis (pH, specific gravity, protein, glucose, micro-albumin, ketones, bilirubin, 
creatinine, nitrite, sodium, urobilinogen, blood, leukocytes). Microscopy will be 
completed as follow up to abnormal urinalysis per discretion of Investigator 
• 
12-lead ECG: 
o Investigator assessment: normal or abnormal 
o Central cardiologist assessment: heart rate, PR interval, RR interval, QT, corrected QT 
Interval (QTc) (QTcB and QTcF), QRS. 
o Methodology: 
 
Timing and registration technique for ECGs will be standardized for all participants 
and will be described in a separate document which will be provided prior to the trial 
start 
 
ECGs are to be recorded for 10 seconds 
 
ECGs are to be performed during a single visit 
 
ECGs should be done before any phlebotomy when both included in a visit 
 
For each participant, the ECGs should, to every extent possible, be collected at 
approximately the same time of day (+/- 1 hours) and in the same fed/fast state 
throughout the trial (e.g. 4 hours after lunch) 
• 
Vital signs: 
o Vital signs (should be done before any phlebotomy in light clothing and with no shoes) 
o Systolic and diastolic blood pressure (mmHg) to be measured in a supine position (after 
5 minutes of rest) using an appropriately sized cuff, and using the same type of 
sphygmomanometer, if possible by the same observer, at each relevant visit 
o Heart rate (beats per minute) 
o Respiratory rate (breaths per minute)  
o Axillary body temperature (°C) 
• 
Physical Examination:  
o Height (m) is measured at the screening visit only 
o Full (complete) and limited (gross neurological, pulmonary, cardiovascular and 
abdominal) examinations will be performed and any clinically significant findings will be 
recorded 
o Weight (kg) (in light clothing and with no shoes) 
o Using the variables of weight and height, the body mass index (BMI) will be calculated 
• 
Ophthalmology Slit Lamp Examination: 
o To be done by an Ophthalmologist trained on Age-Related Eye Disease Scale 2 
(AREDS2) assessment. The ophthalmology slit lamp methodology and requirements will 
be described in a separate document, the Ophthalmology Guideline. The following 
analyses will be performed: AREDS2 opacity typing and grading. 
• 
Adverse events 
• 
Investigator assessment:  
o The Investigator will review the participant status at specified visits in the Synopsis Flow 
Chart and Procedures, including any time the Investigator determines that the participant 
fulfils the criteria for the primary outcome of treatment failure. The Investigator will 
assess whether TB treatment is considered a “success” or “failure”.  If it is considered a 
failure, the Investigator should specify if the assessment is based on bacteriology and/or 
clinical deterioration and/or radiological deterioration. 
7.4 
PK Variables and Procedures 
Plasma concentrations from sparse sampling (see Section 1.2) will be used to update population 
PK models for bedaquiline and its M2 metabolite, pretomanid, and linezolid to further evaluate 
the effects of covariates on model parameters in this trial population.   
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PK data from the current trial may be combined with prior data (e.g., from the NiX-TB trial) to 
enhance this population PK analysis. The models will be used to estimate individual exposure 
metrics (e.g., Cmin, Cmax, AUCτ, Cmean, and time above minimum inhibitory concentration) for 
subsequent analyses exploring relationships between drug exposure and efficacy and safety 
endpoints. 
 
7.5 
Mycobacteriology Characterization Variable and Procedures 
The following Mycobacterial Characterization variables will be collected: 
Positive Culture (for MTB) from: 
 
• 
Day 1 or if Day 1 is not available, first positive result between screening through Week 4 
• 
Pre-screening culture that was used for the tests that qualified the participant for inclusion 
into the trial to be sub-cultured and sent to the central microbiology laboratory from the 
applicable local microbiology laboratory, for relevant participants / no positive cultures 
from screening through week 4  
• 
When applicable, at last visit of the treatment period (Week 17 for the 4-month treatment 
arm and Week 26 for the 6-month treatment arm) or visits with positive cultures, during 
the post-treatment follow-up period 
 
The MTB isolates will be processed at the central microbiology laboratory for: 
 
• 
MIC against bedaquiline, pretomanid and moxifloxacin  
• 
Drug Susceptibility Testing in liquid culture for streptomycin, rifampicin, isoniazid, 
ethambutol, moxifloxacin and pyrazinamide, and second line TB drugs including but not 
limited to fluoroquinolones, and injectables 
• 
Extraction of organismal (MTB) DNA for whole genome sequencing, and the comparison 
of sequences from baseline and relapse isolates. 
 
All Day 1 (Baseline) MTB isolates and isolates from positive cultures to be stored at the local and 
central microbiology laboratories, until trial closure.  Extracted MTB DNA to be stored at the 
central microbiology laboratory until trial closure. The extracted MTB DNA and isolates will then 
be stored for potential further work to advance new assay tools and understanding of MTB as a 
pathogen for a maximum of 5 years after trial closure.  
 
The MTB isolates will be processed at the trial microbiology laboratories for positive MTB complex 
at/after the last visit of the treatment period (Week 17 for the 4-month treatment arm and Week 
26 for the 6-month treatment arm) via Hain MTBDRplus and HainMTBRsl. 
 
8.0 
Adverse Events 
8.1 
Definitions 
8.1.1 
Adverse Event (AE) 
Any untoward medical occurrence in a clinical investigation participant, temporally associated with 
the use of a trial treatment whether or not considered related to trial treatment. An AE can 
therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), 
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symptom, or disease (new or exacerbated) temporally associated with the use of a trial treatment, 
whether or not related to the trial treatment. 
8.1.2 
Serious Adverse Event (SAE) 
Any untoward medical occurrence that at any dose: 
• 
Results in death 
• 
Is life threatening (any event in which the participant was at risk of death at the time of the 
event; it does not refer to an event, which hypothetically might have caused death if it were 
more severe) 
• 
Requires inpatient hospitalisation or prolongation of existing hospitalisation; In general, 
hospitalisation signifies that the participant has been detained (usually involving at least 
an overnight stay) at the hospital or emergency ward for observation and/or treatment that 
would not have been appropriate in the physician’s office or outpatient setting. 
Complications that occur during hospitalisation are AEs. If a complication prolongs 
hospitalisation or fulfils any other serious criteria, the event is serious. When in doubt as 
to whether “hospitalisation” occurred, or was necessary, the AE should be considered 
serious. Hospitalisation for elective treatment of a pre-existing condition that did not 
worsen from baseline is not considered an AE. 
• 
Results in persistent or significant disability/incapacity; the term disability means a 
substantial disruption of a person’s ability to conduct normal life functions. This definition 
is not intended to include experiences of relatively minor medical significance such as 
uncomplicated headache, nausea, vomiting, diarrhoea, influenza, and accidental trauma 
(e.g., sprained ankle) which may interfere with or prevent everyday life functions but do 
not constitute a substantial disruption. 
• 
Is a congenital anomaly/birth defect; or 
• 
Is a medically important event 
Note:  Medical and scientific judgment should be exercised in deciding which is a medically 
important event that may not be immediately life-threatening or result in death or hospitalisation, 
but may jeopardize the participant or may require medical or surgical intervention to prevent one 
of the outcomes listed above.   
Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias or convulsions that do not result in hospitalisation, or the 
development of drug dependency or drug abuse. A “suspected transmission of infectious agent 
by a medicinal product” is also considered a serious adverse event under the SAE criterion “Other 
medically important condition”.     
8.1.3 
Attribution/Causality 
• 
The Investigator is obligated to assess the relationship between trial treatment and each 
occurrence of each AE/SAE 
• 
The Investigator will use clinical judgment to determine the relationship 
• 
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to trial treatment administration 
will be considered and investigated 
• 
The Investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment 
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• 
For each AE/SAE, the Investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality 
• 
There may be situations in which an SAE has occurred and the Investigator has minimal 
information to include in the initial report to the Sponsor/designee. However, it is very 
important that the Investigator always assesses causality for every event before the initial 
transmission of the SAE data to the Sponsor/designee. 
• 
The Investigator may change his/her opinion of causality in light of follow-up information 
and send a SAE follow-up report with the updated causality assessment 
Table 6: Adverse Events Attribution/Causality Ratings  
Relatedness Rating 
Definition 
Not Related 
An AE, which is not related to the use of the drug. 
Unlikely 
An AE for which an alternative explanation is more likely, e.g., 
concomitant drug(s) or concomitant disease(s), and/or the 
relationship in time suggests that a causal relationship is unlikely. 
Possible 
An AE, which might be due to the use of the drug.  An alternative 
explanation, e.g., concomitant drug(s) or concomitant disease(s), is 
inconclusive.  The relationship in time is reasonable; therefore, the 
causal relationship cannot be excluded. 
Probable 
An AE, which might be due to the use of the drug.  The relationship 
in time is suggestive, e.g., confirmed by de-challenge.  An alternative 
explanation is less likely, e.g., concomitant drug(s) or concomitant 
disease(s). 
Certain 
An AE, which is listed as a possible adverse reaction and cannot be 
reasonably explained by an alternative explanation, e.g., concomitant 
drug(s) or concomitant disease(s).   
 
8.1.4 
Severity 
Table 7: Definitions for Adverse Event Severity Gradings 
Grade 
Severity Rating 
Definition 
GRADE 1 
Mild 
Transient or mild discomfort (< 48 hours); no medical 
intervention/therapy required. 
GRADE 2 
Moderate 
Mild to moderate limitation in activity - some assistance 
may be needed; no or minimal medical intervention/therapy 
required. 
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. 
 
See Appendix 2 for full DMID Toxicity Tables. Above ratings should be used to estimate the grade 
for abnormalities NOT found elsewhere in the Toxicity Tables. 
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8.2 
Reporting 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and non-
leading verbal questioning of the participant is the preferred method to inquire about AE 
occurrences. 
All AEs will be collected by the Investigator from the time a participant signs the Informed Consent 
Form through to their Week 104 (Month 24) follow-up visit. The exception to this is early 
withdrawal participants who will only have SAEs collected from their time of early withdrawal to 
their Week 104 (Month 24) follow-up visit at the timepoints specified in the Synopsis Flow Chart 
and Procedures (Section 1.2) and recorded in the CRF.   
Medical occurrences that begin after obtaining informed consent will be recorded as AEs. If an 
AE started before signing of the informed consent, but is ongoing at trial start, it should be 
recorded as medical history.  If the pre-existing medical occurrence worsens during the trial, an 
AE will be recorded. 
All SAEs will be recorded and reported to the Sponsor or designee within 24 hours of the 
information becoming known to the Investigator, as noted in the SAE reporting guidelines. The 
Investigator will submit any updated SAE data to the Sponsor within 24 hours of information 
becoming known to the Investigator.  
The Sponsor/Investigator/designee will inform Regulatory Authorities and/or EC/IRB of all SAEs 
in accordance with local requirements and ICH guidelines for GCP. 
The Sponsor/designee will forward Safety Notification letters to the investigator for submission to 
the EC/IRB. 
Investigators are not obligated to actively seek AE or SAE information in former trial participants. 
However, if the Investigator learns of any SAE, including a death, at any time after a participant 
has been discharged from the trial, and he/she considers the event to be reasonably related to 
the trial treatment or trial participation, the Investigator must promptly notify the Sponsor, EC/IRB 
and regulatory authorities in an expedited basis, in accordance with local requirements and ICH 
GCP Guidelines. 
8.2.1 
Follow up of Adverse Events 
All AEs will be followed until: 
• 
Satisfactory clinical resolution or stabilization; or 
• 
The end of the follow-up period; and  
• 
All queries on these AEs have been resolved.   
Certain long-term AEs cannot be followed until resolution within the setting of this protocol. In 
these cases, follow-up will be the responsibility of the Investigator.  However, this will have to be 
agreed upon with the Sponsor Medical Monitor. 
The Investigator is obligated to perform or arrange for the conduct of supplemental measurements 
and/or evaluations as medically indicated or as requested by sponsor or representative to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may include 
additional laboratory tests or investigations, histopathological examinations, or consultation with 
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other health care professionals.  The Investigator should contact the Sponsor/designee to discuss 
appropriate medical follow-up if consultation is required.  
If a participant dies during participation in the trial or during a recognized follow-up period, the 
Investigator will provide the Sponsor/representative with a copy of any post-mortem findings, 
including histopathology. 
New or updated information will be recorded in the originally completed CRF and submitted to the 
Sponsor within 24 hours of receipt, per SAE reporting guidelines. 
8.2.2 
Clinical Laboratory Adverse Events 
Changes in the results of the clinical laboratory assessment results and which the Investigator 
determines are clinically significant will be reported as AEs.  It is the Investigators’ responsibility 
to review the results of all laboratory tests as they become available.  This review must be 
documented by the Investigators’ dated signature on the laboratory report.  For each abnormal 
laboratory test result, the Investigator needs to ascertain and document if this is a clinically 
significant change from baseline for that individual participant.  This determination, however, does 
not necessarily need to be made the first time an abnormal value is observed.  The Investigator 
may repeat the laboratory test or request additional tests to verify the results of the original 
laboratory tests.  If this laboratory value is determined by the Investigator to be a clinically 
significant change from baseline for that participant, it is considered to be an AE. 
8.2.3 
Disease Symptoms During Trial 
Symptoms of the disease under trial (Tuberculosis) experienced by the participant while on the 
trial will be assessed by the Investigator.  If the symptom has: 
o worsened while the participant is in the trial; and  
o the Investigator assesses it as clinically significant; 
it will be recorded as an adverse event. If there is: 
o no change; and  
o the Investigator assesses the symptom as due to the participant’s TB; and  
o not clinically significant; 
it will not be recorded as an AE and this will be noted in the participant’s source documentation. 
All TB related symptoms that meet SAE criteria will be recorded and reported as a SAE. 
8.2.4 
Overdose 
Overdose of the IMP experienced by the participant while on the trial, will be assessed by the 
Investigator to determine whether the overdose led to an adverse event, including if the taking of 
the suspected medicine led to suicidal intention and subsequent overdose of the suspected 
medicine, or other medication. In this case it will be recorded as an adverse event. If it does not 
lead to an adverse event, it will not be recorded as an AE and this will be noted in the participant’s 
source documentation. 
8.2.5 
Drug Interaction 
If the Investigator becomes aware that the participant has experienced a drug interaction which 
has resulted in an adverse event, it will be recorded as an adverse event. 
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8.2.6 
Pregnancy 
The Investigator will immediately notify the Sponsor of any pregnancy that is discovered during 
IMP administration or which started during IMP administration.  Pregnancy forms will be 
completed for all pregnancies reported during the clinical trial, as defined below. In addition, the 
investigator will report to the Sponsor any follow up information regarding the outcome of the 
pregnancy, including perinatal and neonatal outcome.  Infants will be followed-up for 6 months.   
All women of childbearing potential will be instructed to contact the investigator immediately if 
they suspect they might be pregnant (for example, missed or late menses) for the following 
time-periods: 
• 
Any time during the trial 
• 
Within 6 months after the last dose of IMP 
If a pregnancy is suspected while the participant is receiving IMP, the IMP will be withheld 
immediately until the result of the pregnancy test is known.  If pregnancy is confirmed, the IMP 
will be permanently discontinued in an appropriate manner and the participant withdrawn from 
the trial. Protocol-required procedures for trial discontinuation and follow-up will be performed 
unless contraindicated by the pregnancy. 
Pregnancy reporting will follow the same timelines for a SAE (see above). Instructions and 
forms will be provided separately. SAE reporting will also occur if the pregnancy outcome is a 
congenital anomaly.  This will follow the reporting procedures described above for SAE reporting. 
8.3 
Monitoring for Specific Toxicities  
Monitoring for specific toxicities is based upon target organs as defined in the preclinical toxicity 
studies of the Investigator’s Brochures[8, 15] and Package Inserts.[19, 20, 22, 40] 
AEs still ongoing at the end of the treatment period in the trial will be followed until satisfactory 
clinical resolution or stabilization, or until the end of the follow-up period and until all queries on 
these AEs have been resolved.   
Grade 3 and Grade 4 laboratory abnormalities, and laboratory abnormalities considered clinically 
significant should be followed until satisfactory resolution or stabilization. 
Note: For Grade 3 or 4 laboratory toxicities, participants should have a confirmatory 
measurement within 48 hours, where possible. The recommendations for managing 
participants below assumes that the laboratory abnormalities of concern have been confirmed. 
 
8.3.1 
ALT, AST and Bilirubin Elevations 
The Investigator should refer to Appendix 8 Liver Toxicity Management, to appropriately monitor 
significant elevations of AST, ALT or Bilirubin. A separate Hepatoxicity Management Guideline 
document has been developed to aid investigators in the management of participants. 
When managing participants with elevated liver enzymes at an Unscheduled visit, the investigator 
can request additional tests, in addition to the repeat LFT [e.g. Gamma Glutamyl Transferase 
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(GGT), screening for Hepatitis A, B, C; to assist in ruling out other causes of a dysfunctional liver 
test (e.g. alcohol induced hepatic cell injury, hepatobiliary disease, hepatic viral infection)]. 
8.3.2 
Lipase 
Grade 3 (> 2.0 to ≤ 5.0 x ULN) or Grade 4 (> 5.0 x ULN): 
• 
Contact the Sponsor Medical Monitor to review. Participants with confirmed Grade 3 or 
4 elevations of lipase, the Investigator should consider pausing the full regimen, pending 
further evaluation. 
8.3.3 
Neurological 
Participants co-administration with a serotonergic agent, including anti-depressants, should be 
monitored closely for signs of serotonin syndrome.  The Investigator should determine whether 
the full regimen or the concomitant agent should be discontinued for those who experience signs 
or symptoms of serotonin syndrome such as cognitive dysfunction, hyperrexia, hyperreflexia and 
incoordination. 
8.3.4 
Musculoskeletal System and Cardiac Muscle Myalgia 
Grade 2 (muscle tenderness at a site other than sites of injection and/or venepuncture or with 
moderate impairment of activity) or Grade 3 (severe muscle tenderness with marked impairment 
of activity) or Grade 4 (frank myonecrosis): 
• 
Participants with Grade 2 signs and symptoms should be followed closely. Participants 
with Grade 3 or 4 signs and symptoms should be discussed with the Sponsor Medical 
Monitor to consider pausing trial medication, pending further evaluation. 
8.3.5 
Cardiac Rhythm Disturbances 
Cardiac rhythm disturbances that are Grade 3 (recurrent, persistent, symptomatic arrhythmia 
requiring treatment) or Grade 4 (unstable dysrhythmia requiring treatment): 
• 
Participants should be monitored closely.  The Investigator should discuss with the 
Sponsor Medical monitor to consider pausing the full regimen, pending further evaluation. 
QTc prolongation  
If QTcF is equal to or greater than 500 msec, the ECG should be repeated and serum electrolytes 
should be evaluated. If the second ECG also has a QTcF of > 500 msec, the Sponsor Medical 
monitor should be consulted to consider pausing the full regimen, pending further evaluation. 
New left bundle branch block (LBBB) or Mobitz type 2 or complete heart block. Recordings with 
artifacts that interfere with the interpretation of the ECG should be repeated to confirm the 
findings. If the finding is from the centralized ECG machine reading the result is to be checked 
and confirmed by the Investigator.  If this is confirmed by the Investigator, dosing is to be paused 
until the reading has been confirmed by the central cardiologist and the participant is to be treated 
per the Investigator’s clinical judgment. If it is confirmed by the central cardiologist, the participant 
is to be withdrawn from the full regimen.  Contact Sponsor Medical monitor to review.  
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8.4 
Safety Monitoring by Data Monitoring Committee 
A Data Safety Monitoring Committee (DSMC) will be appointed for the trial. The primary 
responsibility of the DSMC will be to act in an advisory capacity to the Sponsor to safeguard the 
interests of trial participants by monitoring participant safety, assess participant risk versus 
benefit, and assess data quality and general evaluation of the trial progress. Its activities will be 
delineated in a DSMC charter that will define the membership, responsibilities and the scope and 
frequency of data reviews.  
The DSMC will operate on a conflict-free basis independently of the Sponsor and the trial team. 
It will comprise at least 3 voting members that include at least 2 clinicians and one statistician.   
The DSMC may have an organizational meeting prior to commencement of the trial. The DSMC 
will have meetings where it will review unblinded data during a closed session. These meetings 
will be planned at regular intervals.  
The Sponsor or the DSMC may convene ad hoc meetings based on rates of SAEs and/or to 
review results of the futility analysis, or if safety concerns arise during the trial.  After its 
assessment, the DSMC will recommend to the Sponsor continuation, modification or termination 
of the clinical trial.  
9.0 
Statistical Analysis 
The statistical analysis plan (SAP), which will contain details of the analyses specified in this 
section, will be written and signed off prior to first patient randomized. 
9.1 
Analysis Populations 
There will be three main analyses of the primary efficacy endpoint: An intent to treat (ITT) analysis; 
a modified intent to treat (mITT) analysis and a per protocol (PP) analysis 
• 
The ITT population is defined as all randomized participants excluding late screening 
failures. Late screening failures are participants withdrawn from treatment because they 
were found to be ineligible (late exclusions from the trial), based on data collected prior to 
randomization. 
• 
The mITT population is defined as the ITT population with extra exclusions (described in 
the SAP). 
• 
The PP population is defined as the mITT population with extra exclusions (described in 
the SAP). 
• 
The mITT analysis will be considered primary, with consistent findings required from the 
other main analysis populations to support the primary conclusion. 
9.2 
Sample Size 
For the primary endpoint, time-to-culture conversion at 8 weeks,150 participants per arm (DS-TB 
participants) will provide at more than 90% power (5% 2-sided significance) to detect a hazard 
ratio (HR) of at least 2 assuming 50% of control participants are culture negative by 8 weeks. If 
only 25% of the control arm remain culture positive at 8 weeks, then this sample size will still 
retain more than 90% power to detect a HR of least 2.  This sample size also allows for one 
planned interim analysis of the primary endpoint (See Section 9.4.1) 
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For the key secondary endpoint of clinical outcome at 12 months from randomization, 150 patients 
per arm will provide 74% power based on assumptions using data from the largest most recent 
and completed phase 3 TB treatment trial which used the same control arm.[41]  That is, assuming 
16% unfavourable (see Section 9.4.2) in the control arm and 13% unassessable (see Section 9.6) 
at 52 weeks post randomization. A 12% margin of non-inferiority was chosen to preserve at least 
75% of the estimated control arm effect against placebo (estimated to be 54%)[41, 42] which is 
considered an acceptable proportion on which to declare non-inferiority of the test regimen. 
9.3 
Interim Analyses 
There is no planned interim analysis in this trial. 
9.4 
Primary and Secondary Efficacy Endpoint Analysis 
9.4.1 
Primary Efficacy Endpoint, Time to Culture Conversion at 8 Weeks 
The primary analysis will be conducted using culture results from liquid culture (MGIT) media. 
Participants will be classified as being culture positive, culture negative, dead or unassessable at 
8 weeks.  The proportion culture negative will be those classified as being culture negative divided 
by the total considered culture negative, culture positive or have died. This proportion will be 
estimated from the Kaplan Meier estimates from the time to culture conversion to negative status 
analysis and groups compared using a hazard ratio and 95% confidence interval. 
Non-inferiority of the key secondary endpoint of clinical outcome will be assessed using the upper 
bound of the one-sided 97.5% confidence interval for the difference between the proportion of 
participants who are classified as having an unfavourable status on the intervention less the 
control regimen.  If the upper bound of the one-sided 97.5% confidence limit for this difference in 
proportions is less than 12% (the margin of inferiority) the intervention will be non-inferior to the 
control arm. 
9.4.2 
Key Secondary Efficacy Endpoint, Clinical Outcome at 52 Weeks from 
Randomization  
For the key secondary endpoint of clinical outcome (bacteriologic failure or relapse or clinical 
failure), participants will be classified as having a favourable, unfavourable or unassessable 
outcome status which will be defined in detail in the SAP.  In general, participants achieving and 
maintaining culture negative status without any additional treatment will be considered favourable; 
participants who fail on treatment or relapse in follow-up will be considered unfavourable and 
participants who are not assessable (and who have not already been declared as unfavourable) 
will be considered unassessable and excluded from the analysis. 
9.4.3 
Other Secondary Efficacy Endpoints 
The secondary efficacy endpoints and analyses are as follows are: 
• 
Clinical outcome (bacteriologic failure or relapse or clinical failure) at 104 weeks from the start 
of therapy.  
• 
Proportion of participants with sputum culture conversion to negative status in liquid culture 
(MGIT) at 4, 6, 12 and 17 weeks to be explored as a potential biomarker of outcome at 
52 weeks from start of therapy. 
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• 
Change from baseline in weight will be summarised and presented. 
• 
Proportion of participants experiencing a change from baseline in TB symptoms. 
• 
Change from baseline in Patient Reported Health Status will be summarised and presented. 
9.5 
Safety and Tolerability Assessments 
• 
The incidence of all-cause mortality will be summarized. 
• 
All adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) and will be presented by Preferred Term within each MedDRA System Organ 
Class (SOC). 
• 
Treatment-emergent adverse events (TEAEs) are defined as AEs which started at or after the 
first administration of IMP and includes those events started prior to the first administration of 
IMP but which worsened after the first intake.  Adverse events starting after the last 
administration of IMP until the last scheduled visit/assessment/measurement will be regarded 
as treatment-emergent. 
• 
The incidence of the following events will be summarized for further medical analysis: 
o Incidence of TEAEs; 
o Incidence of TEAEs by Severity; 
o Incidence of TEAEs by DMID toxicity grade; 
o Incidence of Drug-Related TEAEs; 
o Incidence of Serious TEAEs; 
o Incidence of TEAEs Leading to Early Withdrawal; 
o Incidence of TEAEs leading to Death. 
9.6 
Pharmacokinetics 
For each analyte and each scheduled sampling time/window, the plasma concentration will be 
summarized by descriptive statistics including the mean, SD, coefficient of variation (CV), median, 
minimum, maximum, geometric mean and geometric CV (%). 
In addition, mean and/or median concentration-versus-time graphs will be provided, with error 
bars and/or scatter plots as appropriate. 
Plasma concentrations from sparse sampling will be used to update existing population PK 
models and derive exposure metrics (e.g., Cmin, Cmax, AUC) for bedaquiline and its M2 metabolite, 
pretomanid, moxifloxacin, and pyrazinamide. Effects of baseline covariates on exposure will be 
assessed; so, too, will the effects of concomitant medications including ART, as feasible. Data 
from other trials may be included to enhance the model-based analysis.  
Detailed plans for the PopPK analysis will be outlined in a separate modelling plan, and results 
will be reported in separate modelling report. 
9.7 
Pharmacokinetics/Pharmacodynamics 
Relationships will be explored between drug exposure and efficacy and safety endpoints. These 
exploratory PK/PD analyses may include HIV status as a covariate. Planning details and results 
will be included in the separate modelling plan and report. 
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10.0 Records Management 
10.1 Data Collection 
All relevant CRF/eCRF pages will be completed for each participant who receives any amount of 
IMP, depending on visits attended.  For screening failure participants, specific eCRF pages will 
be completed as described in the eCRF Completion Guidelines. For participants who are 
prematurely withdrawn, all the visits the participant attended including withdrawal and follow-up 
visits need to be completed. 
10.2 Source Documents 
Source documents are defined as all information in original records and certified copies of original 
records of clinical findings, observations, or other activities in a clinical trial necessary for the 
reconstruction and evaluation of the trial.  Source documents will include, but are not limited to, 
progress notes, in-patient hospital records, electronic data, screening logs, and recorded data 
from automated instruments. 
All source documents pertaining to this trial will be maintained by the Investigators.  The 
Investigator 
must 
permit 
trial 
related 
monitoring, 
audits, 
Independent 
Ethics 
Committee/Institutional Review Board (EC/IRB) review and regulatory inspections providing 
authorized personnel direct access to source documents, including documents required to confirm 
inclusion/exclusion and relevant in-patient records while participants are on trial treatment. 
10.3 File Management at the Trial Centre 
It is the responsibility of the Investigators to ensure that the trial centre files are maintained in 
accordance with International Good Clinical Practice Guidelines and the ethical principles that 
have their origin in the Declaration of Helsinki. 
10.4 Records Retention at the Trial Centre 
The Investigator is obliged to retain records and data from the trial for safety reasons and for audit 
and inspection after trial completion.  The essential documents should be retained for not less 
than 2 years after the last approval of a marketing application and until there are no pending or 
contemplated marketing applications or at least 2 years have elapsed since the formal 
discontinuation of clinical development of the IMP.  Investigator should notify the 
Sponsor/designees prior to destroying any records pertaining to the trial. 
 
11.0 Quality Control and Assurance  
11.1 Site Procedures 
The Investigator undertakes to perform the clinical trial in accordance with this protocol, local 
regulations, International GCP, and the ethical principles that have their origin in the Declaration 
of Helsinki. 
The Investigator undertakes to complete the CRFs according to the Sponsor’s requirements, in a 
timely, accurate and legible manner. CRF entries will be verifiable to source documentation other 
than the CRF. 
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Site Standard Operating Procedures (SOPs), where available, will be adhered to for all clinical 
and bioanalytical activities relevant to the quality of the trial.  Participant compliance will be 
monitored throughout the trial. 
The Investigator will sign and date any analysis results (e.g., laboratory, ECG, etc.) to verify that 
the results have been reviewed. 
The Investigator may appoint other sub-Investigators to assist with the trial. However, the 
Investigator maintains responsibility for the trial and will supervise the sub-Investigators. Written 
EC/IRB approval of the trial will be obtained prior to involvement in the trial. 
The Investigator will ensure that all site personnel are adequately trained in GCP, local 
regulations, the protocol, IBs/package inserts and all trial procedures and requirements. 
11.2 Monitoring 
The Investigator is responsible for the validity of all data collected at the clinical site and must 
accept the various monitoring procedures employed by the Sponsor.  The purpose of monitoring 
is to verify that the rights and well-being of human participants are protected; that trial data are 
accurate, complete and verifiable with source data; and that the trial is conducted in compliance 
with the protocol, International GCP, the ethical principles that have their origin in the Declaration 
of Helsinki and the applicable regulatory requirements.  
Monitors assigned by the Sponsor will conduct regular site visits before, during and after the trial 
for monitoring various aspects of the trial, and to assure appropriate conduct of the trial in 
accordance with ICH GCP.  Visits will take place usually within a predetermined interval, but this 
may vary during the trial.  The Investigator and site staff will allow the trial monitor and authorized 
representatives of the Sponsor to (1) inspect all CRFs, written informed consent documents and 
corresponding source documents (e.g., original medical records), patient records and laboratory 
raw data, site SOPs, training records, facilities and other trial related systems/processes, and (2) 
access clinical supplies, dispensing and storage areas.  The Investigator and site staff should 
also (1) agree to assist with monitoring activities if requested and (2) provide adequate time and 
space for monitoring visits.  
The monitor will query any missing, confusing, spurious, or otherwise ambiguous data with the 
Investigator.  All queries should be resolved in a timely manner.  A monitoring log will be 
maintained recording each visit, the reason for the visit, the monitor’s signature and Investigator 
or designee’s confirmation signature. 
11.3 Protocol Deviations 
A protocol deviation is any noncompliance with the clinical trial protocol, GCP, or Monitoring Plan 
requirements. The noncompliance may be either on the part of the participant, the Investigator, 
or the trial site staff. Because of deviations, corrective actions are to be developed by the site and 
implemented promptly.  
It is the responsibility of the site to use continuous vigilance to identify and report deviations. All 
deviations must be addressed in trial source documents and reported to Sponsor/designee. 
Protocol deviations must be sent to the local IRB per their guidelines. The site PI/trial staff is 
responsible for knowing and adhering to their IRB requirements. 
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11.4 Auditing 
For compliance with International GCP and regulatory agency guidelines, it may be necessary for 
Sponsor-authorized Quality Assurance personnel and/or authorized personnel from an external 
regulatory agency to conduct an audit or inspection of the investigational site.  The purpose of an 
audit is to assess the quality of data about accuracy, adequacy and consistency, and to assure 
that trials are in accordance with the guidelines.  Having the highest quality data from trials is an 
essential aspect of drug development.  
The Investigator and site staff will be given sufficient notice to prepare for such visits, which will 
usually last between one and two days and may be conducted at any stage during the trial.  The 
audit will involve the review of all trial-related documentation required by GCP to be maintained 
by each site; drug storage, dispensing and return; all trial-related supplies; and source documents 
against the CRFs to assure the adequacy and accuracy of the information which has been 
recorded, including the verification of any AEs which have occurred. The auditors or inspectors 
may also review site SOPs, training records, site facilities and other trial related 
systems/processes. 
In the event of the site being notified of a Regulatory Inspection, the Sponsor will help with 
preparation.  It is essential that the Sponsor be notified of the inspection as soon as possible. 
 
12.0 Ethics and Regulatory 
12.1 Basic Principles 
This research will be carried out in accordance with International GCP, the ethical principles that 
have their origin in the Declaration of Helsinki and the applicable regulatory requirements. 
12.2 Independent Ethics Committee/Institutional Review Board (EC/IRB) Review 
The protocol and required trial related documents will be reviewed by the sites respective EC/IRB.  
The trial will not start until the EC/IRB has approved the protocol, written informed consent, any 
written information to be provided to the participant or any modification thereof, plus any other 
trial related documents required for review.  The EC/IRB shall be constituted and shall operate in 
accordance with International GCP, the ethical principles that have their origin in the Declaration 
of Helsinki. The Investigator will maintain an accurate and complete record of all submissions 
made to, and responses from the IRB/EC.  The records should be filed in the Investigator’s Trial 
File, and copies will be sent to the Sponsor. 
12.3 Regulatory Authorities 
The Regulatory Authorities will receive the protocol, amendments, reports on SAEs, and the 
Integrated Clinical Trial Report according to national regulations.  As required by local legislation, 
written approval will be obtained from the Regulatory Authorities prior to commencement of the 
trial and implementation of e.g. amendments as applicable. 
12.4 Informed Consent 
Written informed consent will be obtained from all participants (or legally acceptable 
representative) before any trial-related procedures (including any screening or pre-treatment 
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procedures) are performed.  Investigators may discuss the availability of the trial and the 
opportunity for entry with a potential participant without first obtaining consent.  However, informed 
consent must be obtained and documented prior to initiation of any procedures that are performed 
solely for determining eligibility for research, including withdrawal from current medication(s).  
When this is done in anticipation of, or in preparation for, the research, it is part of the research. 
The Investigators have both ethical and legal responsibility to ensure that each participant being 
considered for inclusion in this trial is given a full explanation of the protocol.  Participants must 
be informed that their participation is voluntary.  The Investigator or his/her representative will 
explain the nature of the trial to the participant or his/her legally authorized representative and 
answer all questions regarding the trial. This shall be documented on a written informed consent 
form that shall be approved by the same EC/IRB responsible for approval of this protocol.  Each 
informed consent form shall include the elements required by the international GCP and must 
adhere to the ethical principles that have their origin in the Declaration of Helsinki.  
The trial will be included and updated in the appropriate Country registry and referenced in the 
informed consent forms (ICF). 
Once the appropriate essential information has been provided to the participant and fully 
explained by the Investigators (or qualified designees) and it is felt that the participant 
understands the implications of participating, the EC/IRB approved written informed consent form 
will be signed and dated by both the participant and the person obtaining consent (Investigators 
or designees), and by any other parties required by the EC/IRB. Ongoing participants must be re-
consented to the most current version of the ICF(s) during their participation in the trial. 
The original signed informed consent form will be kept with the trial records and a copy of signed 
informed consent form will be provided to the participant or the participant’s legally authorized 
representative.  Another copy of the signed informed consent form and a source document 
identifying the trial and recording the dates of participation will be placed in the participant’s 
medical record. 
The monitor will inspect the original completed consent form(s) for all participants. 
12.5 Confidentiality 
All site staff, the Sponsor, and any Sponsor representatives will preserve the confidentiality of all 
participants taking part in the trial, in accordance with International GCP, applicable local 
legislation/regulations.  Participant to the requirement for source data verification by the trial 
personnel by reference to the participant’s notes, confidentiality of all participant identities will be 
maintained.  Unique identifiers will be used on the CRF and in all trial correspondence, as 
permitted.  No material bearing a participant’s name will be kept on file by the Sponsor. The written 
informed consent will contain a clause granting permission for review of the participants’ source 
data by the Sponsor or designees. 
 
13.0 Publication Policy 
The definition of publication for this purpose is any public presentation of the data emerging from 
this trial.  
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All unpublished information given to the Investigator by the Sponsor shall not be published or 
disclosed to a third party, other than to the responsible EC/IRB, within the understanding of the 
confidentiality of their nature, without the prior written consent of the Sponsor. 
Results of this research will be submitted for publication as soon as feasible upon completion of 
the trial in the form of a joint publication(s) between Sponsor and Investigator(s), including site 
clinical and laboratory Investigators, as appropriate. Publication and authorship will be in accord 
with the International Association of Journal Editors.[43]  
Because the Trial is funded, in whole or in part, by the Bill and Melinda Gates Foundation (the 
“Foundation”), all peer-reviewed published research relating to the Trial must comply with the 
Foundation’s 
Open 
Access 
Policy 
as 
described 
from 
time 
to 
time 
at 
http://www.gatesfoundation.org/How-We-Work/General-Information/Open-Access-Policy. 
Specifically, (a) all peer-reviewed published research relating to the Trial must be submitted for 
publication by TB Alliance through the Chronos Open Access Publishing Service established by 
the Foundation to ensure the immediate and unrestricted access and reuse of all peer-reviewed 
published research funded, in whole or in part, by the Foundation without any embargo period, 
and (b) all data underlying the peer-reviewed published research results must be immediately 
made accessible and open to the public in accordance with the Foundation’s Open Access Policy. 
 
14.0 Protocol Amendment Policy 
Any change to the protocol will be affected by means of a protocol amendment.  Any changes 
which affect participant safety or welfare will be submitted to the EC/IRB and Regulatory 
Authorities prior to implementation.  The Investigator, EC/IRB, and Sponsor must agree on all 
amendments.  No amendment will be implemented until approved by the relevant Authorities 
and/or EC/IRB and signed by all required parties.  Exceptions to this are when the Investigator 
considers that the participant’s safety is compromised.  
Protocol amendments detailing minor administrative changes should be submitted by the 
Investigator to the EC/IRB and Regulatory Authorities, either for notification purposes or approval 
as appropriate. 
 
15.0 Sponsor, Financial Aspects, Insurance and Indemnity 
The trial Sponsor is the Global Alliance for TB Drug Development (TB Alliance).  The TB Alliance 
is a not for profit, product development partnership accelerating the discovery and development 
of new TB drugs that will shorten treatment, be effective against susceptible and resistant strains, 
be compatible with antiretroviral therapies for those HIV-TB participants currently on such 
therapies, and improve treatment of latent infection. 
The TB Alliance works with public and private partners worldwide.  It is committed to ensuring 
that approved new regimens are affordable, adopted and available to those who need them. 
The TB Alliance operates with funding mainly from the Bill & Melinda Gates Foundation, the 
Netherlands Ministry of Foreign Affairs (DGIS), the United Kingdom Department for International 
Development (DFID), and the United States Agency for International Development (USAID). 
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The participants will not receive any incentives for their involvement in the trial.  The Sponsor has 
made provision to reimburse the participants for out-of-pocket expenses such as travelling to and 
from the trial site and other miscellaneous costs as a result of their trial participation. 
The Sponsor certifies that it has liability insurance coverage for itself and will provide an 
associated certificate upon request.  The insurance does not relieve the Investigators of the 
obligation to maintain their own liability insurance as required by applicable law. The Sponsor 
does not assume any obligation for the medical treatment of other injuries and illnesses.
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16.0 References 
1. 
Maggi N, Pasqualucci CR, Ballotta R, Sensi P. Rifampicin: a new orally active rifamycin. 
Chemotherapy. 1966;11(5):285-292. 
2. 
Jindani A, Aber VR, Edwards EA, Mitchison DA. The early bactericidal activity of drugs in 
patients with pulmonary tuberculosis. Am Rev Respir Dis. 1980;121(6):939-949. 
3. 
Dietze R, Teixeira L, Rocha LM, Palaci M, Johnson JL, Wells C, et al. Safety and 
bactericidal activity of rifalazil in patients with pulmonary tuberculosis. Antimicrob Agents 
Chemother. 2001;45(7):1972-1976. 
4. 
Donald PR, Sirgel FA, Venter A, Parkin DP, Seifart HI, van de Wal BW, et al. Early 
bactericidal activity of antituberculosis agents. Expert Rev Anti Infect Ther. 2003;1(1):141-
155. 
5. 
Johnson JL, Hadad DJ, Boom WH, Daley CL, Peloquin CA, Eisenach KD, et al. Early and 
extended early bactericidal activity of levofloxacin, gatifloxacin and moxifloxacin in 
pulmonary tuberculosis. Int J Tuberc Lung Dis. 2006;10(6):605-612. 
6. 
Rustomjee R, Diacon AH, Allen J, Venter A, Reddy C, Patientia RF, et al. Early bactericidal 
activity and pharmacokinetics of the diarylquinoline TMC207 in treatment of pulmonary 
tuberculosis. Antimicrob Agents Chemother. 2008;52(8):2831-2835. 
7. 
Package insert: Sirturo.  Janssen Therapeutics, September 2014 Available at: 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/204384s000lbl.pdf. 
8. 
Investigator’s Brochure: TMC207 (bedaquiline).  Edition 10. Janssen Research and 
Development, 02 Dec 2016. 
9. 
Koul A, Dendouga N, Vergauwen K, Molenberghs B, Vranckx L, Willebrords R, et al. 
Diarylquinolines target subunit c of mycobacterial ATP synthase. Nat Chem Biol. 
2007;3(6):323-324. 
10. 
Andries K, Verhasselt P, Guillemont J, Gohlmann HW, Neefs JM, Winkler H, et al. A 
diarylquinoline drug active on the ATP synthase of Mycobacterium tuberculosis. Science. 
2005;307(5707):223-227. 
11. 
Huitric E, Verhasselt P, Andries K, Hoffner SE. In vitro antimycobacterial spectrum of a 
diarylquinoline ATP synthase inhibitor. Antimicrob Agents Chemother. 2007;51(11):4202-
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12. 
Koul A, Vranckx L, Dendouga N, Balemans W, Van den Wyngaert I, Vergauwen K, et al. 
Diarylquinolines are bactericidal for dormant mycobacteria as a result of disturbed ATP 
homeostasis. J Biol Chem. 2008;283(37):25273-25280. 
13. 
Nuermberger E, Rosenthal I, Tyagi S, Williams KN, Almeida D, Peloquin CA, et al. 
Combination chemotherapy with the nitroimidazopyran PA-824 and first-line drugs in a 
murine model of tuberculosis. Antimicrob Agents Chemother. 2006;50(8):2621-2625. 
14. 
Nuermberger E, Tyagi S, Tasneen R, Williams KN, Almeida D, Rosenthal I, et al. Powerful 
bactericidal and sterilizing activity of a regimen containing PA-824, moxifloxacin, and 
pyrazinamide in a murine model of tuberculosis. Antimicrob Agents Chemother. 
2008;52(4):1522-1524. 
15. 
Investigator's Brochure: Pretomanid (PA-824).  Global Alliance for TB Drug Development, 
22 December 2016. 
16. 
Stover CK, Warrener P, VanDevanter DR, Sherman DR, Arain TM, Langhorne MH, et al. 
A small-molecule nitroimidazopyran drug candidate for the treatment of tuberculosis. 
Nature. 2000;405(6789):962-966. 
17. 
Lenaerts AJ, Gruppo V, Marietta KS, Johnson CM, Driscoll DK, Tompkins NM, et al. 
Preclinical testing of the nitroimidazopyran PA-824 for activity against Mycobacterium 
tuberculosis in a series of in vitro and in vivo models. Antimicrob Agents Chemother. 
2005;49(6):2294-2301. 
18. 
Tyagi S, Nuermberger E, Yoshimatsu T, Williams K, Rosenthal I, Lounis N, et al. 
Bactericidal activity of the nitroimidazopyran PA-824 in a murine model of tuberculosis. 
Antimicrob Agents Chemother. 2005;49(6):2289-2293. 
19. 
Package insert: Moxifloxacin.  MacLeods Pharmaceuticals Ltd., January 2014. 
20. 
Package insert: Pyrazinamide.  MacLeods Pharmaceuticals Ltd., November 2012. 
21. 
Zhang Y, Mitchison D. The curious characteristics of pyrazinamide: a review. Int J Tuberc 
Lung Dis. 2003;7(1):6-21. 
22. 
Package insert: HRZE Combination Tablets.  MacLeods Pharmaceuticals Ltd., September 
2011. 
23. 
World Health Organization. Global tuberculosis report 2012.  2015. WHO Press, Geneva, 
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24. 
Pym AS, Diacon AH, Tang S-J, Conradie F, Danilovits M, Chuchottaworn C, et al. 
Bedaquiline safety data in a broad patient population treated for drug-resistant TB 
including XDR-TB (C209 trial). Tuberculosis. 2016;47:394-402. 
25. 
Lee M, Lee J, Carroll MW, Choi H, Min S, Song T, et al. Linezolid for treatment of chronic 
extensively drug-resistant tuberculosis. N Engl J Med. 2012;367(16):1508-1518. 
26. 
A Phase 3 Trial Assessing the Safety and Efficacy of Bedaquiline Plus PA-824 Plus 
Linezolid in Subjects With Drug Resistant Pulmonary Tuberculosis. ClinicalTrials.gov,  
Available at: https://www.clinicaltrials.gov/ct2/show/NCT02333799, Updated 28 February 
2017. 
27. 
Mdluli K, Nuermberger E. Pre-Clinical Drug Combination Trials to Identify Novel Regimens 
for TB.  2009. in Recent Advances in TB Drug Development Symposium. 40th Union World 
Conference, International Union Against TB and Lung Disease. Cancun, Mexico. 
28. 
Tasneen R, Li SY, Peloquin CA, Taylor D, Williams KN, Andries K, et al. Sterilizing activity 
of novel TMC207- and PA-824-containing regimens in a murine model of tuberculosis. 
Antimicrob Agents Chemother. 2011;55(12):5485-5492. 
29. 
Singh R, Manjunatha U, Boshoff HI, Ha YH, Niyomrattanakit P, Ledwidge R, et al. PA-824 
kills nonreplicating Mycobacterium tuberculosis by intracellular NO release. Science. 
2008;322(5906):1392-1395. 
30. 
Manjunatha U, Boshoff HI, Barry CE. The mechanism of action of PA-824: Novel insights 
from transcriptional profiling. Commun Integr Biol. 2009;2(3):215-218. 
31. 
Manjunatha UH, Boshoff H, Dowd CS, Zhang L, Albert TJ, Norton JE, et al. Identification 
of a nitroimidazo-oxazine-specific protein involved in PA-824 resistance in Mycobacterium 
tuberculosis. Proc Natl Acad Sci U S A. 2006;103(2):431-436. 
32. 
Nuermberger E, Tyagi S, Williams KN, Rosenthal I, Bishai WR, Grosset JH. Rifapentine, 
moxifloxacin, or DNA vaccine improves treatment of latent tuberculosis in a mouse model. 
Am J Respir Crit Care Med. 2005;172(11):1452-1456. 
33. 
Tasneen R, Betoudji F, Tyagi S, Li SY, Williams K, Converse PJ, et al. Contribution of 
Oxazolidinones to the Efficacy of Novel Regimens Containing Bedaquiline and 
Pretomanid in a Mouse Model of Tuberculosis. Antimicrob Agents Chemother. 
2015;60(1):270-277. 
34. 
Diacon AH, Dawson R, du Bois J, Narunsky K, Venter A, Donald PR, et al. Phase II dose-
ranging trial of the early bactericidal activity of PA-824. Antimicrob Agents Chemother. 
2012;56(6):3027-3031. 
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35. 
Burman WJ, Goldberg S, Johnson JL, Muzanye G, Engle M, Mosher AW, et al. 
Moxifloxacin versus ethambutol in the first 2 months of treatment for pulmonary 
tuberculosis. Am J Respir Crit Care Med. 2006;174(3):331-338. 
36. 
Rustomjee R, Lienhardt C, Kanyok T, Davies GR, Levin J, Mthiyane T, et al. A Phase II 
trial of the sterilising activities of ofloxacin, gatifloxacin and moxifloxacin in pulmonary 
tuberculosis. Int J Tuberc Lung Dis. 2008;12(2):128-138. 
37. 
Conde MB, Efron A, Loredo C, De Souza GR, Graca NP, Cezar MC, et al. Moxifloxacin 
versus ethambutol in the initial treatment of tuberculosis: a double-blind, randomised, 
controlled phase II trial. Lancet. 2009;373(9670):1183-1189. 
38. 
Dorman SE, Johnson JL, Goldberg S, Muzanye G, Padayatchi N, Bozeman L, et al. 
Substitution of moxifloxacin for isoniazid during intensive phase treatment of pulmonary 
tuberculosis. Am J Respir Crit Care Med. 2009;180(3):273-280. 
39. 
Investigator's Brochure: Bayer HealthCare AG, moxifloxacin.  01 October 2011. 
40. 
Package insert: HR Combination Tablets.  MacLeods Pharmaceuticals Ltd., September 
2011. 
41. 
Gillespie SH, Crook AM, McHugh TD, Mendel CM, Meredith SK, Murray SR, et al. Four-
month moxifloxacin-based regimens for drug-sensitive tuberculosis. N Engl J Med. 
2014;371(17):1577-1587. 
42. 
Tiemersma EW, van der Werf MJ, Borgdorff MW, Williams BG, Nagelkerke NJ. Natural 
history of tuberculosis: duration and fatality of untreated pulmonary tuberculosis in HIV 
negative patients: a systematic review. PLoS One. 2011;6(4):e17601. 
43. 
Recommendations for the Conduct, Reporting, Editing, and Publication of Scholarly work 
in Medical Journals.  Available at: http://www.icmje.org/icmje-recommendations.pdf, 
Updated December 2016. 
44.  
Reuben A (2004). “Hy’s Law”. Landmarks in Hepatology 39(2): 574-578. 
45. 
Temple RJ (2006). “Hy’s Law: predicting serious hepatotoxicity”. Pharmacoepidemoiology 
and Drug Safety 15: 241-243. 
 
 
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Appendices 
Appendix 1: The IUATLD Scale 
The IUATLD scale proposes five groups for reporting the results of reading smears for acid fast 
bacilli. They should be recorded as follows: 
FINDING 
RECORDING 
No acid-fast bacilli found in at least 100 fields 
negative 
1 to 9 acid-fast bacilli per 100 fields 
scanty positive 
10 to 99 acid-fast bacilli per 100 fields 
+ 
1 to 10 acid-fast bacilli per field in at least 50 
fields 
++ 
More than 10 acid-fast bacilli per field in at least 
20 fields 
+++ 
Reference: The Public Health Service National Tuberculosis Reference Laboratory and the 
National Laboratory Network. Minimum Requirements, Role and Operation in a Low-Income 
Country. International Union Against Tuberculosis and Lung Disease 1998. 
 
 
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Appendix 2: Division of Microbiology and Infectious Disease (DMID) Toxicity Table 
Source:  U.S. National Institute of Allergy and Infectious Diseases, DMID, November 2007 (Draft) 
ABBREVIATIONS:  Abbreviations utilized in the Table: 
ULN = Upper Limit of Normal 
LLN = Lower Limit of Normal 
Rx = Therapy 
Req = Required 
Mod = Moderate 
IV  = Intravenous 
ADL = Activities of Daily Living 
Dec = Decreased 
 
ESTIMATING SEVERITY GRADE 
For abnormalities NOT found elsewhere in the Toxicity Tables use the scale below to estimate 
grade of severity: 
Grade 
Severity Rating 
Definition 
GRADE 1 
Mild 
Transient or mild discomfort (< 48 hours); no medical 
intervention/therapy required. 
GRADE 2 
Moderate 
Mild to moderate limitation in activity - some assistance may be 
needed; no or minimal medical intervention/therapy required. 
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. 
 
SERIOUS OR LIFE-THREATENING AEs 
ANY clinical event deemed by the clinician to be serious or life-threatening should be considered 
a grade 4 event. Clinical events considered to be serious or life-threatening include, but are not 
limited to: seizures, coma, tetany, diabetic ketoacidosis, disseminated intravascular coagulation, 
diffuse petechiae, paralysis, acute psychosis, severe depression. 
COMMENTS REGARDING THE USE OF THESE TABLES 
• 
Standardized and commonly used toxicity tables (Division of Acquired Immune Deficiency 
Syndrome (AIDS), NCI’s Common Toxicity Criteria (CTC), and World Health Organization 
(WHO)) have been adapted for use by the DMID and modified to better meet the needs of 
participants in DMID trials. 
• 
For parameters not included in the following Toxicity Tables, sites should refer to the “Guide 
For Estimating Severity Grade” located above. 
• 
Criteria are generally grouped by body system. 
• 
Some protocols may have additional protocol specific grading criteria, which will supersede 
the use of these tables for specified criteria. 
 
 
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HEMATOLOGY 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Hemoglobin 
9.5 - 10.5 gm/dL 
8.0  - 9.4gm/dL 
6.5 - 7.9 gm/dL 
< 6.5 gm/dL 
Absolute Neutrophil 
Count 
1000-1500/mm3 
750-999/mm3 
500-749/mm3 
<500/mm3 
Platelets 
75,000- 
99,999/mm3 
50,000- 
74,999/mm3 
20,000- 
49,999/mm3 
<20,000/mm3 
WBCs 
11,000-13,000/ 
mm3 
13,000-15,000 
/mm3 
15,000- 
30,000/mm3 
>30,000 or <1,000 
/mm3 
% Polymorphonuclear 
Leucocytes + Band 
Cells 
> 80% 
90 – 95% 
>95% 
---------- 
Abnormal Fibrinogen 
Low: 
100-200 mg/dL 
High: 
400-600 mg/dL 
Low: 
<100 mg/dL 
High: 
>600 mg/dL 
Low: 
< 50 mg/dL 
---------- 
Fibrinogen 
associated with 
gross bleeding or 
with disseminated 
coagulation 
Fibrin Split Product 
20-40 mcg/ml 
41-50 mcg/ml 
51-60 mcg/ml 
> 60 mcg/ml 
Prothrombin Time (PT) 
1.01 - 1.25 x ULN 
1.26-1.5 x ULN 
1.51 -3.0 x ULN 
>3 x ULN 
Activated 
Partial 
Thromboplastin (APPT) 
1.01 -1.66 x ULN 
1.67 - 2.33 x ULN 
2.34 - 3 x ULN 
> 3 x ULN 
Methemoglobin 
5.0 - 9.9 % 
10.0 - 14.9 % 
15.0 - 19.9% 
> 20.0 % 
 
CHEMISTRIES 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Hyponatremia 
130-135 mEq/L 
123-129 mEq/L 
116-122 mEq/L 
< 116 mEq/L or abnormal 
sodium with mental status 
changes or seizures 
Hypernatremia 
146-150 mEq/L 
151-157 mEq/L 
158-165 mEq/L 
> 165 mEq/L or abnormal 
sodium with mental status 
changes or seizures 
Hypokalemia 
3.0 - 3.4 mEq/L 
2.5 - 2.9 mEq/L 
2.0 - 2.4 mEq/L or 
intensive 
replacement 
therapy or 
hospitalization 
required 
< 2.0 mEq/L or abnormal 
potassium with paresis, ileus 
or life-threatening arrhythmia 
Hyperkalemia 
5.6 - 6.0 mEq/L 
6.1 - 6.5 mEq/L 
6.6 - 7.0 mEq/l 
> 7.0 mEq/L or abnormal 
potassium with life- 
threatening arrhythmia 
Hypoglycemia 
55-64 mg/dL 
40-54 mg/dL 
30-39 mg/dL 
<30 mg/dL or abnormal 
glucose with mental status 
changes or coma 
Hyperglycemia 
(non-fasting and no 
prior diabetes) 
116 - 160 mg/dL 
161- 250 mg/dL 
251 - 500 mg/dL 
> 500 mg/dL or abnormal 
glucose with ketoacidosis or 
seizures 
 
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Hypocalcemia 
(corrected 
for 
albumin) 
8.4 - 7.8 mg/dL 
7.7 - 7.0 mg/dL 
6.9 - 6.1 mg/dL 
< 6.1 mg/dL or abnormal 
calcium with life threatening 
arrhythmia or tetany 
Hypercalcemia 
(correct for albumin) 
10.6 - 11.5 mg/dL 
11.6 - 12.5 
mg/dL 
12.6 - 13.5 mg/dL 
> 13.5 mg/dL or abnormal 
calcium with life threatening 
arrhythmia 
Hypomagnesemia 
1.4 - 1.2 mEq/L 
1.1 - 0.9 mEq/L 
0.8 - 0.6 mEq/L 
< 0.6 mEq/L or abnormal 
magnesium with life- 
threatening arrhythmia 
Hypophosphatemia 
2.0 - 2.4 mg/dL 
1.5 -1.9 mg/dL 
or replacement 
Rx required 
1.0 -1.4 mg/dL 
intensive therapy or 
hospitalization 
required 
< 1.0 mg/dL or abnormal 
phosphate with life- 
threatening arrhythmia 
Hyperbilirubinemia 
(when accompanied 
by any increase in 
other liver function 
test) 
1.1 - <1.25 x ULN 
1.25 - <1.5 x 
ULN 
1.5 – 1.75 x ULN 
 
> 1.75 x ULN 
Hyperbilirubinemia 
(when 
other 
liver 
function are in the 
normal range) 
1.1 - <1.5 x ULN 
1.5 - <2.0 x ULN 
2.0 – 3.0 x ULN 
> 3.0 x ULN 
BUN 
1.25 - 2.5 x ULN 
2.6 - 5 x ULN 
5.1 - 10 x ULN 
> 10 x ULN 
Hyperuricemia (uric 
acid) 
7.5 – 10.0 mg/dL 
10.1 – 12.0 
mg/dL 
12.1 – 15.0 mg/dL 
>15.0 mg/dL 
Creatinine 
1.1 - 1.5 x ULN 
1.6 - 3.0 x ULN 
3.1 - 6 x ULN 
> 6 x ULN or dialysis 
required 
 
ENZYMES 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
AST (SGOT) 
1.1 - <2.0 x ULN 
2.0 – <3.0 x ULN 
3.0 – 8.0 x ULN 
> 8 x ULN 
ALT (SGPT) 
1.1 - <2.0 x ULN 
2.0 – <3.0 x ULN 
3.0 – 8.0 x ULN 
> 8 x ULN 
GGT 
1.1 - <2.0 x ULN 
2.0 – <3.0 x ULN 
3.0 – 8.0 x ULN 
> 8 x ULN 
Alkaline Phosphatase 
1.1 - <2.0 x ULN 
2.0 – <3.0 x ULN 
3.0 – 8.0 x ULN 
> 8 x ULN 
Amylase 
1.1 - 1.5 x ULN 
1.6 - 2.0 x ULN 
2.1 - 5.0 x ULN 
> 5.1 x ULN 
Lipase 
1.1 - 1.5 x ULN 
1.6 - 2.0 x ULN 
2.1 - 5.0 x ULN 
> 5.1 x ULN 
 
URINALYSIS 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Proteinuria 
1+ or 200 mg - 1 
gm loss/day 
2-3+ or 1- 2 gm 
loss/day 
4+ or 2-3.5 gm 
loss/day 
nephrotic 
syndrome or > 3.5 
gm loss/day 
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Hematuria 
microscopic only 
<10 rbc/hpf 
gross, no clots >10 
rbc/hpf 
gross, with or 
without clots, OR 
red blood cell 
casts 
obstructive or 
required 
transfusion 
 
CARDIOVASCULAR 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Cardiac Rhythm 
asymptomatic, 
transient signs, no 
Rx required 
recurrent/persistent 
; symptomatic Rx 
required 
unstable 
dysrythmia; 
hospitalization and 
treatment required 
Hypertension 
transient increase 
> 20 mm/Hg; no 
treatment 
recurrent, chronic 
increase 
> 
20mm/Hg. 
/treatment required 
acute 
treatment 
required; 
outpatienttreatm 
ent 
or 
hospitalization 
possible 
end organ damage 
or 
hospitalization 
required 
Hypotension 
transient 
orthostatic 
hypotension with 
heart 
rate 
increased by <20 
beat/min 
or 
decreased by <10 
mm Hg systolic 
BP, No treatment 
required 
symptoms due to 
orthostatic 
hypotension or BP 
decreased by <20 
mm 
Hg 
systolic; 
correctable with oral 
fluid treatment 
requires IV fluids; 
no hospitalization 
required 
mean 
arterial 
pressure <60mm/ 
Hg or end organ 
damage or shock; 
requires 
hospitalization and 
vasopressor 
treatment 
Pericarditis 
minimal effusion 
mild/moderate 
asymptomatic 
effusion, 
no 
treatment 
symptomatic 
effusion; pain; EKG 
changes 
tamponade; 
pericardiocentesis 
or surgery required 
Hemorrhage, Blood 
Loss 
microscopic/occult 
mild, no transfusion 
gross blood loss; 
1-2 
units 
transfused 
massive blood 
loss; > 3 units 
transfused 
 
RESPIRATORY 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Cough 
Transient - no 
treatment 
persistent 
cough; 
treatment responsive 
Paroxysmal cough; 
uncontrolled with 
treatment 
-------------------- 
Bronchospasm, 
Acute 
transient; no 
treatment; 70% - 
80% FEV1 of peak 
flow 
requires treatment; 
normalizes with 
bronchodilator; FEV1 
50% - 70% (of peak 
flow) 
no normalization with 
bronchodilator;FEV1 
25% - 50% of peak 
flow; or retractions 
present 
cyanosis: FEV1 < 
25% of peak flow 
or intubation 
necessary 
Dyspnea 
dyspnea on exertion 
dyspnea with normal 
activity 
dyspnea at rest 
dyspnea requiring 
Oxygen therapy 
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GASTROINTESTINAL 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Nausea 
mild or transient; 
maintains 
reasonable intake 
moderate 
discomfort; intake 
decreased 
significantly; some 
activity limited 
no 
significant 
intake; requires IV 
fluids 
hospitalization 
required; 
Vomiting 
1 episode in 24 
hours 
2-5 episodes in 24 
hours 
>6 episodes in 24 
hours or needing 
IV fluids 
physiologic 
consequences 
requiring 
hospitalization 
or 
requiring 
parenteral nutrition 
Constipation 
requiring 
stool 
softener or dietary 
modification 
requiring laxatives 
obstipation 
requiring manual 
evacuation 
or 
enema 
obstruction or toxic 
megacolon 
Diarrhea 
mild or transient; 3- 
4 loose stools/day 
or 
mild 
diarrhea 
last < 1 week 
moderate 
or 
persistent; 5-7 loose 
stools/day 
or 
diarrhea lasting >1 
week 
>7 loose stools/day 
or bloody diarrhea; 
or 
orthostatic 
hypotension 
or 
electrolyte 
imbalance or >2L 
IV fluids required 
hypotensive shock 
or 
physiologic 
consequences 
requiring 
hospitalization 
Oral 
Discomfort/Dysphagia 
mild discomfort; no 
difficulty 
swallowing 
some limits on 
eating/drinking 
eating/talking very 
limited; unable to 
swallow solid foods 
unable to drink 
fluids; requires IV 
fluids 
 
NEUROLOGICAL 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Neuro-Cerebellar 
slight 
incoordination 
dysdiadochokinesis 
intention 
tremor, 
dysmetria, slurred 
speech; nystagmus 
locomotor ataxia 
incapacitated 
Psychiatric 
mild anxiety or 
depression 
moderate anxiety or 
depression; therapy 
required; change in 
normal routine 
severe 
mood 
changes requiring 
therapy; or suicidal 
ideation; 
or 
aggressive ideation 
acute 
psychosis 
requiring 
hospitalization;  or 
suicidal 
gesture/attempt or 
hallucinations 
Muscle Strength 
Subjective 
weakness 
no 
objective 
symptoms/ signs 
mild 
objective 
signs/symptoms no 
decrease in function 
objective 
weakness function 
limited 
paralysis 
Paresthesia (burning, 
tingling, etc.) 
mild discomfort; no 
treatment required 
moderate 
discomfort; 
non- 
narcotic analgesia 
required 
severe discomfort; 
or 
narcotic 
analgesia required 
with symptomatic 
improvement 
incapacitating; or 
not responsive to 
narcotic analgesia 
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Neuro-sensory 
mild impairment in 
sensation 
(decreased 
sensation, 
e.g., 
vibratory, pinprick, 
hot/cold in great 
toes) in focal area 
or 
symmetrical 
distribution; 
or 
change in 
taste, 
smell, vision and/or 
hearing 
moderate 
impairment 
(mod 
decreased 
sensation, 
e.g., 
vibratory, pinprick, 
hot/cold to ankles) 
and/or joint position 
or mild impairment 
that 
is 
not 
symmetrical 
severe impairment 
(decreased or loss 
of 
sensation 
to 
knees or wrists) or 
loss of sensation of 
at 
least 
mod 
degree in multiple 
different 
body 
areas (i.e., upper 
and 
lower 
extremities) 
sensory 
loss 
involves limbs and 
trunk; paralysis; or 
seizures 
 
MUSCULOSKELETAL 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Arthralgia (joint pain) 
mild pain not 
interfering with 
function 
moderate 
pain, 
analgesics 
and/or 
pain interfering with 
function but not with 
activities 
of 
daily 
living 
severe pain; pain 
and/or analgesics 
interfering 
with 
activities of daily 
living 
disabling pain 
Arthritis 
mild 
pain 
with 
inflammation, 
erythema or joint 
swelling – but not 
interfering 
with 
function 
moderate pain with 
inflammation, 
erythema 
or 
joint 
swelling – interfering 
with function, but not 
with 
activities 
of 
daily living 
severe pain with 
inflammation, 
erythema or joint 
swelling 
–and 
interfering 
with 
activities of daily 
living 
permanent and/or 
disabling 
joint 
destruction 
Myalgia 
myalgia 
with 
no 
limitation of activity 
muscle tenderness 
(at 
other 
than 
injection site) or with 
moderate 
impairment 
of 
activity 
severe 
muscle 
tenderness 
with 
marked impairment 
of activity 
frank 
myonecrosis 
 
SKIN 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Mucocutaneous 
erythema; pruritus 
diffuse, 
maculo 
papular rash, dry 
desquamation 
vesiculation or moist 
desquamation 
or 
ulceration 
exfoliative 
dermatitis, mucous 
membrane 
involvement 
or 
erythema, 
multiforme 
or 
suspected Stevens- 
Johnson or necrosis 
requiring surgery 
Induration 
< 15mm 
15-30 mm 
>30mm 
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Erythema 
< 15mm 
15-30 mm 
>30mm 
Edema 
< 15mm 
15-30 mm 
>30mm 
Rash at Injection 
Site 
< 15mm 
15-30 mm 
>30mm 
Pruritus 
slight itching at 
injection site 
moderate itching at 
injection extremity 
itching over entire 
body 
 
SYSTEMIC 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Allergic Reaction 
pruritus without rash 
localized urticaria 
generalized 
urticaria; 
angioedema 
anaphylaxis 
Headache 
mild, no treatment 
required 
transient, moderate; 
treatment required 
severe; responds to 
initial 
narcotic 
therapy 
intractable; requires 
repeated 
narcotic 
therapy 
Fever: oral 
37.7 - 38.5 C or 
100.0 - 101.5 F 
38.6 - 39.5 C or 
101.6 - 102.9 F 
39.6 - 40.5 C or 103 
- 105 F 
> 40 C or > 105 F 
Fatigue 
normal 
activity 
reduced < 48 hours 
normal 
activity 
decreased 25- 50% 
> 48 hours 
normal 
activity 
decreased > 50% 
can’t work 
unable to care for 
self 
 
 
 
 
 
 
 
 
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Appendix 3: Who Clinical Staging of HIV/AIDS for Adults and Adolescents  
Primary HIV Infection 
Asymptomatic 
Acute retroviral syndrome 
Clinical Stage 1 
Asymptomatic 
Persistent generalized lymphadenopathy 
Clinical Stage 2 
Moderate unexplained weight loss (<10% of presumed or measured body weight) 
Recurrent respiratory infections (sinusitis, tonsillitis, otitis media, and pharyngitis) 
Herpes zoster 
Angular cheilitis 
Recurrent oral ulceration 
Papular pruritic eruptions 
Seborrheic dermatitis 
Fungal nail infections 
Clinical Stage 3 
Unexplained severe weight loss (>10% of presumed or measured body weight) 
Unexplained chronic diarrhea for >1 month 
Unexplained persistent fever for >1 month (>37.6ºC, intermittent or constant) 
Persistent oral candidiasis (thrush) 
Oral hairy leukoplakia 
Pulmonary tuberculosis (current) 
Severe presumed bacterial infections (e.g., pneumonia, empyema, pyomyositis, bone 
or joint infection, meningitis, bacteremia) 
Acute necrotizing ulcerative stomatitis, gingivitis, or periodontitis 
Unexplained anemia (hemoglobin <8 g/dL) 
Neutropenia (neutrophils <500 cells/µL) 
Chronic thrombocytopenia (platelets <50,000 cells/µL) 
Clinical Stage 4 
HIV wasting syndrome 
Pneumocystis pneumonia 
Recurrent severe bacterial pneumonia 
Chronic herpes simplex infection (orolabial, genital, or anorectal site for >1 month or 
visceral herpes at any site) 
Esophageal candidiasis (or candidiasis of trachea, bronchi, or lungs) 
Extrapulmonary tuberculosis 
Kaposi sarcoma 
Cytomegalovirus infection (retinitis or infection of other organs) 
Central nervous system toxoplasmosis 
HIV encephalopathy 
Cryptococcosis, extrapulmonary (including meningitis) 
Disseminated nontuberculosis mycobacteria infection 
Progressive multifocal leukoencephalopathy 
Candida of the trachea, bronchi, or lungs 
Chronic cryptosporidiosis (with diarrhea) 
Chronic isosporiasis 
Disseminated mycosis (e.g., histoplasmosis, coccidioidomycosis, penicilliosis) 
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Recurrent nontyphoidal Salmonella bacteremia 
Lymphoma (cerebral or B-cell non-Hodgkin) 
Invasive cervical carcinoma 
Atypical disseminated leishmaniasis 
Symptomatic HIV-associated nephropathy 
Symptomatic HIV-associated cardiomyopathy 
Reactivation of American trypanosomiasis (meningoencephalitis or myocarditis) 
 
REF: World Health Organization. WHO Case Definitions of HIV for Surveillance and Revised Clinical Staging and Immunological 
Classification of HIV-Related Disease in Adults and Children; 2007 
Vital Signs 
The following abnormalities will be defined for vital signs: 
Abnormality Code 
Vital Signs Parameter 
 
Pulse 
DBP 
SBP 
RR 
Abnormalities on actual values 
“Abnormally low” 
≤ 50 bpm 
≤ 50 mmHg 
≤ 90 mm Hg 
<12 
Breaths per minute 
“Grade 1 or mild” 
- 
> 
90 
mmHg-
<100 mmHg 
> 140 mmHg-
<160 mmHg 
17-20 
Breaths per minute 
“Grade 2 or moderate” 
- 
≥ 100 mmHg-
<110 mmHg 
≥ 160 mmHg-
<180 mmHg 
21-25 
Breaths per minute 
“Grade 3 or severe” 
- 
≥ 110 mmHg 
≥ 180 mmHg 
>25 
Breaths per minute 
“Abnormally high or Grade 
4” 
≥ 120 bpm 
- 
- 
Intubation 
 
 
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Appendix 4: Cardiovascular Safety 
CARDIOVASCULAR 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Cardiac 
Rhythm 
 
asymptomatic, 
transient signs, 
no Rx required 
recurrent/persisten
t; symptomatic Rx 
required 
unstable dysrythmia; 
hospitalization and 
treatment required 
Hypertension 
transient increase > 
20 mm/Hg; no 
treatment 
recurrent, chronic 
increase > 
20mm/Hg. 
/treatment 
required 
acute treatment 
required; 
outpatient 
treatment or 
hospitalization 
possible 
end organ damage 
or hospitalization 
required 
Hypotension 
transient orthostatic 
hypotension with 
heart rate increased 
by <20 beat/min or 
decreased by <10 
mm Hg systolic BP, 
no treatment 
required. 
symptoms due to 
orthostatic 
hypotension or 
BP decreased by 
<20 mm Hg 
systolic; 
correctable with 
oral fluid 
treatment 
requires IV fluids; 
no hospitalization 
required 
mean arterial 
pressure <60mm/ 
Hg or end organ 
damage or shock; 
requires 
hospitalization and 
vasopressor 
treatment 
Pericarditis 
minimal effusion 
mild/moderate 
asymptomatic 
effusion, no 
treatment 
symptomatic 
effusion; pain; 
EKG changes 
tamponade; 
pericardiocentesis or 
surgery required 
Hemorrhage, 
Blood Loss 
microscopic/occult 
mild, no 
transfusion 
gross blood loss; 
1-2 units 
transfused 
massive blood loss; 
> 3 units transfused 
All-important abnormalities from the ECG readings will be reported. 
The percentage of participants with increases in QTc of <30, 30-60, or > 60 ms from baseline will 
also be tabulated at each time point. 
Abnormality Code 
ECG parameter 
 
HR 
PR 
QRS 
QTcorrected 
Abnormalities on actual values 
“Abnormally low” 
≤ 50 bpm 
NAP 
≤ 50 ms 
- 
“Abnormally high” 
≥ 120 bpm 
≥ 210 ms 
≥ 120 ms 
- 
“]450 ms, 480 ms] 
- 
- 
- 
450 ms < QTc ≤ 480 ms 
“]480 ms, 500 ms] 
- 
- 
- 
480 ms < QTc ≤ 500 ms 
“More than 500 ms 
- 
- 
- 
QTc > 500 ms 
Abnormalities on changes from baseline 
“[30; 60] ms” 
- 
- 
- 
[30; 60] ms 
“> 60 ms” 
- 
- 
- 
> 60 ms 
 
 
 
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Appendix 5: Karnofsky Performance Status Scale Definitions Rating (%) Criteria 
Description 
% 
Able to carry on normal activity 
and to work; no special care 
needed. 
Normal no complaints; no evidence of disease. 
100 
Able to carry on normal activity; minor signs or 
symptoms of disease. 
90 
Normal activity with effort; some signs or symptoms 
of disease.  
80 
Unable to work; able to live at 
home 
and 
care 
for 
most 
personal needs; varying amount 
of assistance needed. 
Cares for self; unable to carry on normal activity or 
to do active work. 
70 
Requires occasional assistance, but is able to care 
for most of his personal needs. 
60 
Requires considerable assistance and frequent 
medical care.  
50 
Unable to care for self; requires 
equivalent of institutional or 
hospital care; disease may be 
progressing rapidly. 
Disabled; requires special care and assistance. 
40 
Severely disabled; hospital admission is indicated 
although death not imminent. 
30 
Very sick; hospital admission necessary; active 
supportive treatment necessary. 
20 
Moribund; fatal processes progressing rapidly. 
10 
Dead 
0 
 
Ref: Oxford Textbook of Palliative Medicine, Oxford University Press.  1993; 109. 
 
 
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Appendix 6: Tuberculosis Symptoms Profile 
 
 
 
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Appendix 7: Patient Reported Health Status Questionnaire  
 
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Appendix 8: Liver Toxicity Management 
Standard anti-TB chemotherapy is known to cause derangement of liver function tests in a 
substantial number of patients. In many cases this will be asymptomatic and self-limiting. In some 
cases, severe hepatitis and even fulminant liver failure and death can occur. 
In pre-marketing clinical trials of new drugs and regimens it is especially important to identify and 
carefully manage any trial participants who are at risk of progression to serious liver injury. The 
observation of altered liver function to a degree that has a high risk of progressing to liver failure 
as been referred to informally as Hy’s Law;(44, 45); this reflects that pure hepatocellular injury 
sufficient to cause hyperbilirubinemia is an ominous indicator of the potential for a drug to cause 
serious liver injury. Briefly, Hy’s Law cases have the following three components: 
1. The drug causes hepatocellular injury, generally shown by a higher incidence of 3-fold 
or greater elevations above the ULN of ALT or AST than the (non-hepatotoxic) control 
drug or placebo. 
2. Among trial participants showing such aminotransferase (AT) elevations, often with ATs 
much greater than 3x ULN, one or more also show elevation of serum total bilirubin (TBL) 
to >2x ULN, without initial findings of cholestasis (elevated serum alkaline phosphatase 
(ALP)). 
3. No other reason can be found to explain the combination of increased AT and total bilirubin 
level (TBL), such as viral hepatitis A, B, or C; pre-existing or acute liver disease; or another 
drug capable of causing the observed injury. 
 
During the trial, liver function will be monitored regularly with clinical assessment and blood tests 
in trial participants and this will assist in follow up laboratory measurements that can document 
either resolution of abnormalities or signal the potential for drug-induced liver injury (DILI). In a 
clinical trial of new drugs and combinations it is especially important for Investigators to follow 
closely any participants who have evidence of hepatic inflammation or potential toxicity. The 
following procedure describes the management of deranged liver function tests in trial 
participants. 
Procedure 
Blood tests for liver function will be taken routinely at screening (Day -9 to -1) and at the specific 
time points designated in the protocol, and at Early Withdrawal. If at any other visit the clinician 
suspects derangement of liver function, e.g. the participant describes nausea and vomiting, right 
upper abdominal pain or is jaundiced, blood should be taken for liver function tests and the 
participant comprehensively assessed for evidence of hepatitis or hepatic impairment and any 
potentially contributing causes. 
Suspected liver toxicity (or elevated liver enzymes detected in the absence of symptoms) must 
be taken seriously and detailed guidance will be provided in a separate document, Management 
of Hepatotoxicity Guideline. Investigators should refer to this document as a guide to 
management in cases of suspected or proven liver toxicity. Importantly, the Sponsor Medical 
Monitor is available to provide further assistance if there is any uncertainty or additional questions. 
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The laboratory source (print-out of any results) should be stored alongside or transcribed into the 
clinical source document. Each abnormal value should be marked as clinically significant (CS) or 
non-clinically significant (NCS); the assessment of significance is at the discretion of  the 
Investigator. All clinically significant abnormal results must be recorded as Adverse Events in the 
eCRF and graded clinically as per the DMID adult toxicity table grading, (Appendix 2). 
Assessments and decision making for elevations in aminotransferase values or bilirubin of various 
levels of concern are detailed below: 
Elevated liver enzymes considered of clinical significance, but not accompanied by other signs 
and symptoms, should be reported as an adverse event and should usually be recorded as 
elevated liver enzymes. If the term "hepatitis" is used, the Safety Data Manager will question the 
site for additional evidence to support the diagnosis, such as clinical signs and serological or 
biopsy data. While a liver biopsy is not required to make a diagnosis of hepatitis, the term 
"hepatitis" should be reserved in most instances for cases where there is supportive evidence 
beyond a liver enzyme abnormality. However, if the Investigator will confirm the diagnosis of 
hepatitis just on the basis of clinical signs and laboratory values the diagnosis will be accepted. 
Should other symptoms or signs be present, these should also be recorded as adverse events. 
Temporarily Stopping and Restarting Trial Medication 
Liver function tests that are improving should be repeated regularly, such as every 3 days for the 
first week then once a week until they return to near baseline values for the participant. Manage 
the participant symptomatically as required using medications that are not potentially hepatotoxic 
and discontinue any concomitant drugs, if clinically warranted, that may be hepatotoxic. Infection 
control issues must be carefully managed whilst TB medications are being withheld, especially 
if the participant is still culture positive for acid fast bacilli. 
If t r i a l  medication has been temporarily stopped, once the liver function values have 
decreased substantially a decision must be made about further TB management. This will be 
dependent on the clinical context and a decision must be made in discussion with the Sponsor 
Medical Monitor. Investigational treatment can only be restarted if the Sponsor Medical Monitor 
is in agreement with the plan. In all cases treatment should be recommenced under close 
supervision for any evidence of recurrent liver function abnormalities. 
If there is a further significant elevation of hepatic enzymes or bilirubin or symptoms of clinical 
concern after resumption of trial medication, the trial medication should be withdrawn 
permanently. Participants who permanently discontinue trial medication should be managed as 
clinically indicated according to local National TB Programme guidelines. The Sponsor Medical 
Monitor can be contacted for further advice when referring to the National Treatment Program. 
The Sponsor Medical Monitor is available to assist the Investigators in both the management of 
liver toxicity and decisions regarding the holding or re-introduction of trial medication. 
Investigators must involve the Sponsor Medical Monitor in any decisions regarding medication 
hold or re-start, and there should always be a low threshold for contacting the Sponsor Medical 
Monitor in cases of elevated liver enzymes.  
 
 
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Protocol Name:                         SimpliciTB 
 
 
Protocol Amendment 
 
TMP02-C V3.0 dated 06Dec2017 
CONFIDENTIAL 
This document is proprietary and shall not be reproduced without prior written permission from TB Alliance. 
 
Protocol Name / Number: 
SimpliciTB / NC-008 (B-Pa-M-Z) 
Protocol Title: 
An Open-Label, Partially Randomized Trial to Evaluate the Efficacy, Safety and Tolerability of a 4-month 
Treatment of Bedaquiline plus Pretomanid plus Moxifloxacin plus Pyrazinamide (BPaMZ) Compared to a 6-
month Treatment of HRZE/HR (Control) in Adult Participants with Drug-Sensitive Smear-Positive Pulmonary 
Tuberculosis (DS-TB) and a 6-month Treatment of BPaMZ in Adult Participants with Drug Resistant, Smear-
Positive Pulmonary Tuberculosis (DR-TB). 
 
 
Reasons for Protocol Amendment: 
1 
Change of HRZE weight band 1 and 2 in compliance with the HRZE and HR Package Inserts (Synopsis and Section 6.1.2 Instructions for 
Dosing Control Treatment Regime HRZE/HR) 
2 
Removal 
a daily supplement of Vitamin B6 will be provided by 
the trial site to participants randomised to the HRZE/HR treatment 
   
3 
Removal of reporting non-adherence to the Sponsor Medical Monitor from the Synopsis and from Section 6.3 Treatment Modification(s) as it 
-adherence should prompt the Investigator to identify and addresses the cause(s)  this is to prevent over-
reporting of inappropriate protocol non-compliances by the participant. 
4 
Change the number of consecutive missed doses in the Synopsis and Section 6.3 Treatment Modifications, from 7 to 
21
35 and 
stated that no more than 56 cumulative (sum of) consecutive doses may be missed before the IMP is stopped and the participant is 
withdrawn from the trial (consistent with ZeNix). 
5 
Addition of safety laboratory assessments at weeks 5 and 7 (Section 1.2 Synopsis Flow Chart and Procedures) 
6 
Addition of ECG assessments included at weeks 3, 6, 7 and 8 (Section 1.2 Synopsis Flow Chart and Procedures) 
7 
Clarified that if the Screening (Day-9 to -1) spot sputum smear shows an indeterminate result or is AFB negative that a test may be repeated 
on a back-up sample or a freshly collected spot sputum sample (Section 1.2 Synopsis Flow Chart and Procedures, Item f). 
8 
Clarified that if both sputum samples at Weeks 8, 17 (4-month treatment arm), 26 (6-month treatment arm), 52 or 104 are contaminated, the 
participant should return for an unscheduled visit(s) to give additional samples. 
9 
Clarified that if HIV status is a confirmed known positive, a repeated HIV test is not needed provided that a documented HIV test result is 
available, and that a HIV re-test of an indeterminate result can be done within the Screening period (Section 1.2 Synopsis Flow Chart and 
Procedures, Item h.) 
10
Addition of GGT assessment to the clinical chemistry assessments at Screening and Unscheduled visits (only) in the Synopsis Flow Chart 
Item l, and added to Exclusion Criteria #23: f) a GGT greater than 3x ULN (will be excluded at the Screening visit); updated Section 7.3 
Safety and Tolerability Assessments 
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CONFIDENTIAL 
This document is proprietary and shall not be reproduced without prior written permission from TB Alliance. 
 
11
Change of the timing of the chest x-ray from 4 weeks prior to or at the Screening visit, to 6 weeks prior to or at the Screening visit (Section 
1.2 Synopsis Flow Chart and Procedures, and Inclusion Criteria #6, Section 7.1 Demographic and Background Variables and Procedures) 
12
Clarified that the Slit Lamp Ophthalmic Examination will also be performed at the Screening visit (Section 1.2 Synopsis Flow Chart and 
Procedures Item p.), as reflected in the actual flow chart. 
13
Clarified the timing of PK sampling at Weeks 39, 65, 78 and 104 to indicate that the samples can be taken at any time during the specified 
visits, as this was not previously stated (Section 1.2 Synopsis Flow Chart and Procedures, Item s.) 
14
Clarified that the DR-TB participants should not have had previous treatment for DR-TB/MDR-TB, although may have been on a MDR-
TB/MDR-TB treatment regimen for no longer than 7 days at start of screening (Inclusion criteria #5) 
15
Addition of Exclusion 
safety or ability to follow through with all protocol-
 for safety reasons. 
16
Change of the Exclusion Criteria # 11 by increasing the QTcF interval from >450 to >500 msec and specified the following additional 
exclusionary criteria:  heart failure, a personal or family history of congenital QT prolongation, history of or known, untreated, ongoing 
hypothyroidism, a history of or ongoing bradyarrhythmia, a history of Torsade de Pointe (consistent with ZeNix) 
17
Addition of Exclusion criteria #15, Females who have a positive pregnancy test at the Screening visit or already known to be pregnant, 
breast-feeding, or planning to conceive a child during the trial or within 6 months of stopping treatment.  Males planning to conceive a child 
 for safety reasons. 
18
Addition of topical steroids to Exclusion Criteria #20 and Section 5.3 Restrictions, as this was previous limited only to inhaled or intranasal 
glucocorticoids 
19
Removal 
Early Withdrawal to prevent unnecessary 
or inappropriate withdrawal of participants from the study. 
20
Removal of the optional serum pregnancy assessment from Section 5.4.1 Early Withdrawal visit, as urine pregnancy test confirmation is 
sufficient 
21
Removal of the requirement in Section 6.2 Participant Compliance, of checking IMP compliance with the support of the National TB 
Treatment Program personnel (DOTS) 
22
Removal of the address and telephone number of the sponsor from Section 6.4 IMP Packaging and Labelling, as this is not required or 
documented on the approved IMP labels 
23
Removal of the ophthalmic examination from Section 7.3 Safety and Tolerability (consistent with 1.2 Synopsis Flow Chart and Procedures) 
as only ophthalmology slit lamp examination by (AREDS2 trained) ophthalmologist is required 
24
Clarified in Section 7.5 Mycobacteriology Characterisation Variable and Procedures that 
genome sequencing, and the comparison of sequences from baseline and 
wording in Section 1.2 Synopsis Flow Chart and Procedures, Item g.
 
25
Removal of the
Section 8.2.6 Pregnancy, as information from female 
partners of male participants who may become pregnant during the trial, will not be collected 
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This document is proprietary and shall not be reproduced without prior written permission from TB Alliance. 
26
Addition of additional laboratory parameters that require monitoring, in Section 8.3, that were not previously listed, for safety reasons. 
27
Addition 
28
Addition of DMID reference tables to Appendix 2 (previously missing) 
29
Addition of Liver Toxicity Management, Appendix 8 
30
Administrative changes, including spelling, grammar and format changes 
# 
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Version 2.0 dated 16-Feb-18 
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1 
Synopsis and 
Section 6.1.2 
Weeks 1-8: HRZE tablets with the daily dose per 
30-37 kg: 2
tablets; 38-54 kg: 3 tablets; 55-70 kg: 4 tablets; 
71 kg: 5 tablets 
Weeks 9-26: HR tablets with the daily dose per 
30-39 kg: 2
tablets; 40-54 kg: 3 tablets; 55-70 kg: 4 tablets; 
71 kg: 5 tablets 
Weeks 1-26 HRZE/HR tables daily dose per the 
Weight Band
Weight Range
Number of 
tablets 
1 
30-39 kg
2 
2 
40-54 kg
3 
3 
55-70 kg
4 
4 
5 
1 
2 
Synopsis and 
Section 6 
Treatment 
Vitamin B6 25 mg daily supplement to be taken 
with the HRZE/HR treatment. 
Vitamin B6 daily supplement to be taken with the 
Treatment Guidelines. 
2 
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# 
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Previous Text 
Version 1.0 dated 05-Oct-17 
 
Amended Text 
Version 2.0 dated 16-Feb-18 
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Reason for 
Change 
Insert reason # from 
table above
3 
Synopsis and 
Section 6.3 
Treatment 
Modification(s) 
The trial treatment regimens may require 
interruptions/pauses due to toxicities. All dose 
interruptions/pauses should be discussed with the 
implementation, unless an interruption/pause is 
required urgently for a safety concern; the Medical 
Monitor should then be informed within 24 hours of
the interruption/pause if not discussed prior to 
implementation.   
The importance of adherence to the treatment 
schedule will be reinforced at each visit.  Non-
adherence should prompt the investigator to 
identify, capture and address the cause(s) (e.g. 
side effects) of the non-adherence and contact the 
sponsor medical monitor.    
The trial treatment regimens may require 
interruptions/pauses due to toxicities. All dose 
interruptions/pauses should be discussed with the 
implementation, 
unless an interruption/pause is required urgently for 
a safety concern.   
 
3 
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# 
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Amended Text 
Version 2.0 dated 16-Feb-18 
Additional text - bold font. Deleted text  strike-through. 
Reason for 
Change 
Insert reason # from 
table above
4 
Synopsis and 
Section 3.3 
Treatment 
Modifications 
 
Up to 7 consecutive doses of IMP doses: 
restart IMP, no extension of IMP required. 
 
utive doses of 
IMP: restart IMP and extend the IMP treatment 
by the number of consecutive doses missed. 
The final treatment visit should also be pushed 
out to the date of last dose. It is not necessary 
to have an unscheduled visit at the time when 
the end of treatment visit would have been.   
 
Greater than 21 consecutive doses of IMP, 
discontinue IMP and withdraw participant from 
the trial. 
 
 
Up to 7 consecutive doses of IMP doses: restart 
IMP, no extension of IMP required. 
 
restart IMP and extend the IMP treatment by the 
number of consecutive doses missed. The final 
treatment visit should also be pushed out to the 
date of last dose. It is not necessary to have an 
unscheduled visit at the time when the end of 
treatment visit would have been.   
 
Greater than 35 consecutive doses of IMP, 
discontinue IMP and withdraw participant from 
the trial. 
 
If the participant misses a total (sum of) 56 
cumulative missed doses, discontinue IMP and 
withdraw participant from the trial. 
 
4 
5 
Synopsis Flow 
Chart and 
Procedures 
Safety laboratory assessment previously not 
performed at weeks 5 and 7 
Safety laboratory assessment performed at weeks 5 
and 7 (i.e. will be performed weekly, from Baseline 
to Week 8) 
5 
6 
Synopsis Flow 
Chart and 
Procedures  
ECGs not previously performed at weeks 3, 5, 6 
and 7  
ECGs will be performed weekly from Day 1 
(Baseline) to Week 8 
6 
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# 
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Previous Text 
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Amended Text 
Version 2.0 dated 16-Feb-18 
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Reason for 
Change 
Insert reason # from 
table above
7 
Synopsis Flow 
Chart and 
Procedures, Item 
f. 
 
The second sample is collected as a back-up 
sample to the first sample in case it is 
technically not possible to obtain a result/s 
from the first sample. If the Day -9 to -1 
(Screening) spot sputum smear shows an 
indeterminate result or is AFB negative, the 
test may be repeated on a freshly collected 
spot sputum/s and that result will be used.  
 
 
The second sample is collected as a back-up 
sample to the first sample in case it is technically 
not possible to obtain a result/s from the first 
sample. If the Day -9 to -1 (Screening) spot 
sputum smear shows an indeterminate result or 
is AFB negative, the test may be repeated on 
the back-up sample or a freshly collected spot 
sputum/s and that result will be used.  
 
7 
8 
Synopsis Flow 
Chart and 
Procedures, Item 
f. 
 
If both sputum samples at Weeks 8 or later are 
contaminated, the participant should return for 
an unscheduled visit(s) to give additional 
samples or it must be documented that the 
participant is not able to produce sputum.  
 
If both sputum samples at Weeks 8, 17 (4-
month treatment arm), 26 (6-month treatment 
arm), 52 or 104 are contaminated, the 
participant should return for an unscheduled 
visit(s) to give additional samples or it must be 
documented that the participant is not able to 
produce sputum.  
8 
9 
Synopsis Flow 
Chart and 
Procedures, Item 
h. 
If HIV status is a confirmed known positive, 
repeated HIV test is not needed, provided 
documentation is available. 
 
 
 
If HIV status is a confirmed known positive, a 
repeated HIV test is not needed provided that a 
documented HIV test result is available. 
 
Repeated HIV testing, during the Screening 
period is permitted for indeterminate HIV results. 
9 
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# 
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Reason for 
Change 
Insert reason # from 
table above
10
1.2 Synopsis 
Flow Chart and 
Procedures, Item 
l. and Exclusion 
Criteria #23 and 
Section 7.3 
Safety and 
Tolerability 
assessments 
1.2 Synopsis Flow Chart and Procedures, Item 
l 
Clinical Chemistry (albumin, serum urea, 
creatinine, direct, indirect and total bilirubin, uric 
acid, total protein, alkaline phosphatase [ALP], 
aspartate aminotransferase [AST], alanine 
aminotransferase [ALT], lipase, phosphate, 
sodium, potassium, calcium (corrected for 
albumin), chloride, magnesium, glucose, 
bicarbonate/carbon dioxide [CO2], creatine 
phosphokinase [CPK]). 
 
Exclusion Criteria #23 
Addition of item f. not previously present 
 
7.3 Safety and Tolerability Assessments 
3rd bullet in this section not previously present 
 
1.2 Synopsis Flow Chart and Procedures, Item l
Clinical Chemistry (albumin, serum urea, creatinine, 
direct, indirect and total bilirubin, uric acid, total 
protein, alkaline phosphatase [ALP], aspartate 
aminotransferase [AST], alanine aminotransferase 
[ALT], lipase, phosphate, sodium, potassium, 
calcium (corrected for albumin), chloride, 
magnesium, glucose, bicarbonate/carbon dioxide 
[CO2], creatine phosphokinase [CPK]). GGT is only 
routinely included at the Screening visit (Day -9 
to -1).  
 
Exclusion Criteria #23 
f. GGT: great than 3 x ULN 
7.3 Safety and Tolerability Assessments 
When managing participants with elevated liver 
enzymes at an Unscheduled visit, the investigator 
can request additional tests, in addition to the repeat 
LFT [e.g. Gamma Glutamyl Transferase (GGT), 
screening for Hepatitis A, B, C; to assist in ruling out 
other causes of a dysfunctional liver test (e.g. 
alcohol induced hepatic cell injury, hepatobiliary 
disease, hepatic viral infection)]. 
 
10 
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# 
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Reason for 
Change 
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table above
11
1.2 Synopsis 
Flow Chart and 
Procedures, Item 
o., Inclusion 
Criteria #6 and 
Section 7.1 
Demographic and 
Background 
Variables and 
Procedures 
A chest x-ray (digital image) within 4 weeks prior 
to or at screening 
A chest x-ray (digital image) within 6 months prior 
to or at screening 
11 
12
Synopsis Flow 
Chart and 
Procedures, Item 
p. 
Slit lamp will be done at EOT and at 9 month for 4 
and 6-month treatment groups. 
Slit lamp examination will be done at the Screening 
visit, the last visit of the treatment period, Week 
17 or 26, and at Week 39 (9 months) for both 
treatment groups.   
12 
13
Synopsis Flow 
Chart and 
Procedures, Item 
s. 
6. Weeks 39, 65, 78 and 104  PK samples are 
obtained when participant is in the clinic 
 
6. Weeks 39, 65, 78 and 104: PK samples to be 
obtained at any time on the day of the scheduled 
visit. 
13 
14
Section 5.1 
Inclusion Criteria 
#5 
DR-TB treatment arm participants should be:
a. Resistant to rifampicin and/or isoniazid. 
 
DR-TB treatment arm participants should be:
a. Resistant to rifampicin and/or isoniazid.  
b. Should not have had previous treatment 
for DR-TB/MDR-TB, although may have 
been on a DR-TB/MDR-TB treatment 
regimen for no longer than 7 days at start 
of screening. 
 
14 
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# 
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Previous Text 
Version 1.0 dated 05-Oct-17 
 
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Reason for 
Change 
Insert reason # from 
table above
15
Section 5.2 
Exclusion Criteria 
#2 
Not previously stated. 
2. Abuse of alcohol or illegal drugs that in the 
opinion of the Investigator would compromise the 
with all protocol-specified restrictions, visits and 
evaluations. 
 
15 
16
Section 5.2 
Exclusion Criteria 
#11 
10. Participants with any of the following at 
screening (per measurements and reading 
done by ECG): 
11. Cardiac arrhythmia requiring medication; 
12. Prolongation of QT/QTc interval with QTcF 
(Fridericia correction) >450 ms; 
13. History of additional risk factors for Torsade de 
Pointes, (e.g., heart failure, hypokalemia, 
family history of Long QT Syndrome); 
14. Any clinically significant ECG abnormality, in 
the opinion of the investigator. 
 
11. Participants with any of the following at the 
Screening visit (per measurements and 
reading done by ECG): 
 
a. QTcF interval on ECG >500 msec.  
Participants with QTcF > 450 must be 
discussed with the Sponsor Medical 
Monitor before enrolment. 
b. Heart failure 
c. A personal or family history of congenital 
QT prolongation 
d. A history of or known, untreated, ongoing 
hypothyroidism 
e. A history of or ongoing bradyarrhythmia 
f. A history of Torsade de Pointe 
 
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# 
Section 
Previous Text 
Version 1.0 dated 05-Oct-17 
 
Amended Text 
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Reason for 
Change 
Insert reason # from 
table above
17
Section 5.2 
Exclusion Criteria 
#13 
Not previously stated. 
13. Females who have a positive pregnancy test at 
the Screening visit or already known to be 
pregnant, breast-feeding, or planning to conceive 
a child during the trial or within 6 months of 
stopping treatment.  Males planning to conceive 
a child during the trial or within 6 months of 
stopping treatment. 
 
17 
18
Section 5.2 
Exclusion Criteria 
#20 and Section 
5.3 Restrictions 
7. Use of systemic glucocorticoids within one 
year of start of screening (inhaled or intranasal 
glucocorticoids are allowed) due to visual 
opacities or cataracts 
 
Section 5.3 Restrictions 
Chronic systemic glucocorticoids (inhaled or 
intranasal glucocorticoids are allowed) due to their 
potential to cause visual opacities. Short term 
systemic glucocorticoids are allowed for 
emergency situations e.g for treatment of 
pulmonary exacerbation when Inhaled 
glucocorticoids is inadequate. 
20. Use of systemic glucocorticoids within one 
year of start of screening (topical, inhaled or 
intranasal glucocorticoids are allowed) due to 
visual opacities or cataracts. 
 
Section 5.3 Restrictions 
Chronic systemic glucocorticoids (topical, inhaled or 
intranasal glucocorticoids are allowed) due to their 
potential to cause visual opacities. Short term 
systemic glucocorticoids are allowed for emergency 
situations (e.g. for treatment of pulmonary 
exacerbation when Inhaled glucocorticoids is 
inadequate). 
18 
19
Section 5.4 
Treatment 
Discontinuation 
and/or Early 
Withdrawal 
Failure to comply with the protocol (5th bullet) 
Removal of this reason to withdraw the participant 
early. 
19 
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Protocol Number:                      NC-008 
Protocol Amendment Version:  V1 Dated 21 Feb 2018 
Protocol Name:                         SimpliciTB 
 
 
Protocol Amendment 
 
TMP02-C V3.0 dated 06Dec2017 
CONFIDENTIAL 
This document is proprietary and shall not be reproduced without prior written permission from TB Alliance. 
 
# 
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Previous Text 
Version 1.0 dated 05-Oct-17 
 
Amended Text 
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20
Section 5.4.1 
Early Withdrawal 
Serum or Urine Pregnancy test (women of child 
bearing potential, whether they are sexually active 
or not); 
 
Urine Pregnancy test (women of child bearing 
potential, whether they are sexually active or not); 
20 
21
Section 6.2 
Participant 
Compliance 
During site clinic visits, the IMP will be 
administered by the Investigator/designated site 
personnel. During the trial, sites will be 
responsible for ensuring participants are taking 
IMP correctly and are fully trained on how IMP is 
to be taken. When possible, participants will be 
checked for IMP compliance by the Investigators 
or trial personnel/National TB Treatment Program 
personnel via the hand-and-mouth procedure 
(both the hand and the mouth of the participant will 
be checked to ensure that the participant has 
swallowed the IMP).  Additionally, participant 
cards will be checked for unused tablets in the 
blisters at each visit during the treatment phase. 
 
During site clinic visits, the IMP will be administered 
by the Investigator(s)/designated site personnel and 
when possible, the check for IMP compliance via the 
hand-and-mouth procedure (both the hand and the 
mouth of the participant will be checked to ensure 
that the participant has swallowed the IMP). During 
the trial, sites will be responsible for ensuring 
participants are taking IMP correctly and are fully 
trained on how the IMP is to be taken as well as 
check cards for unused tablets in the containers at 
each visit during the treatment phase.  
 
21 
22
Section 6.4 IMP 
Packaging and 
Labelling 
Name, address and telephone number of Sponsor.
 
Name of Sponsor. 
 
22 
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Global Alliance for TB Drug Development 
Protocol Number:                      NC-008 
Protocol Amendment Version:  V1 Dated 21 Feb 2018 
Protocol Name:                         SimpliciTB 
 
 
Protocol Amendment 
 
TMP02-C V3.0 dated 06Dec2017 
CONFIDENTIAL 
This document is proprietary and shall not be reproduced without prior written permission from TB Alliance. 
 
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23
Section 7.3 
Safety and 
Tolerability 
Assessments 
 
Ophthalmic Examination. The ophthalmic 
examinations can be performed by any trained 
study staff. The screening exams must be 
done by the trained study staff AND an 
Ophthalmologist.  Methodology and 
requirements will be detailed in the 
Ophthalmology Guideline. 
o Ophthalmology History (Screening only); 
o Visual Acuity Test  Corrected. Distance 
Vision; 
o Colour Vision Assessment. 
 
Removed  not required.  Only the ophthalmology 
slit lamp examination is required and remains in 
Section 7.3 
23 
24
Section 7.5 
Mycobacteriology 
Characterisation 
Variable and 
Procedures 
The MTB isolates will be processed at the central 
lab(s) for: 
 
MIC against bedaquiline, pretomanid and 
moxifloxacin;   
 
Drug Susceptibility Testing in liquid culture 
for streptomycin, rifampicin, isoniazid, 
ethambutol, moxifloxacin and pyrazinamide, 
and second line TB drugs including but not 
limited to fluoroquinolones, and injectables; 
 
Genotyping. 
 
The MTB isolates will be processed at the central 
microbiology laboratory for: 
 
 
MIC against bedaquiline, pretomanid and 
moxifloxacin  
 
Drug Susceptibility Testing in liquid culture for 
streptomycin, rifampicin, isoniazid, 
ethambutol, moxifloxacin and pyrazinamide, 
and second line TB drugs including but not 
limited to fluoroquinolones, and injectables 
 
Extraction of organismal (MTB) DNA for 
whole genome sequencing, and the 
comparison of sequences from baseline 
and relapse isolates. 
 
24 
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Protocol Number:                      NC-008 
Protocol Amendment Version:  V1 Dated 21 Feb 2018 
Protocol Name:                         SimpliciTB 
 
 
Protocol Amendment 
 
TMP02-C V3.0 dated 06Dec2017 
CONFIDENTIAL 
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25
8.2.6 Pregnancy 
Should the female partner of a male participant 
become pregnant during the trial or in 12 weeks 
after the completion of IMP and the Investigator 
becomes aware that this situation has occurred, 
the sponsor may request information from the 
female partner on her pregnancy history and on 
the current pregnancy and birth. 
 
Paragraph removed from this section. 
25 
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Protocol Number:                      NC-008 
Protocol Amendment Version:  V1 Dated 21 Feb 2018 
Protocol Name:                         SimpliciTB 
 
 
Protocol Amendment 
 
TMP02-C V3.0 dated 06Dec2017 
CONFIDENTIAL 
This document is proprietary and shall not be reproduced without prior written permission from TB Alliance. 
 
# 
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Version 1.0 dated 05-Oct-17 
 
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26
Section 8.3 
Monitoring for 
Specific Toxicities
Not previously listed in this section. 
8.3.1 ALT, AST and Bilirubin Elevations 
The Investigator should refer to Appendix 8 Liver 
Toxicity Management, to appropriately monitor 
significant elevations of AST, ALT or Bilirubin. A 
separate Hepatoxicity Management Guideline 
document has been developed to aid investigators 
in the management of participants. 
When managing participants with elevated liver 
enzymes at an Unscheduled visit, the investigator 
can request additional tests, in addition to the repeat 
LFT [e.g. Gamma Glutamyl Transferase (GGT), 
screening for Hepatitis A, B, C; to assist in ruling out 
other causes of a dysfunctional liver test (e.g. 
alcohol induced hepatic cell injury, hepatobiliary 
disease, hepatic viral infection)]. 
8.3.2 Lipase 
Grade 3 (> 2.0 to  5.0 x ULN) or Grade 4 (> 5.0 x 
ULN): 
 
Contact the Sponsor Medical Monitor to 
review. Participants with confirmed Grade 3 
or 4 elevations of lipase, the Investigator 
should consider pausing the full regimen, 
pending further evaluation. 
26 
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Global Alliance for TB Drug Development 
Protocol Number:                      NC-008 
Protocol Amendment Version:  V1 Dated 21 Feb 2018 
Protocol Name:                         SimpliciTB 
 
 
Protocol Amendment 
 
TMP02-C V3.0 dated 06Dec2017 
CONFIDENTIAL 
This document is proprietary and shall not be reproduced without prior written permission from TB Alliance. 
 
# 
Section 
Previous Text 
Version 1.0 dated 05-Oct-17 
 
Amended Text 
Version 2.0 dated 16-Feb-18 
Additional text - bold font. Deleted text  strike-through. 
Reason for 
Change 
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27
Section 16.0 
References 
Not previously listed 
44. Reuben A 
 
 Landmarks in 
Hepatology 39(2): 574-578. 
45. Temple RJ (2006). 
 Law: predicting 
serious 
 
Pharmacoepidemoiology and Drug Safety 
15: 241-243. 
27 
28
Appendix 2 
DMID tables tot previously listed 
Refer to tables in Appendix 2 
28 
29
Appendix 8 
Not previously present 
Refer to Appendix 8 
29 
30
Entire Document 
Administrative changes, including spelling, grammar and format changes have been applied to the entire 
 
30 
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Global Alliance for TB Drug Development 
Protocol Number:                      NC-008 
Protocol Amendment Version:  V1 Dated 21 Feb 2018 
Protocol Name:                         SimpliciTB 
 
 
Protocol Amendment 
 
TMP02-C V3.0 dated 06Dec2017 
CONFIDENTIAL 
This document is proprietary and shall not be reproduced without prior written permission from TB Alliance. 
Sponsor 
I agree to the terms of this protocol amendment 
Signature of Senior Medical Officer 
 
Printed name 
 
Date 
 
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Global Alliance for TB Drug Development 
Protocol Number:                      NC-008 
Protocol Amendment Version:  V1 Dated 21 Feb 2018 
Protocol Name:                         SimpliciTB 
 
 
Protocol Amendment 
 
TMP02-C V3.0 dated 06Dec2017 
CONFIDENTIAL 
This document is proprietary and shall not be reproduced without prior written permission from TB Alliance. 
 
Principal Investigator 
 
I hereby confirm I have read the above Protocol Amendment and agree to conduct this clinical trial as outlined in the above 
Protocol Amendment. I will provide copies of the Protocol Amendment and access to all of the information required to conduct the 
clinical trial according to the above Protocol Amendment to the site personnel under my supervision. I will discuss this material with 
them and ensure they are fully informed on all trial requirements.  
 
 
 
 
 
 
Signature of Principal Investigator 
 
Printed name 
 
Date 
 
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CONFIDENTIAL  
 
 
 
Protocol Number: 
NC-008 (BPaMZ) 
Title: 
An Open-Label, Partially Randomized Trial to Evaluate the 
Efficacy, Safety and Tolerability of a 4-month Treatment of 
Bedaquiline plus Pretomanid plus Moxifloxacin plus Pyrazinamide 
(BPaMZ) Compared to a 6-month Treatment of HRZE/HR (Control) 
in Adult Participants with Drug-Sensitive Smear-Positive 
Pulmonary Tuberculosis (DS-TB) and a 6-month Treatment of 
BPaMZ in Adult Participants with Drug Resistant, Smear-Positive 
Pulmonary Tuberculosis (DR-TB). 
Drug(s)/Combination(s): 
Bedaquiline tablets (B), pretomanid tablets (Pa), moxifloxacin 
tablets (M), pyrazinamide tablets (Z), HRZE tablets [isoniazid (H), 
rifampicin (R), pyrazinamide (Z) and ethambutol (E)] and HR 
tablets [isoniazid (H) plus rifampicin (R) combination tablets] 
Protocol Version/Date: 
V3.0 / 14 January 2019, Incorporating Amendments 1 and 2 
Protocol Name: 
SimpliciTB 
 
 
 
 
 
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TB Alliance
Protocol Number: NC-008 (B-Pa-M-Z) 
Protocol Version: V3.0 / 14 JAN 2019 
Protocol Name: 
SimpliciTB 
CONFIDENTIAL 
Page 2 of 101 
 
PROTOCOL SIGNATURE PAGE 
Protocol Title:  An Open-Label, Partially Randomized Trial to Evaluate the Efficacy, 
Safety and Tolerability of a 4-month Treatment of Bedaquiline plus Pretomanid plus 
Moxifloxacin plus Pyrazinamide (BPaMZ) Compared to a 6-month Treatment of 
HRZE/HR (Control) in Adult Participants with Drug-Sensitive Smear-Positive Pulmonary 
Tuberculosis (DS-TB) and a 6-month Treatment of BPaMZ in Adult Participants with 
Drug Resistant, Smear-Positive Pulmonary Tuberculosis (DR-TB). 
Protocol Number:  
NC-008 (BPaMZ) 
Protocol Date: 
V3.0 / 14 January 2019, Incorporating Amendments 1 and 2 
Protocol Name:  
SimpliciTB 
Sponsor: 
TB Alliance 
 
I agree to the terms of this trial protocol. 
 
 
 
 
 
 
Morounfolu Olugbosi 
Signature of Study Physician  
 
 
Printed Name 
 
 
40 Wall Street, 24th Floor 
New York, NY 10005 
Phone +27 87 700 3900 / +27 79 045 4917 
E-mail: morounfolu.olugbosi@tballiance.org 
Date 
 
 
 
 
 
 
 
 
 
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TB Alliance 
Protocol Number: NC-008 (B-Pa-M-Z) 
Protocol Version: V3.0 / 14 JAN 2019 
Protocol Name: 
SimpliciTB 
CONFIDENTIAL 
Page 3 of 101 
 
PRINCIPAL INVESTIGATOR PROTOCOL SIGNATURE PAGE 
 
An Open-Label, Partially Randomized Trial to Evaluate the Efficacy, Safety and 
Tolerability of a 4-month Treatment of Bedaquiline plus Pretomanid plus Moxifloxacin 
plus Pyrazinamide (BPaMZ) Compared to a 6-month Treatment of HRZE/HR (Control) in 
Adult Participants with Drug-Sensitive Smear-Positive Pulmonary Tuberculosis (DS-TB) 
and a 6-month Treatment of BPaMZ in Adult Participants with Drug Resistant, Smear-
Positive Pulmonary Tuberculosis (DR-TB). 
Protocol Number:  
NC-008 (BPaMZ) 
Protocol Date:  
V3.0 / 14 January 2019, Incorporating Amendments 1 and 2 
Protocol Name:  
SimpliciTB 
 
I hereby confirm that I have read the above protocol and agree to conduct this clinical trial as 
outlined in the above protocol. I will provide copies of the protocol and access to all the information 
required to conduct the clinical trial according to the above protocol to the site personnel under 
my supervision. I will discuss this material with them and ensure they are fully informed on all trial 
requirements. 
 
 
 
 
 
Signature 
 
Printed Name 
 
 
 
Date 
 
 
 
 
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TB Alliance 
Protocol Number: NC-008 (B-Pa-M-Z) 
Protocol Version: V3.0 / 14 JAN 2019 
Protocol Name: 
SimpliciTB 
CONFIDENTIAL 
Page 4 of 101 
 
Table of Contents 
Page 
List of Tables ............................................................................................................................. 8 
List of Figures ............................................................................................................................ 8 
List of Appendices ...................................................................................................................... 8 
1.0 
Synopsis ........................................................................................................................11 
1.1 
Synopsis Summary ................................................................................................11 
1.2 
Synopsis Flow Chart and Procedures .....................................................................18 
2.0 
Introduction and Rationale .............................................................................................23 
2.1 
Tuberculosis Disease .............................................................................................23 
2.2 
Tuberculosis Clinical Research ..............................................................................23 
2.3 
Trial Rationale ........................................................................................................25 
2.3.1 
Trial Design Rationale ...............................................................................25 
2.3.2 
Trial Drug Regimen Rationale ...................................................................26 
2.4 
Agents used within SimpliciTB................................................................................27 
2.5 
Background of Agents to be Studied in SimpliciTB .................................................29 
2.5.1 
Bedaquiline (B) .........................................................................................29 
2.5.2 
Pretomanid (P) ..........................................................................................36 
2.5.3 
Moxifloxacin (M) ........................................................................................42 
2.5.4 
Pyrazinamide (Z) .......................................................................................44 
2.6 
Overall Benefit/Risk Assessment ............................................................................45 
2.6.1 
Bedaquiline (B) .........................................................................................45 
2.6.2 
Pretomanid (P) ..........................................................................................46 
2.6.3 
Moxifloxacin (M) ........................................................................................47 
2.6.4 
Pyrazinamide (Z) .......................................................................................47 
2.6.5 
HRZE/HR Control ......................................................................................47 
3.0 
Trial Objectives ..............................................................................................................47 
3.1 
Primary Endpoint ....................................................................................................47 
3.2 
Secondary Endpoints .............................................................................................48 
3.3 
Exploratory Objectives ...........................................................................................49 
4.0 
Trial Design ...................................................................................................................49 
4.1 
Summary of Trial Design ........................................................................................49 
4.2 
Treatment Plan: Schedule of Assessments ............................................................49 
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Protocol Number: NC-008 (B-Pa-M-Z) 
Protocol Version: V3.0 / 14 JAN 2019 
Protocol Name:  
SimpliciTB 
 
Table of Contents (continued) 
Page 
CONFIDENTIAL 
Page 5 of 101 
5.0 
Trial Population .............................................................................................................50 
5.1 
Inclusion Criteria ....................................................................................................50 
5.2 
Exclusion Criteria ...................................................................................................52 
5.3 
Restrictions ............................................................................................................55 
5.4 
Treatment Discontinuation and/or Early Withdrawal ...............................................57 
5.4.1 
Early Withdrawal .......................................................................................57 
5.4.2 
Unscheduled Visits ....................................................................................58 
5.4.3 
Lost-to-Follow-up ......................................................................................60 
5.4.4 
Early Withdrawal due to TB .......................................................................60 
5.5 
Participant Progress Definitions ..............................................................................61 
5.6 
Trial Stopping Rules ...............................................................................................61 
6.0 
Treatment ......................................................................................................................62 
6.1 
IMP Administration .................................................................................................62 
6.1.1 
Instructions for Dosing of Test Regimen (BPaMZ) .....................................62 
6.1.2 
Instructions for Dosing Control Treatment Regimen (HRZE/HR) ...............62 
6.2 
Participant Compliance ..........................................................................................62 
6.3 
Treatment Modification(s) .......................................................................................62 
6.4 
IMP Packaging and Labelling .................................................................................63 
6.5 
Blinding and Procedures for Breaking the Blind ......................................................64 
6.6 
Handling, Storage and Accountability .....................................................................64 
7.0 
Trial Variables and Procedures......................................................................................65 
7.1 
Demographic and Background Variables and Procedures ......................................65 
7.2 
Efficacy Variables and Procedures .........................................................................66 
7.3 
Safety and Tolerability Assessments ......................................................................66 
7.4 
PK Variables and Procedures.................................................................................68 
7.5 
Mycobacteriology Characterization Variable and Procedures .................................68 
8.0 
Adverse Events .............................................................................................................69 
8.1 
Definitions ..............................................................................................................69 
8.1.1 
Adverse Event (AE) ...................................................................................69 
8.1.2 
Serious Adverse Event (SAE) ...................................................................69 
8.1.3 
Attribution/Causality ..................................................................................70 
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Protocol Number: NC-008 (B-Pa-M-Z) 
Protocol Version: V3.0 / 14 JAN 2019 
Protocol Name:  
SimpliciTB 
 
Table of Contents (continued) 
Page 
CONFIDENTIAL 
Page 6 of 101 
8.1.4 
Severity .....................................................................................................71 
8.2 
Reporting ...............................................................................................................71 
8.2.1 
Follow up of Adverse Events .....................................................................72 
8.2.2 
Clinical Laboratory Adverse Events ...........................................................73 
8.2.3 
Disease Symptoms During Trial ................................................................73 
8.2.4 
Overdose ..................................................................................................73 
8.2.5 
Drug Interaction.........................................................................................73 
8.2.6 
Pregnancy .................................................................................................73 
8.3 
Monitoring for Specific Toxicities ............................................................................74 
8.3.1 
ALT, AST and Bilirubin Elevations .............................................................74 
8.3.2 
Lipase .......................................................................................................74 
8.3.3 
Musculoskeletal System and Cardiac Muscle Myalgia ..............................75 
8.3.4 
Cardiac Rhythm Disturbances ...................................................................75 
8.4 
Safety Monitoring by Data Monitoring Committee ...................................................75 
9.0 
Statistical Analysis .........................................................................................................76 
9.1 
Analysis Populations ..............................................................................................76 
9.2 
Sample Size ...........................................................................................................76 
9.3 
Interim Analyses .....................................................................................................76 
9.4 
Primary and Secondary Efficacy Endpoint Analysis ................................................77 
9.4.1 
Primary Efficacy Endpoint, Time to Culture Conversion at 8 Weeks ..........77 
9.4.2 
Key Secondary Efficacy Endpoint, Clinical Outcome at 52 Weeks 
from Randomization ..................................................................................77 
9.4.3 
Other Secondary Efficacy Endpoints .........................................................78 
9.5 
Safety and Tolerability Assessments ......................................................................78 
9.6 
Pharmacokinetics ...................................................................................................78 
9.7 
Pharmacokinetics/Pharmacodynamics ...................................................................79 
10.0 
Records Management ...................................................................................................79 
10.1 
Data Collection .......................................................................................................79 
10.2 
Source Documents .................................................................................................79 
10.3 
File Management at the Trial Centre ......................................................................79 
10.4 
Records Retention at the Trial Centre ....................................................................79 
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Protocol Number: NC-008 (B-Pa-M-Z) 
Protocol Version: V3.0 / 14 JAN 2019 
Protocol Name:  
SimpliciTB 
 
Table of Contents (continued) 
Page 
CONFIDENTIAL 
Page 7 of 101 
11.0 
Quality Control and Assurance ......................................................................................80 
11.1 
Site Procedures ......................................................................................................80 
11.2 
Monitoring ..............................................................................................................80 
11.3 
Protocol Deviations ................................................................................................81 
11.4 
Auditing ..................................................................................................................81 
12.0 
Ethics and Regulatory ...................................................................................................81 
12.1 
Basic Principles ......................................................................................................81 
12.2 
Independent Ethics Committee/Institutional Review Board (EC/IRB) Review .........81 
12.3 
Regulatory Authorities ............................................................................................82 
12.4 
Informed Consent ...................................................................................................82 
12.5 
Confidentiality .........................................................................................................82 
13.0 
Publication Policy ..........................................................................................................83 
14.0 
Protocol Amendment Policy ...........................................................................................83 
15.0 
Sponsor, Financial Aspects, Insurance and Indemnity ...................................................83 
16.0 
References ....................................................................................................................85 
Appendices ...............................................................................................................................90 
 
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Protocol Number:  NC-008 (B-Pa-M-Z) 
Protocol Version: V3.0 / 14 JAN 2019 
Protocol Name:  
SimpliciTB 
 
CONFIDENTIAL 
Page 8 of 101 
List of Tables 
Table 1.  Bedaquiline Adverse Drug Reactions .........................................................................34 
Table 2.  Key findings of Pretomanid in Safety and Toxicity Trials.............................................37 
Table 3.  Summary of Phase 2b trials in which moxifloxacin were administered as part of a four-
drug regimen during the intensive phase of treatment (total treatment duration: 2 months) .......43 
Table 4: Treatment Groups .......................................................................................................50 
Table 5: Follow-up Visits Required for Early Withdrawal Participants ........................................58 
Table 6: Summary of Scenarios Requiring Unscheduled Visits for Mycobacteriology Testing ...59 
Table 7: Participant Progress Definitions...................................................................................61 
 
List of Figures 
Figure 1.  Unified Drug Sensitive/Drug Resistant Regimen Development Path .........................24 
Figure 2.  Log10 CFU Counts in Lungs .....................................................................................37 
Figure 3.  Mean log Colony Forming Unit Values over Time Trial CL-010 .................................40 
 
List of Appendices 
Appendix 1: The IUATLD Scale ................................................................................................90 
Appendix 2: Division of Microbiology and Infectious Disease (DMID) Toxicity Table .................91 
Appendix 3: Who Clinical Staging of HIV/AIDS for Adults and Adolescents ..............................98 
Appendix 4: Cardiovascular Safety ......................................................................................... 100 
Appendix 5: Karnofsky Performance Status Scale Definitions Rating (%) Criteria ................... 101 
 
 
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Protocol Number:  NC-008 (B-Pa-M-Z) 
Protocol Version: V3.0 / 14 JAN 2019 
Protocol Name:  
SimpliciTB 
 
CONFIDENTIAL 
Page 9 of 101 
Abbreviations and Definition of Terms 
 
3TC 
Lamivudine 
ABC 
Abacavir 
AE  
Adverse Event  
AFB 
Acid-fast bacilli 
AIDS 
Acquired Immune Deficiency Syndrome 
ALP 
Alkaline Phosphatase 
ALT 
Alanine aminotransferase 
AREDS2 
Age Related Eye Disease Scale 2 
ART 
Anti-Retroviral Therapy 
AST 
Aspartate aminotransferase 
AUCτ 
Area Under Curve over a dosing interval 
B 
Bedaquiline 
BA 
Bacterial activity 
BMI 
Body Mass Index 
BPaMZ 
Combination of bedaquiline plus pretomanid plus moxifloxacin plus 
pyrazinamide 
C 
Clofazimine 
CFU 
Colony Forming Units 
C(max), (min) 
plasma Concentration (maximum), (minimum) 
CO2 
Carbon dioxide 
CPK 
Creatine Phosphokinase 
CYP3A4 
Cytochrome P450 3A4 
DMID 
Division of Microbiology and Infection Disease 
DNA 
Deoxyribonucleic Acid 
DR-TB 
Drug-resistant tuberculosis 
For this particular protocol defined as TB participants with  
1. mono-resistance to rifampicin or isoniazid, OR 
2. resistance to both rifampicin and isoniazid (MDR-TB) 
(participants with fluoroquinolone resistance are excluded) 
DS-TB 
Drug-sensitive tuberculosis 
DSMC 
Data Safety and Monitoring Committee 
DST 
Drug Susceptibility Testing  
E 
Ethambutol 
EBA 
Early Bactericidal Activity 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
EFV 
Efavirenz 
(e)CRF 
(electronic) Case Report Form 
EMS 
Early Morning Sputum 
EWD 
Early Withdrawal 
FTC 
Emtricitabine 
FSH 
Follicle-stimulating hormone 
GCP  
Good Clinical Practice 
GMR 
Geometric Mean Ratio 
H 
Isoniazid 
HR 
Hazard Ratio 
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Protocol Number:  NC-008 (B-Pa-M-Z) 
Protocol Version: V3.0 / 14 JAN 2019 
Protocol Name:  
SimpliciTB 
 
CONFIDENTIAL 
Page 10 of 101 
 
 
hERG 
Human Ether-à-go-go Related Gene 
HIV  
Human Immunodeficiency Virus 
HRZE 
Isoniazid, Rifampicin, Pyrazinamide, Ethambutol 
HR 
Isoniazid plus rifampicin combination tablet 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IMP 
Investigational Medicinal Product 
IRB 
Institutional Review Board 
ITT 
Intent to Treat 
IUATLD 
International Union Against Tuberculosis and Lung Disease 
IWRS 
Interactive Web Randomization System 
kg 
Kilogram 
L 
Linezolid 
LH 
Luteinizing hormone 
LLN 
Lower Limit of Normal 
LPV 
Lopinavir 
LTFU 
Lost to follow-up  
M 
Moxifloxacin 
MBD 
Minimum Bactericidal Dose 
MIC 
Minimum Inhibitory Concentration 
MTB 
Mycobacterium tuberculosis 
MDR-TB 
Multi Drug Resistant Tuberculosis 
MGIT 
Mycobacterial Growth Inhibiting Tube 
mITT 
Modified Intent to Treat 
ms 
millisecond 
NVP 
Nevirapine 
NO 
Nitric Oxide 
NOAEL 
No Observed Adverse Effect Level 
NRTI 
(Triple) Nucleosidase Reverse Transcriptase Inhibitor 
Pa 
Pretomanid 
PD 
Pharmacodynamic 
PP 
Per Protocol 
PK 
Pharmacokinetic 
PR 
PR interval 
R 
Rifampicin 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SSCC 
Serial sputum colony counting 
TB 
Tuberculosis 
TDF 
Tenofovir 
TEAE 
Treatment Emergent Adverse Events 
TTP 
Time to Positivity  
ULN 
Upper Limit of Normal 
WGS 
Whole Genome Sequencing 
WHO 
World Health Organization 
XDR-TB 
Extensively Drug Resistant Tuberculosis 
μg(/ml) 
micrograms (per millilitre) 
Z 
Pyrazinamide (tablets) 
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Page 11 of 101 
1.0 
Synopsis 
1.1 
Synopsis Summary 
Synopsis 
Description  
Name of 
Sponsor/Company 
TB Alliance 
Name of Finished 
Products 
Bedaquiline tablets (B), pretomanid tablets (Pa), moxifloxacin tablets 
(M), pyrazinamide tablets (Z), HRZE tablets [isoniazid (H), rifampicin 
(R), pyrazinamide (Z) and ethambutol (E)] and HR tablets [isoniazid 
(H) plus rifampicin (R) combination tablets] 
 
Protocol 
Number/Title 
NC-008 (BPaMZ) An Open-Label, Partially Randomized Trial to 
Evaluate the Efficacy, Safety and Tolerability of a 4-month 
Treatment of Bedaquiline plus Pretomanid plus Moxifloxacin plus 
Pyrazinamide (BPaMZ) Compared to a 6-month Treatment of 
HRZE/HR (Control) in Adult Participants with Drug-Sensitive Smear-
Positive Pulmonary Tuberculosis (DS-TB) and a 6-month Treatment 
of BPaMZ in Adult Participants with Drug Resistant, Smear-Positive 
Pulmonary Tuberculosis (DR-TB) 
 
Treatment Indication 
Pulmonary Tuberculosis (TB) 
 
Trial Objective(s) 
To evaluate the efficacy, safety and tolerability at 8 weeks (2-
months), 52 weeks (12-months), and 104 Weeks (24-months) post 
the start of the treatment regimens in participants with Drug 
Sensitive TB (DS-TB) and Drug Resistant TB (DR-TB).  
 
DR-TB is defined as participants with:  
 
1. mono-resistance to rifampicin or isoniazid, OR 
2. resistance to both rifampicin and isoniazid (MDR-TB) 
 
Trial Design 
Phase 2c multi-centre, open-label, partially randomized clinical trial 
in Drug Sensitive-TB (DS-TB) and Drug Resistant-TB (DR-TB) 
participants.  
 
All participants will enter post-treatment follow-up which continues 
until Week 104 from start of treatment / randomisation. 
 
Participants with DS-TB: 
 
Participants with DS-TB will be randomized to one of two treatment 
arms. These participants will receive either BPaMZ daily for 17 
weeks (4 months), or HRZE/HR tablets daily for 26 weeks (6 
months). Participants will be stratified for co-infection with human 
immunodeficiency virus (HIV) and cavitation. 
 
Participants with DR-TB: 
 
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Page 12 of 101 
Synopsis 
Description  
Participants with DR-TB will be assigned to receive BPaMZ daily for 
26 weeks (6 months). 
Participant 
Population 
Up to 450 male and female participants, diagnosed with DS-TB or 
DR-TB, aged 18 years and over with a target of up to 50% being HIV 
positive. 
300 DS-TB participants (150 per treatment arm) will be randomized 
and stratified for co-infection with HIV and cavitation. 
Up to 150 DR-TB participants will be enrolled. 
Test Product, Dose 
and Mode of 
Administration 
The Test Product (BPaMZ) consists of a combination of the following 
products and will be supplied as: 
 
Product 
Tablet Strength 
Abbreviation 
Bedaquiline 
100 mg 
(B) 
Pretomanid 
200 mg 
(Pa) 
Moxifloxacin 
400 mg 
(M) 
Pyrazinamide 
500 mg 
(Z) 
 
Instructions for Dosing of BPaMZ 
 
Investigational Medicinal Product (IMP) will be administered orally 
once daily, to be taken during breakfast, with a full glass of water 
(approximately 240 ml), for 17 weeks (4 months) or 26 weeks (6 
months) in the following dosing schemes: 
 
Participants with DS-TB:  
Bedaquiline 200 mg daily for 8 weeks then 100 mg daily for 9 
weeks, together with pretomanid 200 mg + moxifloxacin 400 
mg + pyrazinamide 1500 mg daily for 17 weeks (total 
treatment duration 4 months)  
 
OR 
 
Participants with DR-TB: 
Bedaquiline 200 mg daily for 8 weeks then 100 mg daily for 
18 weeks, together with pretomanid 200 mg + moxifloxacin 
400 mg + pyrazinamide 1500 mg daily for 26 weeks (Total 
treatment duration 6 months). 
 
Positive Control 
Product, Dose and 
Mode of 
Administration 
The Control Treatment Regimen (HRZE/HR) will be supplied as:  
 
HRZE Tablets: isoniazid 75 mg plus rifampicin 150 mg plus 
pyrazinamide 400 mg plus ethambutol 275 mg combination tablets. 
This combination will be given for the first 8 weeks. 
 
AND 
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Protocol Version: V3.0 / 14 JAN 2019 
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CONFIDENTIAL 
Page 13 of 101 
Synopsis 
Description  
 
HR Tablets: isoniazid 75 mg plus rifampicin 150 mg combination 
tablets. This combination will be given from Weeks 9 to 26. 
 
Instructions for Dosing Control Treatment Regimen 
 
To be taken with a glass of water (approximately 240 ml).  HRZE or 
HR should not be taken with a meal (generally, no closer to meals 
than 1 hour before or 2 hours after a meal) in the following dosing 
schemes: 
 
Treatment will be administered orally once daily to the HRZE/HR 
randomized DS-TB participants as follows: 
 
 
Weeks 1-26: HRZE/HR tablets daily dose per the 
 
participant’s weight as follows:  
 
 
Weight Band 
Weight Range 
Number of 
tablets 
1 
30-39 kg 
2 
2 
40-54 kg 
3 
3 
55-70 kg 
4 
4 
≥ 71 kg 
5 
 
The participant’s weight at the Screening (HRZE) and Week 8 (HR) 
visits will be used to determine which weight band and HRZE and 
HR dose to administer. 
 
Vitamin B6 daily supplement to be taken with the HRZE/HR 
treatment, as per each country’s TB Treatment Guidelines.  
 
Treatment 
Interruptions/Pauses 
For All Trial Regimens 
The trial treatment regimens may require interruptions/pauses due to 
toxicities. All dose interruptions/pauses should be discussed with the 
Sponsor’s Medical Monitor prior to implementation, unless an 
interruption/pause is required urgently for a safety concern.   
Action required for participants missing the following number of 
doses within the trial treatment regimens:  
• 
Up to 7 consecutive doses: restart treatment, no extension of 
treatment required. 
• 
If more than 7 and to ≤ 35 consecutive doses missed, before 
the end of the treatment period (Week 17/26): restart 
treatment, extend the treatment by the number of 
consecutive doses missed. In this case, the last visit of the 
treatment period should also be pushed out to the date of the 
last dose. 
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Page 14 of 101 
Synopsis 
Description  
• 
If more than 35 consecutive doses: discontinue treatment 
and withdraw participant from the trial. 
• 
If the participant misses a total of 56 cumulative missed 
doses, discontinue the IMP and withdraw the participant from 
the trial. 
• 
If more than 7 to ≤ 35 consecutive doses are missed, these 
must be made up with the same treatment combination or 
dose, that was missed.  
Any participant for whom the trial IMP is discontinued (including for 
non-adherence) should be discussed with the Sponsor Medical 
Monitor and, if applicable, the participant will be restarted on trial 
IMP as soon as possible. 
Statistical Methods 
 
A general description of the statistical methods planned to be used 
to analyse efficacy data is outlined below. Specific details will be 
provided in the Statistical Analysis Plan (SAP) which will be written 
and signed off prior to the interim analysis. 
 
Criteria for Evaluation 
 
Primary Endpoint 
 
The primary efficacy endpoint will be time to culture negativity over 8 
weeks. The primary hypothesis to be evaluated is:  
 
• 
In the participants with DS-TB in the experimental BPaMZ 
treatment regimen, the time to culture negativity by 8 weeks will 
be superior, compared to the participants who are treated with 
the standard HRZE/HR regimen. 
 
Secondary Endpoints 
 
• 
A key secondary efficacy endpoint will be the proportion of 
participants experiencing bacteriologic failure or relapse or 
clinical failure (unfavourable outcome) at 52 weeks. 
 
The hypothesis to be evaluated for this endpoint is: 
 
• 
In the participants with DS-TB in the experimental BPaMZ 
treatment regimen, the proportion experiencing an unfavourable 
outcome will be non-inferior compared to the participants who 
are treated with the standard HRZE regimen. 
 
Abbreviated Definitions, full definitions will be described in the 
Statistical Analysis Plan (SAP):  
 
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Page 15 of 101 
Synopsis 
Description  
• 
Bacteriologic failure: During the treatment period, failure to attain 
or maintain culture conversion to negative.  
• 
Bacteriologic relapse: During the follow-up period, failure to 
maintain culture conversion to negative status, with culture 
conversion to positive status with a strain of Mycobacterium 
tuberculosis (MTB) genetically identical to the infecting strain at 
baseline.  
• 
Clinical failure: A change from protocol-specified TB treatment to 
a new regimen before end of protocol specified treatment due to 
treatment failure, retreatment for TB during follow up, or TB-
related death.  
 
Note:  
 
o Culture conversion requires at least 2 consecutive culture 
negative/positive samples at least 7 days apart.  
o Participants who are documented at a visit as unable to 
produce sputum and who are clinically considered to be 
responding well to treatment will be considered to be culture 
negative at that visit.  
 
Other Secondary Endpoints 
 
Efficacy: 
 
• 
Incidence of bacteriologic failure or relapse or clinical failure at 
104 weeks from the start of treatment.  
• 
Proportion of participants with sputum culture conversion to 
negative status in liquid culture (MGIT) at 4, 6, 12 and 17 weeks 
to be explored as a potential biomarker of outcome at 52 weeks 
from start of treatment. 
• 
Change from baseline in weight. 
• 
Change from baseline in TB symptoms. 
• 
Change from baseline in Participant Reported Health Status. 
 
Safety and Tolerability: 
 
• 
Incidence of Treatment Emergent Adverse Events (TEAEs) 
presented by incidence, severity, drug relatedness, seriousness, 
leading to early withdrawal, and leading to death.  
• 
Quantitative and qualitative clinical safety laboratory 
measurements, including observed and change from baseline. 
• 
Quantitative and qualitative electrocardiogram (ECG) results 
(heart rate, RR interval, PR interval, QRS interval, QT interval 
and QTc interval), including observed. QT/QTc intervals, change 
from baseline, will be categorized as these will be centrally read. 
• 
Changes in male reproductive hormones. 
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Page 16 of 101 
Synopsis 
Description  
• 
Changes in lens opacities. 
 
These data will be presented as descriptive analyses, and no 
inferential tests will be carried out. 
 
Pharmacokinetics (PK) and Pharmacokinetics/Pharmacodynamics 
(PK/PD): 
 
Plasma concentrations from sparse sampling will be used to update 
existing population PK models and derive exposure metrics (e.g., 
minimum plasma concentration [Cmin], maximum plasma 
concentration [Cmax], area under curve over a dosing interval [AUC]) 
for bedaquiline and its M2 metabolite, pretomanid, moxifloxacin, and 
pyrazinamide.  
 
Effects of baseline covariates on exposure will be assessed; so too, 
will the effects of concomitant medications, including antiretroviral 
therapy (ART), where feasible. Data from other trials may be 
included to enhance the model-based analysis. Relationships will be 
explored between drug exposure and efficacy and safety endpoints. 
These exploratory PK/PD analyses may include HIV status as a 
covariate. 
 
Exploratory Objectives: 
 
Evaluate whether any of the secondary endpoints predict relapse 
free cure. Subgroup analysis of populations by HIV status will be 
performed. 
 
No formal statistical comparisons will be made for the participants 
enrolled with DR-TB. 
 
Sample Size 
 
Primary endpoint: 150 participants per arm (DS-TB patients) will 
provide at least 90% power (5% 2-sided significance) to detect a 
hazard ratio (HR) of at least 2 assuming 50% of control participants 
are culture negative by 8 weeks.  
 
Additional efficacy parameters will be evaluated including the 
incidence of bacteriologic failure or relapse or clinical failure 
(unfavourable outcome) at 52 weeks and 104 weeks from the start 
of treatment. Time to unfavourable outcome from assignment of trial 
treatment through follow-up as a function of time will be analysed 
using Kaplan-Meier analysis. 
 
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Page 17 of 101 
Synopsis 
Description  
Interim Analysis 
 
There is one planned interim efficacy analysis which will occur after 
approximately 60 assessable participants have been randomised to 
the control arm and have reached the 8-week primary endpoint. 
Time to culture negative status in liquid media up to 8 weeks will be 
analysed using a Cox regression model, censoring for death and lost 
to follow up/withdrawal to estimate the hazard ratio (HR). Following 
a review of these interim findings, the following considerations will 
be given to modify the trial objectives and sample size: 
If the observed HR (time to culture negativity, experimental arm vs. 
HRZE control arm) is >2, the sample size may be increased to 
adequately power the trial on the key secondary efficacy endpoint 
(clinical and microbiological outcome at 52 weeks from 
randomization), which will then become the primary efficacy 
endpoint. The trial efficacy objectives will be updated as follows: 
• 
Primary Objective 
 
To determine the incidence of bacteriologic failure or 
 
relapse or clinical failure at 52 weeks from the start of 
 
treatment / randomisation.  
• 
Secondary Objective 
 
To evaluate the time to culture negativity over 8 weeks, 
 
from the start of treatment / randomisation. 
All other trial objectives will remain unchanged. 
To achieve 90% power and overall 5% 2-sided significance after 
adjusting for the interim analysis, this will mean increasing the 
sample size to 225 participants per randomised arm, i.e., to a total of 
450 DS-TB participants (and up to 225 DR-TB participants). This 
adaptation is based on the Multi-arm Multi-stage (MAMS) framework 
[46, 47, 48] and full details are provided in the Statistical Analysis Plan. 
 
Trial Duration 
Approximately 4 years (18-month enrolment period for DS-TB 
participants, up to 26 week-treatment, and follow-up until 104 weeks 
from start of treatment). Depending on the DR-TB recruitment rate, 
enrolment into this arm may continue after enrolment into the DS-TB 
arms are complete.  
 
 
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Page 18 of 101 
1.2 
Synopsis Flow Chart and Procedures 
Period 
Screen-
inga 
Treatment 
Follow-Upc 
Visitb 
Day -9 to -1 
Day 1 
(Baseline)d 
Week 1  
Week 2 
Week 3 
Week 4 
Week 5 
Week 6 
Week 7 
Week 8  
Week 12 
Week 17 
4-mth treatmente 
Week 17  
6-mth treatmente 
Week 22  
Week 26  
4-mth treatmente 
Week 26  
6-mth treatmente 
Week 39 
Week 52 
Week 65 
Week 78 
Week 104 
Early 
Withdrawalc 
Visit Windowv 
N/A 
+/- 3 Days 
+/- 5 Days 
+/- 14 Days 
Written Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/Treatment/ Smoking History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sputum Samplingf,g 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HIV Statush and CD4 Counti 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Karnofsky Scorex 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Drug Screenj 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Pregnancy Testk 
X 
X 
 
 
 
 
 
 
 
X 
 
X 
X 
 
X 
X 
 
 
 
 
 
X 
Laboratory Safety Testl 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
 
 
 
 
X 
Male Reproductive Hormone Testsm 
X 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
 
 
 
 
12-lead ECGn 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
X 
 
 
 
 
X 
Chest X-Rayo 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TB Symptoms Profile 
X 
X 
 
X 
 
X 
 
 
 
X 
 
X 
X 
 
X 
X 
 
X 
 
 
X 
X 
Patient Reported Health Status  
X 
X 
 
X 
 
X 
 
 
 
X 
 
X 
X 
 
X 
X 
 
X 
 
 
X 
X 
Vital Signs and weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Ophthalmic Examinationp 
X 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
X 
X 
X 
 
 
 
 
X 
Physical Examination – fullq 
X 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
Physical Examination – limitedr 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
Pharmacokinetic Samplings 
 
X 
 
X 
 
 
 
 
 
X 
X 
X 
X 
 
 
 
X 
 
X 
X 
X 
 
IMP Randomization/ Assignmentt 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IMP Compliance Checku 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 Xe 
 
X 
 
 
 
 
 
Xt 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Investigator Assessmentv 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
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Page 19 of 101 
 
GENERAL: Vital signs and blood draws are to be performed before dosing, unless 
otherwise specified. Vital signs and/or ECGs should be done before blood draws 
(safety and PK) on days with those assessments. 
 
a. Screening: Screening assessments can occur on different days, within nine days before 
Day 1 (Baseline).  
b. Visit Schedule (due to unforeseen circumstances): If the duration of treatment is 
extended due to dose interruptions / pauses (7 to ≤ 35 consecutive doses), the last visit 
of the corresponding treatment period should also be pushed out to the date of the last 
dose. It is not necessary to have an unscheduled visit at the time that the last visit of the 
treatment period would have been scheduled on.   
c. Follow-up Visits for Early Withdrawal Participants: Once a participant has been 
permanently withdrawn from the trial, they will be required to attend an Early Withdrawal 
visit (Week 52, if not already performed) and Week 104 follow-up visits. The Week 52 
and Week 104 visits will be performed to collect Serious Adverse Event (SAE) 
information (including verification of survival) and the participant reported TB outcome 
information only, and may be performed telephonically, at home or a site visit. Visits will 
occur at Week 52 and/or Week 104 after the participant’s start of treatment date.  Refer 
to Table 5 for additional guidance. 
d. Day 1 (Baseline): All procedures are to be completed before dosing.  
e. Last Visit of the Treatment Period: Investigational Medicinal Product (IMP) 
Compliance Check is not performed at the Week 22 visit for participants who have 
completed treatment at Week 17. 
f. Sputum Sampling: The sputum sampling methodology, requirements and tests will be 
described in a separate document, the Mycobacteriology Laboratory Manual. 
 
• 
Screening (Days -9 to -1). Two spot sputum samples taken 30 minutes apart will be 
collected at the research site under the coaching and observation of the trial staff. 
The following analyses will be performed on the first of these samples: 
o Smear microscopy for acid-fast bacilli (AFB); 
o Rapid molecular tests for fluoroquinolones, isoniazid and rifampicin 
resistance (Hain MTBDRplus and Hain MTBRsl);  
o Liquid Culture (MGIT) for Mycobacterium tuberculosis (MTB), followed by a 
speciation test to detect the presence or absence of MTB and obtain the time 
to positivity (TTP) when positive. 
o The second sample is collected as a back-up sample to the first sample in 
case it is technically not possible to obtain a result/s from the first sample. If 
the Screening spot sputum smear shows an indeterminate result or is AFB 
negative, the test may be repeated on the back-up sample or on a freshly 
collected spot sputum, and then that result will be used.  
• 
Day 1 (Baseline) to Week 104 and Unscheduled visits for additional sputum 
samples:  
o Two sputum samples are collected, ideally one Early Morning Sputum (EMS) 
brought from home and one spot sputum sample at the research site, under 
the coaching and observation of the trial staff. If the participant forgets to 
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Protocol Number:  NC-008 (B-Pa-M-Z) 
Protocol Version: V3.0 / 14 JAN 2019 
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CONFIDENTIAL 
Page 20 of 101 
bring in the EMS, then two spot sputum samples are to be collected at the 
site, at least 30 min apart, and this altered sample collection is captured 
within case report form (CRF).   
o If both sputum cultures at Week 8 or later are contaminated, the participant 
should return for an unscheduled visit(s) to give additional sputum samples or 
to document that the participant is not able to produce a sputum sample.  
• 
If after having converted to culture negative, and the participant has a MTB 
confirmed positive culture at or after the last visit of the treatment period (Week 17 or 
Week 26), the participant should return for unscheduled visit/s to provide additional 
sputum samples, at a minimum of 7 days apart, or to document that the participant is 
not able to produce a sputum sample. 
• 
Additional samples may be required to define a participants’ primary outcome status 
as described in Sections 5.4.2 and 7.2.  
• 
Liquid Culture (MGIT) for MTB, followed by a speciation test to detect the presence 
or absence of MTB and obtain TTP when positive, will be performed on all samples. 
g. Mycobacteriology Characterisation Tests Performed: 
• 
Day 1 (Baseline) sputum sample (or any positive sample from Screening to Week 4, 
if the baseline cultures are contaminated or negative); 
• 
MTB confirmed positive cultures (after the participant has previously converted to 
culture negative) at or after the last visit of the treatment period (Week 17 or Week 
26) or visits with positive cultures, during the post-treatment follow-up period. 
• 
Refer to the Mycobacteriology Laboratory Manual for full details. 
Mycobacterial Characterization - MTB isolates (from the first MTB positive culture) will 
be processed for: 
• 
Rapid molecular tests for fluoroquinolones, injectables, isoniazid and rifampicin 
resistance (only on MTB positive cultures in the follow-up period); 
• 
Minimum Inhibitory Concentration (MIC) against bedaquiline, pretomanid, and 
moxifloxacin;  
• 
Drug Susceptibility Testing (DST) for streptomycin, rifampicin, isoniazid, ethambutol, 
moxifloxacin, and pyrazinamide in liquid culture;  
• 
Extraction of organismal (MTB) DNA for whole genome sequencing (WGS), and 
comparison of sequences from baseline and relapse isolates. 
 
h. HIV Testing: If HIV status is a confirmed known positive, a repeated HIV test is not 
needed provided that a documented HIV test result (ELISA, Western Blot or Electro-
Chemiluminescence) is available. If the HIV status is unknown or suspected negative, a 
HIV test will be requested. If an ELISA and/or Western Blot and/or Electro-
Chemiluminescence based HIV test was performed within 4 weeks prior to screening, it 
should not be repeated if documentation of testing method and negative HIV results can 
be provided. Repeated HIV testing, during the Screening period is permitted for 
indeterminate HIV results. 
i. 
CD4 Count: Required for all HIV-positive participants.  
j. 
Urine Drug Screen: Cannabinoids, cocaine, amphetamines, opiates, benzodiazepines, 
barbiturates, at Screening only. Investigator to utilize this result to determine whether 
participant meets Exclusion Criteria 2. Positive results will not automatically exclude a 
participant from the trial. 
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Page 21 of 101 
k. Urine Pregnancy Test: Women of childbearing potential only, whether they are sexually 
active or not.  
l. 
Safety Laboratory Assessments: The safety laboratory sampling methodology and 
requirements will be described in a separate document, the Safety Laboratory Manual, 
which will be provided prior to the trial start. The following analyses will be performed: 
• 
Full Blood Count (haemoglobin, haematocrit, red blood cell count, white blood cell 
count with differential, platelet count).  
• 
Clinical Chemistry (albumin, serum urea, creatinine, direct, indirect and total bilirubin, 
uric acid, total protein, alkaline phosphatase [ALP], aspartate aminotransferase 
[AST], alanine aminotransferase [ALT], lipase, phosphate, sodium, potassium, 
calcium (corrected for albumin), chloride, magnesium, glucose, bicarbonate/carbon 
dioxide [CO2], creatine phosphokinase [CPK]). GGT is only routinely included at the 
Screening visit (Day -9 to -1).  
• 
Urinalysis (pH, specific gravity, protein, glucose, micro-albumin, ketones, bilirubin, 
creatinine, nitrite, sodium, urobilinogen, blood, leukocytes). Microscopy will be 
completed as follow-up to abnormal urinalysis per discretion of Investigator.  
• 
When managing participants with elevated liver enzymes at an Unscheduled visit, 
the investigator can request additional tests, in addition to the repeat LFT [e.g. 
Gamma Glutamyl Transferase (GGT), screening for Hepatitis A, B, C; to assist in 
ruling out other causes of a dysfunctional liver test (e.g. alcohol induced hepatic cell 
injury, hepatobiliary disease, hepatic viral infection)]. 
m. Male Reproductive Hormone Tests: Testosterone, follicle-stimulating hormone (FSH), 
luteinizing hormone (LH) and Inhibin B to be done on male participants in ALL treatment 
groups. 
n. Single 12-Lead ECG: ECGs to be performed prior to pre- and post-dose PK sampling 
as described below: 
• 
Day 1: pre-dose (within 2 hours prior to dosing) 
• 
Week 2: pre-dose (within 2 hours prior to dosing), 1.5–3 hours post-dose and 4-6 
hours post-dose 
• 
Week 8: pre-dose (within 2 hours prior to dosing), 1.5–3 hours post-dose and 4-6 
hours post-dose 
• 
Week 12: pre-dose (within 2 hours prior to dosing)  
• 
Week 17 or at early withdrawal if prior to week 17: pre-dose (within 2 hours prior to 
dosing) and 1.5–3 hours post-dose 
Central ECG analysis will be performed. Results from central reading of Screening ECG 
must be used to determine eligibility.  
o. Chest X-Ray: A chest x-ray (digital image only) within 6 months prior to or at the 
Screening visit, will be obtained and read locally by the Investigator or designee. Digital 
images will be provided to the Sponsor and this process will be described in a separate 
document, the Radiology Manual. 
p. Slit Lamp Ophthalmic Examination: Slit lamp examination will be done at the 
Screening visit, the last visit of the treatment period (Week 17 or 26) and at Week 39 for 
both treatment groups.  An additional slit lamp at Week 26 will be done for the 4-month 
treatment group. Slit lamp ophthalmology examination will be performed by an 
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Ophthalmologist with AREDS2 training. Ophthalmology examinations may occur at any 
time within the window period for the applicable visit i.e. they do not have to be 
performed on the same day as the trial procedures. 
q. Physical Examination, Full: Height (m) will only be collected at Screening.  
r. Physical Exam, Limited: Limited physical exams will include weight and gross 
neurological, pulmonary, cardiovascular and abdominal exam(s). 
s. Pharmacokinetic (PK) Sampling: This process will be described in a separate 
document, the PK Sampling Manual. No PK samples will be collected for the HRZE/HR 
treatment arm.  Blood draws for PK samples collected pre- and post-dose must be done 
after the ECG is performed.  The dates and times of IMP taken prior to all pre-dose PK 
samples will be collected.  Specific PK blood draws will be obtained as follows: 
 
• 
Day 1: pre-dose (within 2 hours prior to dosing) 
• 
Week 2: pre-dose (within 2 hours prior to dosing), 1.5–3 hours post-dose and 4-6 
hours post-dose 
• 
Week 8: pre-dose (within 2 hours prior to dosing), 1.5–3 hours post-dose and 4-6 
hours post-dose 
• 
Week 12: pre-dose (within 2 hours prior to dosing)  
• 
Week 17 or at early withdrawal if prior to week 17: pre-dose (within 2 hours prior to 
dosing) and 1.5–3 hours post-dose 
• 
Weeks 39, 65, 78 and 104: PK samples are to be obtained at any time on the day of 
the scheduled visit. 
Only bedaquiline and M2 will be measured. 
If IMP is not administered during Week 2, 8 and or 17, then only a single PK sample is 
required to be obtained at any time during the visit assessment. 
t. Investigational Medicinal Product (IMP) Randomization/Assignment: 
Randomization/Assignment may occur once all the Screening results are available and 
the Investigator has determined that the participant is eligible for the trial. 
u. IMP/Compliance Check: IMP administration will be supervised per local site practice to 
assure compliance to the regimen. Performed at all visits and Early Withdrawal (EWD), if 
during the treatment period.  
v. Investigator Assessment: Investigator to review the participant status and assess 
whether IMP or TB treatment at Week 52 and 104 is considered a “success” or “failure”.  
If considered a failure, the Investigator should specify if the assessment is based on 
bacteriology and/or clinical deterioration and/or radiological deterioration. Investigator 
Assessment to be completed, at Week 52 and 104, and at any time the Investigator 
determines that the participant fulfils the criteria for outcome of treatment failure. 
w. Visit Windows: The windows noted on the flowchart for timing of visit also apply to the 
timing within a visit.  Procedures should be performed within +/- 3 days of scheduled visit 
from Day 1 to Week 8 or +/- 5 Days of scheduled visit from Week 12 to Week 26 or +/- 
14 days of scheduled visit at or after Week 39.  Sites should make every effort to ensure 
all procedures are done on the same day, when possible. 
x. Karnofsky Score: Only to be performed on HIV+ participants.  
 
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2.0 
Introduction and Rationale 
2.1 
Tuberculosis Disease 
Although some progress has been made in recent years in controlling tuberculosis (TB) globally, 
TB has remained a persistent problem in the developing countries of Africa, Asia and South 
America.  TB is currently one of the top three killer infectious diseases, and there is more TB in 
the world today than at any other time in history.  The current first-line anti-tuberculosis agents 
have been in use for over 40 years and are relatively ineffective in controlling TB as a public health 
problem.  Although the current regimens and drugs have been very successful in controlled 
clinical trials resulting in the permanent cure of more than 95% of trial participants, treatment takes 
6 months or more to complete. This, long duration treatment plus side effects, result in poor 
adherence which particularly occurs after the second month of treatment.  
The current TB treatment regimens and treatments for drug-sensitive TB are decades old. The 
available treatments have a lengthy duration of treatment, involve multi-drug therapy, and require 
large commitments of resources and infrastructure. High rates of noncompliance are common, 
which often results in increased mortality and chronic, infectious, drug-resistant cases. The 
present TB epidemic and the challenge of current treatment options demonstrate the clear need 
for effective novel TB drugs and drug regimens that are safe for drug sensitive and drug resistant 
TB disease and that are well-tolerated and will shorten the current treatment duration for patients. 
The full application of the Directly Observed Treatment, Short-Course strategy is becoming more 
and more difficult in the developing countries of the world that are also battling to control the HIV-
epidemic.  Because of poor treatment adherence, drug resistance is becoming more common 
and fears of an epidemic with virtually untreatable strains of TB are growing.  Since the discovery 
of the rifamycins,[1] and their introduction into standard antituberculosis regimens, very few new 
classes of drugs have been evaluated with a view to their registration as antituberculosis agents.  
On December 28, 2012 the U.S. Food and Drug Administration approved bedaquiline (B) as part 
of combination therapy to treat adults with multi-drug resistant (MDR) pulmonary tuberculosis (TB) 
when other alternatives are not available. Following the declaration of TB as a global emergency 
by the World Health Organization (WHO) in 1993, there has been a resurgence of efforts to 
develop improved TB therapies and several promising new agents are presently in or approaching 
clinical evaluation.   
New combination regimens are desperately needed for two reasons: to shorten treatment to a 
duration more easily manageable by patients and public health services, and to provide more 
efficacious, safer and better tolerated, affordable treatments for the growing number of patients 
suffering from multidrug-resistant and extensively drug-resistant tuberculosis. 
2.2 
Tuberculosis Clinical Research 
TB currently must be treated with multiple drugs to achieve maximal efficacy and prevent 
resistance. To transform treatment, novel TB regimens are needed. To telescope the time, it takes 
to develop novel, tolerable multi-drug treatments, it is necessary to use the regimen development 
paradigm. This approach tests promising combinations of drugs together to find the most 
impactful treatment once the individual drug candidates have been tested in a robust pre-clinical 
program and the establishment of the individual drug candidates’ safety and efficacy have been 
evaluated.  It evaluates novel combinations of TB drugs — instead of single drugs — as part of a 
single development program, enabling the development of novel TB drug regimens that have 
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potential to transform treatment for drug-sensitive and drug-resistant tuberculosis. This approach 
offers the potential to reduce the time previously needed to develop a novel treatment regimen 
by up to 75%, shortening the clinical development from decades to years. The steps followed in 
this development model are shown in Figure 1 Between each step on the unified development 
pathway a decision is made as to whether to proceed. 
Figure 1.  Unified Drug Sensitive/Drug Resistant Regimen Development Path 
 
Early Bactericidal Activity (EBA) Trials 
EBA trials are the backbone clinical trials to quantify the bactericidal action of anti-tuberculosis 
agents alone or in combination by either trialling the fall in the number of colony forming units 
(CFU) or measuring the TTP in liquid culture of M. tuberculosis (MTB) present in the sputum of 
participants with microscopy smear-positive pulmonary TB. EBA trials have been conducted over 
2, 5, 7 and 14 days.[2]. A review of EBA trials conducted on the key anti-TB drugs has shown the 
value these trials offer to demonstrate the early anti-TB effect that a new therapeutic agent may 
have and to explore the relationships between dose, pharmacokinetics and bactericidal activity in 
participants.[3] 
8-week Bactericidal Activity (BA) Trials 
EBA methodology of quantitative colony counting on solid medium has been adapted to Phase 2, 
8-week TB treatment trials based on serial sputum colony counting (SSCC) or measurement of 
TTP liquid culture to provide a more sensitive efficacy endpoint than the previously used binary 
endpoint of rate of sputum conversion measured after 8 weeks of treatment.[4-6] Such trials are 
conducted to provide data on which to base the selection of treatment-shortening regimens.  
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2.3 
Trial Rationale 
The SimpliciTB NC-008 (BPaMZ) trial will evaluate and support that, in addition to previous 
studies evaluated with BPaMZ, this drug regimen will be safe and effective, is well-tolerated and 
could potentially shorten the current treatment duration compared to the standard HRZE/HR 
treatment for patients with drug sensitive TB disease. This trial will also evaluate if the BPaMZ 
drug regimen given for 6 months will be safe and effective in drug resistant TB disease. 
Therefore, the trial design addresses the need to find and evaluate a potentially effective and 
shorter regimen compared to regimens (standard HRZE/HR) that are currently being used. 
2.3.1 
Trial Design Rationale 
The SimpliciTB NC-008 (BPaMZ) trial is a Phase 2c multi-centre, open-label, partially randomized 
clinical trial in DS-TB and DR-TB participants. This trial is to evaluate the combination regimen of 
Bedaquiline (B) plus Pretomanid (Pa) plus Moxifloxacin (M) plus Pyrazinamide (Z) (BPaMZ), 
in participants with pulmonary TB. 
All participants will enter post-treatment follow-up which continues until Week 104 after start of 
treatment / randomisation. 
Participants with DS-TB: 
Participants with DS-TB will be randomized to one of two treatment arms. These participants will 
receive either: 
• 
BPaMZ daily for 17 weeks (4 months),  
OR  
• 
HRZE/HR combination tablets daily for 26 weeks (6 months).  
Participants will be stratified for co-infection with HIV and cavitation. 
Participants with DR-TB are defined as: 
1. mono-resistance to rifampicin or isoniazid, OR 
2. resistance to both rifampicin and isoniazid (multi-drug resistant tuberculosis [MDR-TB]) 
Up to 150 participants with DR-TB will be assigned to receive BPaMZ daily for 26 weeks (6 
months).  Approximately 300 DS-TB participants (150 per treatment arm) will be randomized and 
stratified for co-infection with HIV and cavitation to either BPaMZ for 4 months or HRZE/HR for 6 
months.  
 
The trial is sufficiently statistically powered to not only show superiority of 8 Weeks culture 
conversion but should also demonstrate non-inferiority for cure at 52 Weeks (this is in the 
participants with DS-TB in the experimental BPaMZ treatment regimen, the proportion 
experiencing an unfavourable outcome will be non-inferior compared to the participants who are 
treated with the standard HRZE regimen). 
 
There is one planned interim efficacy analysis which will occur after approximately 60 assessable 
participants have been randomised to the control arm and have reached the 8-week primary 
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endpoint. Time to culture negative status in liquid media up to 8 weeks will be analysed using a 
Cox regression model, censoring for death and lost to follow up/withdrawal to estimate the hazard 
ratio (HR). Following a review of these interim findings, the following considerations will be given 
to modify the trial objectives and sample size: 
If the observed HR (time to culture negativity, experimental arm vs. HRZE control arm) is >2, the 
sample size may be increased to adequately power the trial on the key secondary efficacy 
endpoint (clinical and microbiological outcome at 52 weeks from randomization), which will then 
become the primary efficacy endpoint. The trial efficacy objectives will be updated as follows: 
- 
Primary Objective 
To determine the incidence of bacteriologic failure or relapse or clinical failure at 
52 weeks from the start of treatment / randomisation.  
- 
Secondary Objectives 
To evaluate the time to culture negativity over 8 weeks, from the start of treatment 
/ randomisation. 
All other trial objectives will remain unchanged. 
To achieve 90% power and overall 5% 2-sided significance after adjusting for the interim analysis, 
this will mean increasing the sample size to 225 participants per randomised arm, i.e., to a total 
of 450 DS-TB participants (and up to 225 DR-TB participants). This adaptation is based on the 
Multi-arm Multi-stage (MAMS) framework [46, 47, 48] and full details are provided in the Statistical 
Analysis Plan.  
As previously described in the background information, in order to telescope the time it takes to 
develop novel, tolerable multi-drug treatments, it is necessary to use the regimen development 
paradigm and utilize data generated in non-clinical and clinical studies regarding combining of 
anti-tuberculosis agents which could contribute significantly to the sterilization of lesions and thus 
treatment shortening. Therefore, the trial design and proposed trial regimen (BPaMZ) which is 
supported with previous non-clinical and clinical studies outlined below should address the need 
and manner of evaluating an effective shorter regimen compared to regimes that are currently 
being used. 
2.3.2 
Trial Drug Regimen Rationale 
The BPaMZ regimen has been studied singularly and in different combinations as outlined above. 
Moxifloxacin has been added to the B-Pa-Z regimen because of the high rate of pyrazinamide 
resistance seen in MDR-TB participants in the NC-002 trial. It essentially provides protection 
against the development of new resistance to the B-Pa-Z drugs. Based on the exciting and 
promising results seen in NC-005, this regimen can be initiated in drug sensitive and drug resistant 
TB participants whom are sensitive to the individual drugs in the regimen (excluding extensively 
drug-resistant tuberculosis [XDR-TB] and Pre-XDR tuberculosis) and has the potential to shorten 
TB treatment to less than 4 months in drug sensitive TB. These are also oral regimens, removing 
the need for injectables as part of MDR-TB treatment, and also project to be markedly less 
expensive than current MDR-TB therapy. Additionally, these regimens can be administered in a 
fixed dose for all patients and will therefore be simpler for health systems to deliver and patients 
to use. 
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2.4 
Agents used within SimpliciTB 
Bedaquiline (TMC207; SirturoTM package insert)[7]  is a novel agent approved for TB treatment. 
As detailed in the Investigator’s Brochure,[8] bedaquiline is a diarylquinoline that offers a novel 
mechanism of anti-tuberculosis action by specifically inhibiting mycobacterial adenosine 
triphosphate synthase.[9, 10]) In vitro, bedaquiline potently inhibits both drug-sensitive and drug-
resistant M. Tb isolates,[10, 11], and is also bactericidal against non-replicating M. Tb.[12] In the 
murine model of TB, bedaquiline was as active as the triple combination of isoniazid (H), rifampin 
(R), and pyrazinamide (Z). Addition of bedaquiline to HRZ results in accelerated clearance of M. 
Tb.[3, 4] There appears to be a synergistic interaction with pyrazinamide: 100% of mice were 
culture negative after 8 weeks of treatment with bedaquiline and pyrazinamide compared to 0% 
of mice treated with the standard regimen of rifampicin, isoniazid and pyrazinamide.[13] 
Collectively, these findings in the mouse model have led to the suggestion that regimens 
containing bedaquiline and pyrazinamide could be effective in the treatment of both DS- and 
MDR-TB and shorten treatment duration in patients. While the combination of bedaquiline and 
pretomanid in the murine model of TB appeared somewhat antagonistic relative to bedaquiline 
alone, it was as active as the triple combination of HRZ[13] and in a subsequent trial it was more 
active in the mouse model than HRZ.[14] Thus, a novel regimen with a bedaquiline plus pretomanid 
core could be effective in the treatment of MDR-TB by providing two novel drugs for which there 
is no known pre-existing resistance.  
Pretomanid, (Pa)[15]  is a new chemical entity being developed by TB Alliance for the treatment 
of TB.  It is a member of a class of compounds known as nitroimidazo-oxazines, which possess 
significant anti-tuberculosis activity and a unique mechanism of action.[16] PRETOMANID has 
been under development for several years and entered clinical trials in 2005. Several trials of 
pretomanid have also been conducted previously in healthy volunteers.  Collectively, these trials 
in participants with active TB and healthy participants have defined the efficacy, safety and 
pharmacokinetic features of the drug.  Overall, pretomanid has mycobactericidal activity in 
participants and is well tolerated and bioavailable after oral dosing.  Pretomanid demonstrated in 
vitro activity against both drug-sensitive (DS) and MDR-TB,[17] and in vivo activity in a mouse 
model of TB[17, 18] with a significant promise for shortening treatment of active TB. 
Moxifloxacin (M)[19]  is a microbial compound, approved in most countries around the world for 
the treatment of acute bacterial sinusitis, acute bacterial exacerbation of chronic bronchitis, 
community-acquired pneumonia, skin and soft tissue infections.  Clinical studies have been 
carried out for many additional indications (urinary tract infections, pelvic infections, 
pharyngitis/tonsillitis, and tuberculosis). Moxifloxacin is an 8-methoxyquinolone whose oral 
formulation (which will be used in this trial) has enhanced activity against Gram-positive 
pathogens, and anaerobes while retaining useful activity against Gram-negative organisms. 
Moxifloxacin is not metabolized by or induces the cytochrome P450 system, thus the risk of 
clinically relevant drug interactions is reduced. It has a positive safety profile within the 
fluoroquinolone class at the approved daily dose of 400 mg. Moxifloxacin while not approved for 
TB by most regulatory authorities, it is regularly used in second line MDR-TB treatment. The WHO 
TB Treatment Guidelines place moxifloxacin in the category of Group 3 drugs and notes that “all 
patients [with MDR-TB] should receive a Group 3 medication if the MTB strain is susceptible or if 
the agent is thought to have efficacy. One of the higher generation fluoroquinolones, such as 
levofloxacin or moxifloxacin, is the fluoroquinolone of choice.[5]” It is currently in late stage clinical 
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development for first-line TB treatment in combination with other TB drugs, including 
pyrazinamide in two different four-month long regimens.  
Pyrazinamide (Z)[20] is a pyrazine analogue of nicotinamide and an approved anti-tuberculosis 
agent which is indicated for the initial treatment of active tuberculosis in adults and children when 
combined with other anti-tuberculosis agents and contributes significantly to the sterilization of 
lesions and thus treatment shortening.[21]   
Control Group: HRZE/HR 
The HRZE/HR combination [HRZE tablets [isoniazid (H), rifampicin (R), pyrazinamide (Z) and 
ethambutol (E)] and HR tablets [isoniazid (H) plus rifampicin (R) combination tablets] is approved 
indicated and commonly used as a 6-month treatment for drug-sensitive TB patients.  Participants 
with DS-TB that are randomized to the HRZE/HR control arm in this trial will be given standard 
weight-adjusted doses of HRZE.  Please see the HRZE package insert for more information.[22]   
Additional background data supporting the combined use of new novel agents in this 
BPaMZ regimen for the treatment of TB: 
Data from preclinical studies suggest that a regimen consisting of moxifloxacin plus pretomanid 
plus pyrazinamide may not only be appropriate for treating both DS and MDR-TB but may also 
shorten duration of therapy.  Results from an 8-week Phase 2b SSCC trial, NC-002-(M-Pa-Z), 
showed that this combination regimen was effective as measured by time dependent decline of 
viable bacteria in participants with DS pulmonary TB.  The combination was also shown to be 
safe and well tolerated supporting the evaluation of this combination in a Phase 3 trial. In this NC-
002 trial 71.4% of participants with DS-TB treated with PaMZ at the 100-mg daily dose of 
pretomanid converted sputum to negative for MTB growth in liquid culture in comparison with only 
37.8 % of participants treated with the HRZE control (p<0.05).  
Studies in mice infected with MTB demonstrated reductions in cultured colony counts from lungs 
over an 8-week period when treated with the PaMZ regimen that were substantially, and 
statistically significantly greater, than the reductions in mice treated with an HRZ control.  
Experiments in mice found that mice did not relapse with MTB infection when treated with PaMZ 
for 4 months and followed for 3 months off treatment, in comparison to mice that required 6 
months of treatment with HRZ to prevent relapse.[14]   
Drug Resistant TB Background: 
Although some progress has been made in recent years in controlling tuberculosis (TB) globally, 
TB has remained a persistent problem in many countries. TB is the world’s leading cause for 
mortality from infectious disease and is responsible for more deaths than HIV.[23] It is the leading 
cause of death among HIV-infected individuals, and there is more TB in the world today than at 
any other time in history. Because of poor treatment adherence, in addition to primary 
transmission, drug resistance is becoming more common and fears of an epidemic with strains 
of extensively drug-resistant TB (XDR-TB) that is very difficult to treat are growing.  Novel drugs 
and regimens for TB are needed for the growing number of patients with drug resistant-TB.  
The regulatory approvals of bedaquiline and delamanid have given hope that outcomes for 
patients with drug resistant TB might be improved when added to background regimens. 
Experience recently published from the C209 uncontrolled trial of bedaquiline given on a 
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background of multiple drugs notes that the subset of 38 participants with XDR-TB had rates of 
sputum culture conversion to negative of 62.2%.[24] However, in this trial only one participant with 
XDR-TB was co-infected with HIV. All participants were required to have Mycobacterium 
tuberculosis (MTB) isolates susceptible to at least 3 drugs at enrolment and participants had a 
median of only 5.4 months of treatment-free follow-up. This trial added bedaquiline for 6 months 
to a background regimen of many drugs given for 18 months or longer. While treatment success 
for MDR-TB is better than for XDR-TB, overall success in treating MDR-TB is still 
approximately 50% according to the World Health Organization 2015 Global TB Report.[23]  This 
report presented that overall, the proportion of MDR-TB patients in the 2012 cohort who 
successfully completed treatment (i.e. cured or treatment completed) was 50%; 16% died, 16% 
were lost to follow-up, 10% failed treatment, and for 8% there was no outcome information.   
With such poor historical outcomes for patients with drug resistant-TB and with the complexity, 
expense and toxicity of treatments for all forms of drug resistant TB, novel drug combinations 
are desperately needed to improve treatment outcomes. Linezolid was identified in a small 
trial as a potentially efficacious drug in patients with XDR-TB when added to a failing regimen[25] 
and this drug has increasingly been added to complex regimens to treat patients with MDR-TB. 
With the current availability of the following three drugs for which there is little, if any, pre-existing 
resistance among strains of MTB (pretomanid [Pa], bedaquiline [B], and linezolid [L]). Mice 
infected with MTB had relapse-free cures with 3 months of treatment with a B-Pa-L regimen. 
While it is not known whether that treatment duration will translate to humans, the ongoing Nix-
TB clinical trial hypothesizes patients with pulmonary XDR-TB or MDR-TB not responsive to or 
intolerant to therapy may have relapse-free cure after as little as 6 months’ treatment with the B-
Pa-L regimen.[26]  Moxifloxacin has been added to the B-Pa-Z regimen because of the high rate of 
pyrazinamide resistance seen in MDR-TB participants in the NC-002 trial. The proposed trial 
[SimpliciTB] allows the opportunity to assess the efficacy, safety and tolerability of BPaMZ, a new 
6 months regimen that may be administered orally once daily to treat patients with drug resistant 
-TB (excluding participants with XDR-TB). 
Therefore, the overall purpose of the present proposed trial [SimpliciTB] is to assess the 
efficacy, safety and tolerability of the BPaMZ regime after 4 months of treatment in adult 
participants with drug sensitive TB and after 6 months of treatment in participants with multi drug-
resistant TB. The trial will also generate data of the potential for a shorted treatment duration with 
the BPaMZ regime after 4 months compared to a 6-month HRZE/HR (control) treatment regime 
in adult participants with drug sensitive TB. 
This trial will be conducted in accordance with the Protocol, ICH Guidelines for Good Clinical 
Practice (GCP), the ethical principles that have their origin in the Declaration of Helsinki and the 
applicable regulatory requirement(s). 
2.5 
Background of Agents to be Studied in SimpliciTB 
2.5.1 
Bedaquiline (B) 
Bedaquiline (formerly known as TMC-207; SirturoTM package insert[7]) is approved agent for TB 
treatment. As detailed in the Investigator’s Brochure,[8] bedaquiline is a diarylquinoline that offers 
a novel mechanism of anti-tuberculosis action by specifically inhibiting mycobacterial adenosine 
triphosphate synthase.[11] In vitro, bedaquiline potently inhibits both drug-sensitive and 
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drug-resistant MTB isolates,[11, 12] and is also bactericidal against non-replicating MTB[12] In the 
murine model of TB, bedaquiline was as active as the triple combination of isoniazid (H), 
rifampicin (R), and pyrazinamide (Z). Addition of bedaquiline to HRZ results in accelerated 
clearance of MTB.[1, 2]. There appears to be a synergistic interaction with pyrazinamide: 100% of 
mice were culture negative after 8 weeks of treatment with bedaquiline and pyrazinamide 
compared to 0% of mice treated with the standard regimen of rifampicin, isoniazid and 
pyrazinamide.[27].Collectively, these findings in the mouse model have led to the suggestion that 
regimens containing bedaquiline and pyrazinamide could be effective in the treatment of both 
drug sensitive and drug resistant TB and shorten treatment duration in patients. While the 
combination of bedaquiline and pretomanid in the murine model of TB appeared somewhat 
antagonistic relative to bedaquiline alone, it was as active as the triple combination of HRZ[27] and 
in a subsequent trial it was more active in the mouse model than HRZ.[28]. Thus, a novel regimen 
with a bedaquiline plus pretomanid core could be effective in the treatment of MDR-TB/XDR-TB 
by providing two novel drugs for which there is no known pre-existing resistance. 
Bedaquiline is currently registered in many countries to be administered to patients with 
pulmonary tuberculosis by the following scheme: 400mg once daily for Days 1-14 followed by 
200mg three times per week for the remainder of treatment. In this trial bedaquiline will be 
administered as 200 mg daily for 8 weeks, followed by 100 mg daily for the remaining 17 weeks 
or 30 weeks if treatment is extended.  This daily dosing scheme will allow more convenient dosing 
that should ultimately enhance patient adherence and may allow the formulation of fixed dose 
combinations with other drugs.  This daily dosing regimen is supported by safety and efficacy 
demonstrated in the NC-005 trial that administered bedaquiline 200 mg daily over 8 weeks, and 
by pharmacokinetic modelling and simulation of the daily dosing scheme.  This supportive 
information is detailed below. 
2.5.1.1 
Bedaquiline Non-Clinical Studies 
Full details of the preclinical studies are provided in the current bedaquiline Investigator’s 
Brochure,[8] and Sirturo 
TM label.[7] In vitro studies have demonstrated that the range of minimum 
inhibitory concentrations (MICs) for MTB H37Rv, the international reference strain, and 6 fully 
drug-susceptible clinical isolates, was 0.030 to 0.120 μg/ml. The activity of bedaquiline appears 
to be specific for mycobacteria, as the MICs for non- mycobacteria were at least 500-fold higher. 
The activity of the main metabolite of bedaquiline, M2, was determined against MTB.  H37Rv in 
both solid and liquid media and its MIC was found to be 0.1 μg/ml. This MIC shows that M2 is 
active against MTB but 3-6 times less active than the parent compound bedaquiline. Bedaquiline 
demonstrated similar in vitro efficacy against MTB clinical isolates resistant to the known anti-TB 
drugs (isoniazid, rifampicin, pyrazinamide, streptomycin, ethambutol, or fluoroquinolones). As 
expected, from the lack of cross-resistance with currently used anti-tuberculosis agents, 
bedaquiline retained activity against MDR-TB isolates. 
The non-clinical safety evaluation of bedaquiline includes pharmacology, pharmacokinetics, 
toxicology and metabolism studies that were conducted in accordance with current International 
Council for Harmonisation (ICH) guidelines. Repeated dose toxicity studies were performed with 
dosing durations up to 3 months in mice and up to 6 months in rats and in dogs. Recovery was 
studied in rats and dogs. In repeated dose toxicity studies, up to 3 months in mice, up to 6 months 
in the rat and up to 9 months in dogs, bedaquiline was associated with target organ changes in 
the mononuclear phagocytic system (indicative of phospholipidosis), stomach, liver, pancreas, 
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and muscle. Toxicity was often associated with an increased presence of neutrophils in some 
tissues such as the female genital tract and this was preceded by a peripheral neutrophilia. For 
more detailed information please refer to the bedaquiline IB.[8] 
Respiratory parameters in rats were unaffected by treatment. There were no effects suggestive 
of neurological impairment or delayed neurotoxicity in rats. In single dose toxicity studies, there 
were no mortalities following oral doses of up to 200 mg/kg in mice and rats. No mutagenicity or 
clastogenic effects were seen in a series of in vitro and in vivo genotoxicity tests. Bedaquiline 
was evaluated for possible developmental toxicity effects in the rat and the rabbit. No teratogenic 
effects were found. In vitro, bedaquiline slightly to moderately inhibited the delayed rectifier 
potassium current (IKr) in the human ether-à-go-go-related gene (hERG) model. Bedaquiline and 
M2 had no notable effects on IKr at 0.01 μM (0.006 and 0.005 μg/mL, respectively). However, at 
higher concentrations (0.03 to 3 μM), both compounds had a slight to strong concentration-
dependent effect with a 50% inhibitory concentration (IC50) of 0.37 μM (0.2 μg/mL) for bedaquiline 
and up to 0.45 μM (0.24 μg/mL) for M2. However, this effect did not manifest as a prolongation of 
repolarization in subsequent in vivo studies. 
There were no relevant effects on the isolated right atrium of guinea pigs in vitro, or in the isolated 
Langendorff-perfused rabbit heart. In vivo, positive chronotropic effects were seen in the 
anesthetized guinea pig after IV administration, but not in the conscious dog. In conscious, 
telemetered dogs, oral bedaquiline had no relevant effects on cardio-hemodynamic and ECG 
parameters. 
Prior to the use of pretomanid in combination with bedaquiline in clinical trial NC-001, a preclinical 
cardiovascular safety pharmacology trial was conducted in unrestrained beagle dogs with both 
drugs to explore the potential for additive effects on QT prolongation induced by the combination. 
Results indicate that administration of 100 mg/kg bedaquiline daily, for 7 days, causes a small 
increase in QTc interval by Day 6 in some animals that is not influenced by the addition of 
100 mg/kg pretomanid on Day 7.[28] 
 The effect of pretomanid dosing alone on QT interval 
appeared to be due to discomfort related to the SC route of administration and not related to the 
plasma exposure (please see the pretomanid) Investigators Brochure for more detail. 
2.5.1.2 
Bedaquiline Clinical Studies 
In the clinical studies conducted to date, a total of approximately 645 participants (including 
265 healthy volunteers) have been exposed to bedaquiline in the Phase 1 and 2 clinical trials 
conducted as a part of the development program for the treatment of MDR-TB. An additional 45 
participants received bedaquiline, either as monotherapy (B) or in combination with other agents 
(B-Pa or B-Z) in trial NC-001, and 45 more in trial NC-003 (B-Pa-Z, B-Pa-C, B-Pa-Z-C). Four 
short-term Phase 2a trials enrolled treatment-naïve participants (C202, TMC207-CL001, NC-001 
and NC-003). One long-term, open-label, Phase 2 trial, in MDR-TB participants (bedaquiline- 
TiDP13-C209) and one long-term, Phase 2b trial, consisting of 2 different stages in participants 
infected with newly diagnosed sputum smear-positive pulmonary MDR-TB (bedaquiline-TiDP13-
C208), have been completed. The principal findings of these trials are summarized below. Full 
details of the completed clinical studies are provided in the current bedaquiline IB,[8] and Sirturo
TM 
label.[7]. 
The Phase 1 trials have provided a basic understanding of bedaquiline’s pharmacokinetic 
characteristics, drug- drug interaction potential, and short-term safety/tolerability profile in healthy 
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participants. Bedaquiline was well absorbed with time to reach the maximum plasma 
concentration at approximately 5 hours post-dose. The maximum plasma concentration and AUC 
increased proportionally up to the highest doses studied (up to 700 mg in a single dose-ranging 
trial, 800 mg single dose in trial bedaquiline-TBC1003 and 400 mg q.d. multiple doses). 
Accumulation from Days 1 to 14 was approximately 2-fold expressed as increase in AUC, while 
trough concentrations increased up to 3.5-fold. The pharmacokinetics of bedaquiline were 
comparable between healthy participants and participants with pulmonary TB. The apparently 
close to steady-state concentrations in plasma after 14 days of daily treatment is ascribed to the 
important amount of the drug that is eliminated from the circulation during the ἀ and β phases of 
the plasma concentration-time curve. The average terminal elimination half-life of bedaquiline and 
metabolite M2 noted on extended follow-up after repeat dosing of participants with TB infection is 
about 5.5 months. 
Administration of bedaquiline as the tablet formulation with food, increased the relative 
bioavailability (by 95%) compared to administration without food, and drug-drug interaction trials 
confirmed the role of cytochrome P450 3A4 (CYP3A4) in the metabolism of bedaquiline to M2. A 
recently completed trial (DMID 10-0043) demonstrated that when given in combination, rifampicin, 
and to a lesser degree rifabutin, decreased exposure to bedaquiline presumptively due to 
induction of P450 enzymes. The clinical significance of these findings is unknown, however the 
current trial (NC-005) will not permit the concomitant use of bedaquiline with any rifamycin. 
The efficacy of bedaquiline was initially demonstrated in two monotherapy EBA studies C202 and 
TMC207- CL001. Trial C202 was a 7-day trial of three daily doses of bedaquiline (25, 100 and 
400mg) in treatment-naïve participants with MDR-TB. In this trial, the 400mg dose group 
demonstrated positive EBA and was numerically superior to the 25 and 100mg doses. In trial 
TMC207-CL001, doses of 100, 200, 300 and 400mg daily (following a 2-day loading dose) were 
studied in participants with newly-diagnosed pulmonary TB for 14 days. There were no statistically 
significant differences between the treatment groups, although there was a numerical trend 
suggesting a positive dose-response relationship. Taken together, these studies establish that 
bedaquiline monotherapy has EBA in participants with TB and that higher doses appear to have 
greater efficacy. 
A 14-day EBA regimen trial (TB Alliance Trial NC-001-(B-M-Pa-Z)) evaluated bedaquiline 
administered as monotherapy at 400 mg/d or in combination at that dose with either pretomanid 
administered at 200 mg/d or weight-adjusted pyrazinamide, to participants with pulmonary TB at 
2 clinical sites in South Africa. The results indicate that over 14 days, the mean logCFU decreased 
by 1.3 from baseline in the 15 participants given bedaquiline 400 mg/d after a 2-day loading dose. 
In the cohort of 15 participants given bedaquiline 400 mg/d after a loading dose plus weight-
adjusted daily doses of pyrazinamide (Z), the mean logCFU decreased by 2.0 logs from baseline, 
indicating that Z potentiates the early bactericidal effect of bedaquiline. In the cohort with 15 
participants given bedaquiline 400 mg/d after a loading dose plus 200 mg/d pretomanid, the mean 
logCFU decreased by 1.9. While it appeared that the addition of pretomanid potentiated the anti-
tuberculosis activity of bedaquiline, the mean logCFU decrease of the combination was similar to 
that of two previous EBA studies using pretomanid monotherapy at 200 mg/day. 
The second 14-day EBA combination trial (NC-003) included a number of bedaquiline-containing 
arms: bedaquiline, pyrazinamide and clofazimine (B-Z-C), bedaquiline, pretomanid and 
clofazimine (B-Pa-C), bedaquiline, pretomanid, and pyrazinamide (B-Pa-Z) and bedaquiline, 
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pretomanid, pyrazinamide and clofazimine (B-Pa-Z-C). Among these, B-Pa-Z had the best activity 
which was at least as good as the HRZE control (Daily Log CFU – 0.167 vs 0.151, respectively). 
The long-term efficacy of bedaquiline in participants with MDR-TB has been studied in a placebo-
controlled, randomized Phase 2b trial (C208) and an open-label, uncontrolled, Phase 2b trial 
(C209). In the Phase 2b placebo-controlled trial, C208, the addition of bedaquiline to a 5-drug 
MDR-TB regimen resulted in significantly faster time to culture conversion compared to placebo. 
During the 8-week treatment in Stage 1, 47.6% of participants in the bedaquiline group became 
MGIT culture negative compared to 8.7% of participants in the placebo group. At Week 24 in Stage 
1, after 8 weeks of investigational treatment and 24 weeks of background treatment, 81.0% of 
participants in the bedaquiline group and 65.2% of participants in the placebo group showed 
treatment success, (i.e., completed week 24 and were liquid culture negative, at this time point). 
For C208 Stage 2, in the interim analysis as well as in the primary efficacy analysis, a statistically 
significant difference in time to culture conversion between the treatment groups (p < 0.0001) in 
favour of bedaquiline was shown. In both analyses, an identical number of participants with culture 
conversion at week 24 (i.e., 24-week responders [missing = failure]) was observed: 78.8% in the 
bedaquiline group and 57.6% in the placebo group, which was statistically significantly different 
(p =   0.008) based on a logistic regression model with only treatment as covariate. Microbiological 
response at Week 24 was durable in C208 Stage 2: the percentage of responders (missing = 
failure) at week 72 was 71.2% in the bedaquiline group and 56.1% in the placebo group. 
In the Phase 2b uncontrolled trial, C209, treatment with bedaquiline in combination with an 
individualized MDR- TB treatment regimen was effective against pulmonary MDR-TB both in 
newly diagnosed and in non-newly diagnosed participants. Culture conversion rates after 2 weeks 
of treatment with bedaquiline as part of an individualized anti-tuberculosis regimen were higher in 
participants with lower extent of resistance of the M. Tb strain and in participants with no lung 
cavitation compared to participants with cavitations (in one or both lungs). 
2.5.1.3 
Bedaquiline Clinical Safety 
In the clinical trials conducted to date, a total of approximately 645 participants (including 
265 healthy volunteers) have been exposed to bedaquiline in the Phase 1 and 2 clinical trials 
conducted as a part of the development program for the treatment of MDR-TB. An additional 60 
participants received bedaquiline in a monotherapy EBA trial of 14 days (trial TMC207-CL001) 45 
participants received bedaquiline, either as monotherapy (B) or in combination with other agents 
(B-Pa or B-Z) in trial NC-001 and 45 more in trial NC- 003 (B-Pa-Z, B-Pa-C, B-Pa-Z-C). In these 
trials, bedaquiline has been shown to be an effective treatment for participants with both DS and 
MDR-TB. Specifically, the regimen B-Pa-Z was demonstrated to have efficacy at least as good 
as the HRZE control in trial NC-003. Furthermore, bedaquiline is a novel agent with no pre-existing 
resistance and, based on mouse model data, may result in shortened treatment durations when 
included in novel regimens to treat both DS- and MDR-TB. Based on the combined experience in 
these clinical trials, the following known and potential risks have been identified. 
Adverse Drug Reactions for bedaquiline 
During the Investigational Treatment phase in the controlled trials, the most frequently reported 
Adverse Drug Reactions in the any bedaquiline group (> 10.0% of participants) were nausea, 
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arthralgia, headache, vomiting, and dizziness. Details of Adverse Events, none of which were 
Serious, that were considered Adverse Drug Reactions are in the table below: 
Table 1.  Bedaquiline Adverse Drug Reactions 
 
Mortality 
Overall, there was an imbalance in the number of deaths in the pooled Stage 1 and Stage 2 C208 
trial. In the pooled analysis (Stage 1 and Stage 2), 12 participants in the Any bedaquiline group 
and 5 participants in the Any Placebo group experienced a SAE leading to death; causes of death 
were varied with only death due to TB reported more than once, and none of these participants 
had a treatment-emergent QTcF ≥ 500 ms. The imbalance in deaths is primarily driven by the 
C208 Stage 2 results in which the imbalance was 10 bedaquiline participants (12.7%) compared 
to 3 placebo participants (3.7%). Based on the pooled results (Stage 1 and 2) while being followed 
in the placebo- controlled trial, 7 participants in the Any bedaquiline group and 1 Participant in the 
Any Placebo group died. Of these deaths, 1 occurred during the Investigational Treatment phase 
with bedaquiline/placebo, the remaining deaths occurred afterwards. In the Any bedaquiline 
group, causes of death were myocardial infarction, TB (2 cases), alcohol poisoning, hepatitis and 
hepatic cirrhosis (1 case), septic shock and peritonitis (1 case), and cerebrovascular accident. In 
the Any Placebo group, cause of death was haemoptysis. The Investigator considered the SAEs 
leading to death not related to bedaquiline intake in the Any bedaquiline group and doubtfully 
related to investigational medication in the Any Placebo group. The analysis of long-term follow-
up for survival outcomes in participants who prematurely discontinued in trial C208 (Stage 1 and 
2), based on data collection every 24 weeks (6 months) after withdrawal (up to LSLV in the rollover 
arm [16 Oct 2012] in Stage 2), included 9 deaths. One Participant in the bedaquiline group 
(pulmonary TB) and 2 participants in the Placebo group (TB-related illness and pulmonary TB) in 
Stage 1 died, and 4 participants in the bedaquiline group (3 participants with TB-related illness, 1 
Participant motor vehicle accident) and 2 participants in the Placebo group (both TB-related 
illness) died after they discontinued Stage 2 of the trial. None of these participants had a 
treatment-emergent QTcF ≥ 500 ms. The imbalance in deaths is unexplained.  In addition, no 
discernible pattern between death and sputum culture conversion, relapse, sensitivity to other 
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drugs used to treat TB, human immunodeficiency virus (HIV) status, or severity of disease was 
observed. 
In the uncontrolled Phase 2b trial, C209, the most frequently reported AEs during the 
investigational phase were hyperuricemia, arthralgia, nausea, vomiting, headache, diarrhoea, 
blood uric acid increased, hypokalaemia, pruritus, injection site pain, insomnia, and tinnitus. From 
start of the trial up to the final analysis, 12 participants died during the C209 trial due to SAEs that 
included TB (5 cases), congestive cardiac failure, renal impairment, lung infection, cardiac arrest 
(underlying cause pneumonia), haemoptysis, hypertension, and pyopneumothorax/respiratory 
failure. These SAEs leading to death were considered not related to bedaquiline by the 
Investigator, except for renal impairment that was judged doubtfully related to bedaquiline. 
The analysis of long-term follow-up for survival outcomes for participants who prematurely 
discontinued in trial C209, based on data collection every 24 weeks (6 months) after withdrawal, 
included 4 deaths (all described as TB-related). In total, since the start of the C209 trial, 16 
participants (6.9%) have died (12 participants during the trial and 4 participants during the survival 
follow-up phase after premature discontinuation). None of the fatal SAEs were considered related 
to bedaquiline by the Investigator and none of these participants has a treatment- emergent 
adverse event. 
Cardiovascular safety 
During clinical trials with bedaquiline a prolongation of QTc interval was observed. The US 
Product Label for bedaquiline[7] notes that treatment initiation is not recommended in patients with: 
• 
Heart failure; 
• 
QTcF interval > 500 ms (confirmed by repeat electrocardiogram); 
• 
A personal or family history of congenital QT prolongation; 
• 
Concomitant administration of fluoroquinolone antibiotics that have a greater potential 
for significant QT prolongation (i.e., gatifloxacin, moxifloxacin and sparfloxacin). 
• 
Hypokalaemia 
The US Product Label recommends that bedaquiline treatment must be discontinued if the patient 
develops clinically significant ventricular arrhythmia. An additive or synergistic effect on QT 
prolongation of bedaquiline when co-administered with other medicinal products that prolong the 
QT interval cannot be excluded. Caution is recommended when using bedaquiline concomitantly 
with medicinal products with a known risk of QT prolongation. If co-administration of such 
medicinal products with bedaquiline is necessary, clinical monitoring including frequent ECG 
assessment is recommended. 
Hepatic safety 
The US product label notes increases in transaminases were seen in clinical trials during 
administration of bedaquiline with the background regimen. participants should be monitored 
during treatment. Other hepatotoxic medicinal products and alcohol should be avoided while 
taking bedaquiline, especially in those participants with diminished hepatic reserve.[7]  
Additional safety information from a recently completed trial 
In a recently completed phase I trial not yet included in the bedaquiline Investigators Brochure 
that evaluated drug-drug interactions between bedaquiline and either rifampin or rifabutin, 7 
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participants experienced SAEs. Of those participants, 5 experienced SAEs of lymphocytopenia 
(all received rifabutin), which did not appear to be related to the AUC or Cmax of TMC207 or 
rifabutin. One participant experienced an SAE of elevated Creatine Kinase (rifampicin arm) and 
one experienced a grade 4 Total Bilirubin SAE (rifampicin arm). Lymphopenia was previously 
noted to be an infrequent toxicity associated with rifabutin, but not previously seen with 
bedaquiline. 
The bedaquiline/rifabutin regimen demonstrated significant reversible lymphopenia, which did not 
appear to be related to the AUC or Cmax of TMC-207 or rifabutin. 
2.5.2 
Pretomanid (P) 
As detailed in the Investigator’s Brochure,[15] pretomanid is a new chemical entity and a member 
of a class of compounds known as nitroimidazo-oxazines, which possess significant anti-
tuberculosis activity and a unique mechanism of action.[16] Pretomanid demonstrated in vitro 
activity against both DS- and MDR-TB,[17] and in vivo activity in a mouse model of tuberculosis.[16, 
17]  
2.5.2.1 
Pharmacology 
Key in Vitro Evaluation of Pretomanid Bactericidal Activity 
Non-clinical in vitro trials demonstrated that pretomanid was active against actively growing drug- 
sensitive and drug-resistant MTB strains as well as against non-replicating MTB. The minimum 
inhibitory concentration (MIC) of pretomanid against a variety of drug-sensitive MTB isolates in 
vitro was shown to be like the MIC of isoniazid (MIC of pretomanid, ≤0.015 to 0.25 µg/mL; MIC of 
isoniazid, 0.03 to 0.06 µg/mL). Pretomanid was efficacious in vitro against drug-resistant clinical 
isolates of MTB with MIC values ranging from 0.03 to 0.53 µg/mL. The Investigator’s Brochure 
contains further information on in vitro bactericidal activity.[16] 
Although not thoroughly elucidated at this time, pretomanid has a novel mechanism of action that 
appears to involve inhibition of the synthesis of cell wall lipids under aerobic conditions and 
generation of reactive nitrogen species under anaerobic conditions. Reduction of pretomanid by 
a deazaflavin (F420)-dependent nitroreductase has been shown to be associated with generation 
of reactive nitrogen species, including nitric oxide (NO),[29] although the exact target(s) of the 
reactive nitrogen species are not known. Transcriptional profiling trials also suggest that 
pretomanid affects both cell wall biosynthesis and the respiratory complex of MTB.[30, 31] 
2.5.2.2 
Key Non-Clinical Trials of Pretomanid 
The activity of pretomanid as a single agent or as part of a multi-drug combination regimen has 
been examined in a number of mouse trials.[13, 14, 18, 32, 33] In a mouse model of established TB, the 
activity of various doses of pretomanid (given once daily, 5 days/week, for 1 month), initiated 22 
days after inhalation infection with H37Rv MTB is shown in Figure 2. In this model, the minimum 
effective dose (MED) for pretomanid, defined as the lowest dose able to prevent the development 
of gross lung lesions and splenomegaly, was 12.5 mg/kg/day, while the minimum bactericidal 
dose (MBD), defined as the lowest dose able to reduce lung colony forming units (CFU) by 99%, 
was 100 mg/kg/day. Moreover, in these experiments, the activity of pretomanid at 100 mg/kg was 
comparable to the activity of isoniazid at 25 mg/kg. 
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Figure 2.  Log10 CFU Counts in Lungs  
After One Month of Daily Treatment with the Indicated Dose (in mg/kg) of Pretomanid 
 
Arrows denote the minimum effective dose (MED) and minimum bactericidal dose (MBD). 
2.5.2.3 
Non-Clinical Toxicology and Safety 
Pretomanid has been evaluated in an ICH recommended battery of safety pharmacology trials, in 
repeat-dose toxicity trials in rats (2 to 26 weeks) and cynomolgus monkeys (7 days to 9 months), 
in 8 genotoxicity trials, and in fertility and teratology trials in rats and rabbits.  
In the repeat-dose toxicity trials, the lowest no-observed adverse effect level (NOAELs) was 
10 mg/kg/day in a 26-week trial in rats, 50 mg/kg/day in a 13-week trial in monkeys and 
<25 mg/kg/day (based on findings of thickening of the gastrointestinal tract at all doses) in a 9-
month trial in monkeys. The major findings in safety and toxicity trials are listed below in Table 2 
and are detailed in the Investigator’s Brochure.[15] 
Table 2.  Key findings of Pretomanid in Safety and Toxicity Trials 
Nervous system-related effects.  
Rats given single oral pretomanid doses had decreased body tone, touch responses and 
decreased grooming behaviour at ≥150 mg/kg, which resolved within 24 hours. Rats given 
repeated daily doses of pretomanid had convulsions, ataxia, hypoactivity, recumbency, 
hyperactivity and sensitivity to touch, and squinting at ≥100 mg/kg/day, and early deaths 
occurred at doses ≥500 mg/kg/day. Monkeys given repeated daily doses of pretomanid had 
hypoactivity, ataxia, tremors, and convulsions at ≥450/300 mg/kg/day. These effects were 
reversible when dosing stopped and were absent at ≤30 mg/kg/day in rats and ≤150 mg/kg/day 
in monkeys. 
 
Testicular toxicity 
Although rat and rabbit embryonic development trials indicate no effects of pretomanid on foetal 
development, testicular atrophy in rats was observed in 3-month and 6-month repeat-dose 
toxicology trials and a Segment I fertility trial. In this fertility trial, testicular atrophy was 
associated with infertility; an approximate 30% reduction in fertility was also observed at a lower 
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dose not associated with testicular atrophy. A detailed trial in sexually mature male monkeys 
demonstrated no effects on testicular histology or function in adult cynomolgus monkeys after 
3 months’ dosing.  
 
Cataracts 
Cataracts developed in rats with prolonged daily administration of pretomanid at doses 
≥100 mg/kg/day. In one 13-week trial in monkeys, cataracts did develop at 450/300 mg/kg/day, 
but only by the end of a 13-week recovery period. In a second 13-week trial in monkeys that 
included extensive ophthalmic examinations, cataracts did not develop at the high-dose level 
of 300 mg/kg/day. 
 
hERG inhibition and QT prolongation 
Altered ventricular repolarisation due to inhibition of hERG-mediated potassium current and 
manifested on the ECG as a prolonged QT interval corrected for heart rate (QTc). Pretomanid 
inhibited hERG current with IC50 values of approximately 6.2 µg/mL. Following a single 
pretomanid dose of 450 mg/kg in monkeys, QTc interval prolongation ranged from 21 to 
36 msec using Fridericia’s formula (QTcF) to correct for heart rate. Co-administration of 
pretomanid with moxifloxacin in the monkey or with bedaquiline in the dog did not result in any 
greater effect on the QT interval than with either agent alone. After repeated daily doses, the 
QTc interval in the monkey was prolonged at pretomanid doses of ≥150 mg/kg/day. 
 
 
2.5.2.4 
Clinical Background Information 
Pretomanid has been evaluated in 8 single- and multi-dose Phase 1 trials with healthy adult male 
and female participants, with 163 participants receiving single oral doses ranging from 50 to 
1500 mg and multiple oral doses ranging from 50 to 1000 mg/day given for up to 7 days. These 
Phase 1 trials have evaluated the safety, tolerability, and pharmacokinetics (PK) of pretomanid. 
Two additional Phase 1 trials Sponsored by the NIH included a Thorough QT trial and a trial of 
drug interactions among pretomanid, efavirenz and ritonavir/lopinavir.  Further details of the trials 
are in the Investigator’s Brochure.[15] 
2.5.2.5 
Pharmacokinetics 
Several Phase 1 trials have evaluated the safety, tolerability, and pharmacokinetics (PK) of 
pretomanid and have demonstrated that pretomanid has a half-life of approximately 18 hours, 
which supports daily dosing, and an effect of food with the 200-mg dose that increases total 
exposure by 88%. Interaction trials with midazolam, efavirenz and ritonavir/lopinavir demonstrate 
effects that are not likely to be clinically significant. 
Drug interaction with midazolam: Trial CL-006 was an open-label, fixed-sequence drug-drug 
interaction trial to evaluate the effects of multiple-dose administration of pretomanid on the PK of 
midazolam, a sensitive probe substrate and representative compound for drugs metabolised by 
CYP3A enzymes. Dosing with pretomanid at 400 mg/day for 14 days (to steady state) had minimal 
effect on the PK of midazolam and its 1-hydroxy metabolite as assessed by measurement of the 
Day 17: Day 1 ratios of maximum concentration (Cmax, AUC0-t, and AUC0-inf. The Cmax and AUC 
values for midazolam after co-administration with pretomanid were approximately 85% of those 
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observed after treatment with midazolam alone. Furthermore, midazolam and 1-hydroxy 
midazolam time to maximum concentration (Tmax) and half-life (t1/2) values were not different in 
the presence or absence of pretomanid. Therefore, 14 days’ dosing with 400 mg/day pretomanid 
does not appear to significantly inhibit CYP3A4 in humans. 
Drug interaction with efavirenz, ritonavir/lopinavir, and rifampicin: The US NIH Sponsored this 
drug interaction trial with rifampicin, a known hepatic enzyme inducer, and with the antiretroviral 
drugs efavirenz and ritonavir/lopinavir (LPV/r) in healthy participants. Participants in Arm 1 were 
randomised to Sequence 1 (pretomanid 200 mg once daily for 7 days, two-week washout period, 
efavirenz (EFV) 600 mg once daily for 14 days, then both drugs for 7 days) or Sequence 2 
(Treatment 1B: EFV, then EFV + pretomanid, washout, and pretomanid). Results indicate that 
comparing pretomanid given with EFV versus pretomanid alone in 16 participants, the geometric 
mean ratio (GMR) for Cmax was 0.71, the GMR for AUC0-24h was 0.65, and the GMR for Cmin was 
0.54. Concentrations of EFV when given with pretomanid versus given alone were similar. 
Participants in Arm 2 were randomised to Sequence 1 (pretomanid 200 mg once daily for 7 days, 
then a 2-week washout period, then LPV/r 400/100 mg twice daily for 14 days, then LPV/r + 
pretomanid together for 7 days) or Sequence 2 (LPV/r, then LPV/r + pretomanid, washout, then 
pretomanid alone). Comparing pretomanid + LPV/r versus pretomanid- alone from 16 PK-
evaluable participants, the GMR for Cmax was 0.87, for AUC0-24h was 0.83, and for Cmin was 0.78. 
In Arm 3, participants received pretomanid for 7 days, then rifampicin 600 mg for 7 days, then 
pretomanid + rifampicin together for 7 days. Comparing pretomanid + rifampicin versus 
pretomanid alone from 16 PK-evaluable participants, the GMR for Cmax, AUC0-24h, and Cmin were 
0.47, 0.34, and 0.15, respectively.  
In conclusion, compared to pretomanid alone, plasma pretomanid values (based on geometric 
mean ratios) for Cmax, AUC0-24h, and Cmin were reduced 28%, 35%, and 46% with efavirenz; 13%, 
17%, and 21% with LPV/r; and 53%, 66%, and 85% with rifampicin, respectively. 
2.5.2.6 
Pretomanid Clinical Efficacy 
The first two Phase 2 trials to evaluate the early bactericidal effect (EBA) of pretomanid oral 
monotherapy (50 to 1200 mg/day for 14 days) examined the dose-response for pretomanid in 
participants with newly diagnosed pulmonary TB infection. The first trial (CL-007) demonstrated 
good EBA, but all doses in this trial (200 to 1200 mg/day) had the same activity. The second trial 
(CL-010) evaluated a lower dose range (50 to 200 mg/day) and the maximum effect on EBA was 
seen at a dose of 100 mg/day over 14 days (Figure 3).[34] 
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Figure 3.  Mean log Colony Forming Unit Values over Time Trial CL-010 
 
CFU = colony-forming unit; PRETOMANID = pretomanid 
* Day 0 = (Day -2 + Day -1)/2 = baseline measurement 
Pretomanid has been evaluated in patients with TB as monotherapy for a maximum duration of 
14 days, the longest considered acceptable for a TB patient to be treated in a clinical trial with a 
single drug.  Trials of pretomanid for both 14 days and for up to 6 months, in combination with 
either bedaquiline and/or linezolid, are described below.  
2.5.2.7 
Pretomanid Clinical Safety 
The pretomanid Investigator’s Brochure[15] provides detailed safety information. 
Across the 16 clinical trials with pretomanid completed to date, a total of 649 participants have 
been exposed to pretomanid, including 289 healthy participants across the 10 Phase 1 trials and 
360 participants with newly diagnosed smear positive pulmonary TB across 5 Phase 2 
trials.  Among the 289 healthy participants, 174 received exposure to a single dose of pretomanid 
ranging from 50 to 1500 mg and 115 received exposures to repeated daily doses of pretomanid 
(50 to 1000 mg) for up to 14 days. The 360 participants with newly diagnosed smear positive 
pulmonary TB were exposed to pretomanid either as a single agent at daily doses of 50 to 
1200 mg for 14 days or in combination with other anti-TB agents (bedaquiline, moxifloxacin, 
pyrazinamide, linezolid and/or clofazimine) at a dose of 100 mg or 200 mg for up to 26 weeks.  The 
overall safety profile determined from the clinical trials completed to date indicates pretomanid is 
well tolerated in healthy adults and in TB patients when administered alone and in combination 
with moxifloxacin, pyrazinamide, bedaquiline and clofazimine.   
4
4.5
5
5.5
6
logCFU
0
2
4
6
8
10
12
14
Day
 PA-824 50mg
 PA-824 100mg
 PA-824 150mg
 PA-824 200mg
 Rifafour e275 
Bi-linear regression of logCFU vs day over treatment
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Pretomanid is an investigational drug and there is limited experience in humans; the safety 
database is being developed and Investigators should be vigilant to any adverse events noted in 
clinical trials.  Across these trials, the most common side effects or AEs associated with 
pretomanid exposure include: 
• 
Headache 
• 
Stomach discomfort (nausea, vomiting, flatulence, and/or diarrhoea) 
• 
Skin and subcutaneous tissue disorders 
The only adverse drug reaction identified in clinical trials completed to date as likely caused by 
pretomanid is blood creatinine increased.  A trial of the effects of repeat doses of pretomanid in 
healthy volunteers determined that the drug does not adversely affect glomerular filtration rate, 
effective renal plasma flow or filtration fraction and the elevations in serum creatinine reverse.  
The following parameters will be followed with particular care in the Phase 3 development 
program: 
• 
Hepatic Safety – Specific guidelines are included in the protocol to assure close 
surveillance and careful management of participants who have elevations in 
aminotransferases and/or bilirubin. Serious liver injury, including death in 3 participants 
taking a combination of pretomanid, pyrazinamide and moxifloxacin, has occurred during 
clinical trials and the risk of liver injury may be higher for participants taking a combination 
of pretomanid and pyrazinamide than it is for the standard HRZE treatment. Therefore, 
close monitoring of liver function is required for participants who are administered 
pretomanid, especially when combined with pyrazinamide.  Administration of the regimen 
of PaMZ has been associated with death in 3 participants associated with hepatic injury. 
Furthermore, the HRZE control regimen, and both pyrazinamide and moxifloxacin, has 
been associated with drug induced liver injury and in rare cases hepatic necrosis.  
Consequently, hepatic safety will be under close surveillance in all clinical trials. 
• 
Ophthalmologic Evaluations – while the detailed examinations in Phase 2 have not raised 
concern for humans, ophthalmologic examinations, with slit lamp exam and grading of 
lens opacities, will continue in all human trials that involve exposure to pretomanid longer 
than 14 days.  These examinations will be conducted at baseline, near the end of the 
dosing period and 3 months after the end of trial drug exposure.  These examinations are 
to follow up on the finding of cataracts in rats exposed to pretomanid in clinical trials. 
• 
Cardiovascular Safety – All participants will have ECGs taken at baseline and at multiple 
time points during the trial.  Although the Thorough QT Trial in healthy participants found 
that pretomanid did not increase corrected QT intervals in a clinically meaningful way and 
did not add to the known effect of moxifloxacin, the ECGs will be carefully monitored during 
Phase 3.  All ECGs will be interpreted, and conduction intervals will be confirmed by a 
central cardiology service. 
• 
Central Nervous System Safety –While pretomanid alone or combined in various regimens 
has been well tolerated overall, one participant in Trial NC-002 of the Pa-M-Z regimen had 
a seizure without any prior seizure history, and some animals in toxicology trials have had 
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seizures at high drug exposures.  Consequently, close surveillance will be made of 
participants in the Phase 3 trial for seizures or any central nervous system adverse events 
of potential concern. 
Of note, preclinical toxicology trials found that rats, but not primates, had testicular toxicity when 
treated with pretomanid. Clinical evaluations of potential testicular toxicity in Phase 2 trials have 
evaluated over 300 participants exposed to pretomanid over 2-6 months with evaluations of 
testosterone, LH, or Inhibin B (2 trials) or FSH values (3 trials) at baseline and after daily dosing 
of regimens containing pretomanid in various combinations with moxifloxacin, pyrazinamide and 
bedaquiline.  A review of data from the 3 trials by an independent reproductive endocrine expert 
concluded that, based on the hormone evaluations to date, there is no evidence that pretomanid 
is a testicular toxicant in men at the doses and exposure times evaluated. 
2.5.3 
Moxifloxacin (M) 
Moxifloxacin (M)[19]  is an 8-methoxyquinolone whose oral formulation (which will be used in 
this trial) has enhanced activity against Gram-positive pathogens, and anaerobes while retaining 
useful activity against Gram-negative organisms. Moxifloxacin is not metabolized by nor induces 
the cytochrome P450 system, thus the risk of clinically relevant drug interactions is reduced. It 
has a positive safety profile within the fluoroquinolone class at the approved daily dose of 400 mg. 
Moxifloxacin while not approved for TB by most regulatory authorities, it is regularly used in 
second line MDR-TB treatment. The WHO TB Treatment Guidelines place moxifloxacin in the 
category of Group 3 drugs and notes that “all patients [with MDR-TB] should receive a Group 3 
medication if the strain of MTB is susceptible or if the agent is thought to have efficacy. One of 
the higher generation fluoroquinolones, such as levofloxacin or moxifloxacin, is the fluoroquinolo-
ne of choice.[5]” It is currently in late stage clinical development for first-line TB treatment in 
combination with other TB drugs, including pyrazinamide in two different four-month long 
regimens.  
2.5.3.1 
Moxifloxacin Clinical Trials 
Moxifloxacin is commonly used as second line therapy for TB (e.g. MDR- TB) and has also been 
evaluated in several clinical studies of participants with TB, including four 8-week treatment period 
Phase 2b studies (see Table 3 below).  
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Table 3.  Summary of Phase 2b trials in which moxifloxacin were administered as 
part of a four-drug regimen during the intensive phase of treatment (total 
treatment duration: 2 months) 
Trial 
Design 
Objective 
Participants 
(N) 
Status 
Trial 27 
Randomized, 
double-blind, 
controlled 
To compare the sputum culture-
conversion rate at the end of the 4-drug 
(intensive) phase of therapy using the 
standard 4-drug regimen HRZE with a 
standard regimen with M replacing E.  
336 
Completed 
OFLOTUB 
Trial 
Randomized, 
Open label, 
Controlled 
To compare the bactericidal activities of 
regimens where gatifloxacin, M, and 
ofloxacin were substituted for E in the 2-
month initial phase of standard TB 
treatment with HRZE.  
 
217 
Completed 
Johns 
Hopkins 
(FDA 
orphan 
drug) Trial 
Randomized, 
double-blind, 
Controlled 
To compare the sputum culture 
conversion rate at the end of the 4-drug 
(intensive) phase of therapy using a 
standard 4-drug regimen (HRZE) with a 
regimen with M replacing E (HRZM). 
170 
Completed 
Trial 28 
Randomized, 
double-blind, 
Controlled 
To compare the culture-conversion rate 
at the end of the 4-drug (intensive) 
phase of therapy using a standard 4-
drug regimen (HRZE 5 days per week) 
with a regimen with M replacing H 
(MRZE 5 days per week). 
 
433 
Completed 
 
2.5.3.2 
Moxifloxacin Clinical Safety 
In Trial 27,[35] the moxifloxacin-containing TB regimens (HRZM) were shown to be safe and well 
tolerated. There was no difference in SAEs between the HRZM and HRZE treatment arms, and 
most SAEs were hospitalizations thought to be unrelated to the trial treatment.  Participants 
treated with the moxifloxacin-containing regimen were more likely to report nausea (22% vs. 9%, 
p = 0.002), but this was generally mild and did not lead to treatment discontinuation as similar 
proportions of participants in both groups completed trial drug treatment (88% HRZM-treated vs. 
89% HRZE-treated).  The one death during the first 2 months of treatment was thought to be 
caused by a pulmonary embolism unrelated to tuberculosis therapy.   
In the OFLOTUB trial,[36] AEs and SAEs occurred with equal frequency in the four treatment arms.  
The most frequent AEs were raised amylase (in 41% of participants due to HIV infection), raised 
transaminase (10%), arthralgia (9%), anaemia (7%), hypokalaemia (6%) and vomiting (5%).  No 
Participant was withdrawn from the trial due to an adverse event.  There were 4 deaths in the 
trial: 2 in the control group, 1 each in the moxifloxacin and ofloxacin arms.  Importantly, 
participants in this trial who received moxifloxacin and pyrazinamide in addition to isoniazid and 
rifampin had more rapid sputum clearance than participants on the four standard first line drugs 
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(isoniazid, rifampin, pyrazinamide and ethambutol). This difference was evident 14 days after 
initiation of treatment. 
In the JHU trial,[37] AEs did not differ by treatment group. There were 16 SAEs (8 in each group) 
in 12 participants. Only 1 event was judged related to trial drug (grade 3 cutaneous reaction in 
the ethambutol group). Eight participants died during the trial, including 1 in each group still 
receiving trial phase treatment. No death was attributed to trial treatment. Only 5 participants 
discontinued treatment because of toxic effects; 2 participants in the moxifloxacin group stopped 
because of grade 2 nausea and vomiting and 1 because of grade 2 paraesthesia’s and ataxia. 
Two participants in the E group stopped because of grade 2 rash and pruritus and 1 because of 
grade 3 peripheral neuropathy.  There was no change in the QTc interval on serial 
electrocardiograms taken during the trial. 
In Trial 28,[38] the proportions of participants with SAEs during the intensive phase treatment were 
similar between arms (isoniazid 3.9% vs. moxifloxacin 4.2%; P = 0.88). Three SAEs attributed to 
trial treatment during the first 2 months occurred among the moxifloxacin group and two in the 
isoniazid group.  Seven participants died during the trial including 3 participants receiving the 
moxifloxacin treatment regimen and 4 participants receiving the isoniazid treatment regimen. The 
3 moxifloxacin participants died during the intensive phase of TB treatment. Two participants died 
from advanced pulmonary TB judged not related to trial treatment and 1 Participant (who 
developed diabetic ketoacidosis considered possibly related to trial treatment) died from possible 
acute pulmonary embolus unrelated to trial treatment. The 4 isoniazid deaths occurred during the 
continuation phase, and all 4 were considered unrelated to trial treatment.  Nausea was more 
common among participants in the moxifloxacin arm than in the isoniazid arm (19.6% vs. 11.7%, 
respectively; P = 0.03) although similar proportions reported vomiting.  However, the proportions 
of participants with hepatitis, defined as serum AST 3 times or greater than the upper limit of 
normal, were similar between treatment arms during intensive phase (isoniazid 3.4% vs. 
moxifloxacin 3.3%; P = 0.93).  Moxifloxacin has also been evaluated in combination with 
pretomanid for two weeks in participants with TB (Trial NC-001) and for 8 weeks in NC-002 (as 
reviewed above). 
For additional information on moxifloxacin, refer to the IB[39] and the manufacturer’s package 
insert.[19] 
2.5.4 
Pyrazinamide (Z) 
Pyrazinamide (Z) is a standard drug used as part of the four drug HRZE regimen used for the first 
two months of intensive therapy for drug-sensitive TB as recommended by the WHO and many 
National TB programs.  Please see the Package Insert[20] for more detail.  Z is active against TB 
in vitro and it potentiates the bactericidal and sterilizing activity of both bedaquiline and  
pretomanid in mouse models of TB infection.[8, 15]  Pyrazinamide enhanced the bactericidal activity 
of both bedaquiline and  pretomanid in Trial NC-001-(J-M-Pa-Z) as noted by decreases over 14 
days in the CFU counts in sputum among participants. 
The pyrazinamide product label notes that pyrazinamide is contraindicated in persons with severe 
hepatic damage, who have shown hypersensitivity to it, and with acute gout.  The most serious 
side effect is hepatotoxicity. Its frequency appears to be dose-related and thus liver function 
should be assessed before and regularly during treatment with pyrazinamide.  Hyperuricemia 
commonly occurs and is occasionally accompanied by arthralgia and may lead to attacks of gout. 
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Photosensitivity and skin rash have been reported less frequently. Other side effects that have 
been reported are anorexia, nausea and vomiting, malaise, fever, sideroblastic anaemia and 
dysuria.  
Pyrazinamide may decrease the efficacy of gout therapy (e.g. allopurinol, colchicine, probenecid 
or sulphinpyrazone) and dosage adjustments of these medications may be necessary.  For 
additional information on pyrazinamide, refer to the manufacturer’s package insert. [20] 
2.6 
Overall Benefit/Risk Assessment 
Some participants with pulmonary TB in this trial will be given a regimen of BPaMZ. These drugs 
individually and in combination are known to have anti-tuberculosis activity and is not expected 
to have an adverse impact on the ultimate cure of TB in these participants. Based on NC-005 and 
other regimens using each of the regimen drugs in different combinations there is good evidence 
that this may be a highly effective therapy for both DS-TB and DR-TB.  
For DS-TB the potential for a shorter regimen than 6 months is expected to be successful based 
on preclinical and clinical information as listed before.  Participants in this trial will have their TB 
infection carefully characterized, with drug sensitivity profiles established, and they will receive 
treatment with trial drugs that have demonstrated activity against MTB.   
Participants will receive individualized medical attention; this will allow a continuous monitoring of 
the health conditions of each participant, any of whom can be withdrawn at any stage of the trial 
and removed from trial treatment should his/her condition suggest to the Investigator that this 
would be in his/her best interest.  Multiple blood samples will be taken for safety laboratory 
studies, and ECGs will be taken at multiple time points.  
One concern, the combination of two agents with known QT-prolonging effects (bedaquiline and 
moxifloxacin), has been addressed specifically by carefully identifying and excluding participants 
with risk factors that might predispose them to cardiac arrhythmias, screening all participants for 
evidence of existing cardiac disease and monitoring all participants with ECGs throughout the 
trial.  
The trial drugs in the proposed regimens to be tested in this trial have all demonstrated safety 
and efficacy in the treatment of pulmonary tuberculosis in non-clinical and clinical studies. 
Specifically, the regimen B-Pa-Z was generally well-tolerated and demonstrated bactericidal 
activity in a 14-day EBA trial. The potential risks associated with the trial drugs and regimens has 
been identified as outlined below and will be monitored carefully throughout the conduct of the 
trial. 
The BPaMZ regimen is a novel regimen treatment expected to be effective, safe and well-
tolerated and might even shorten the current treatment duration for patients with TB. Based on 
data from previous trial evaluations of key monitoring and safety information as outlined before 
suggests a favourable benefit-to-risk ratio trials.  
Key Monitoring and Safety Information Regarding Regimen Agents 
2.6.1 
Bedaquiline (B) 
2.6.1.1 
Adverse Drug Reactions for bedaquiline  
Participants in the Any bedaquiline group compared to the Any Placebo group (difference > 5.0%) 
had headache (23.5% versus 11.4%, respectively), nausea (35.3% versus 25.7%, respectively), 
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arthralgia (29.4% versus 20.0%, respectively), and transaminases increased (6.9% versus 1.0%, 
respectively).and diarrhoea (11.4% versus 5.9%, respectively). 
2.6.1.2 
Cardiovascular safety 
During clinical studies with bedaquiline a prolongation of QTc interval was observed. An ECG 
should be obtained prior to and after initiation of therapy with bedaquiline to monitor the QTc 
interval. 
Bedaquiline treatment initiation is not recommended in patients with: 
• 
Heart failure 
• 
QTcF interval > 450 ms (confirmed by repeat electrocardiogram) 
• 
A personal or family history of congenital QT prolongation 
• 
Concomitant administration of fluoroquinolone antibiotics that have a greater potential for 
significant QT prolongation (i.e., gatifloxacin, moxifloxacin and sparfloxacin) 
• 
Hypokalemia 
Bedaquiline treatment must be discontinued if the patient develops clinically significant ventricular 
arrhythmia. An additive or synergistic effect on QT prolongation of bedaquiline when co-
administered with other medicinal products that prolong the QT interval cannot be excluded. 
Caution is recommended when using bedaquiline concomitantly with medicinal products with a 
known risk of QT prolongation. If co-administration of such medicinal products with bedaquiline is 
necessary, clinical monitoring including frequent ECG assessment is recommended. 
In the DR-TB treatment arm of the present trial, moxifloxacin will be co-administered with 
bedaquiline. This is to prevent the development of resistance to the other drugs in the regimen in 
case the participant’s strain of MTB is resistant to pyrazinamide. ECG assessments will be 
performed on all participants at screening, baseline, and at treatment visits specified in the flow 
chart.   
2.6.1.3 
Hepatic safety 
Increases in transaminases were seen in clinical studies during administration of bedaquiline with 
the background regimen. Participants should be monitored during treatment. 
Other hepatotoxic medicinal products and alcohol should be avoided while taking bedaquiline, 
especially in participants with diminished hepatic reserve. 
2.6.2 
Pretomanid (P) 
The most common side effects or AEs associated with pretomanid exposure include: 
• 
Headache 
• 
Benign, isolated and reversible elevations of serum creatinine 
• 
Stomach discomfort (nausea, vomiting, flatulence, and/or diarrhoea) 
• 
Skin and subcutaneous tissue disorders 
2.6.2.1 
Hepatic Safety 
Hepatic enzyme increases have been seen in participants treated with pretomanid in 
combinations with various other medications during the clinical development program. It is difficult 
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to assign specific causality to any one drug within a regimen; nonetheless, the NC-008 trial will 
include specific monitoring of hepatic enzymes. 
For additional information refer to  pretomanid IB.[15] 
2.6.3 
Moxifloxacin (M) 
In the usual daily doses of 400 mg/day, moxifloxacin is well tolerated.  As stated in the Package 
Insert[19]  the most frequent individual drug related AEs observed in clinical trials with 400 mg oral 
moxifloxacin therapy were nausea (7.5%) and diarrhoea (5.8%).  Fluoroquinolones, including 
moxifloxacin, are associated with an increased risk of tendinitis and tendon rupture in all ages.   
A known but rare side effect of fluoroquinolones, including moxifloxacin is exacerbation of 
myasthenia gravis. In addition, moxifloxacin has been shown to prolong the QT interval of the 
electrocardiogram in some participants.  It should be used with caution in participants being 
treated concomitantly with other drugs where an additive effect on the QT interval cannot be 
excluded.  
Serious and sometimes fatal hypersensitivity reactions, including anaphylactic reactions, as well 
as peripheral neuropathy may occur after the first or subsequent doses of moxifloxacin. For 
additional information, refer to the moxifloxacin package insert.[19] 
2.6.4 
Pyrazinamide (Z) 
The dose of pyrazinamide that will be used in this trial is an approved dosage for the treatment of 
TB. The most serious side-effect of pyrazinamide is hepatotoxicity and its frequency appears to 
be dose-related. Hyperuricemia commonly occurs, occasionally accompanied by arthralgia and 
may lead to attacks of gout.  Photosensitivity and skin rash have been reported less frequently.  
Other side-effects that have been reported are anorexia, nausea and vomiting, malaise, fever, 
sideroblastic anaemia and dysuria.  Pyrazinamide may decrease the efficacy of gout therapy (e.g. 
allopurinol, colchicine, probenecid or sulphinpyrazone) and dosage adjustments of these 
medications may be necessary.  For additional information on pyrazinamide, refer to the 
manufacturer’s package insert.[20] 
2.6.5 
HRZE/HR Control 
The HRZE (isoniazid 75 mg plus rifampicin 150 mg plus pyrazinamide 400 mg plus ethambutol 
275 mg combination tablets) combination will be given the first 8 weeks and the HR (isoniazid 75 
mg plus rifampicin 150 mg combination tablets) combination will be given from Weeks 9 to 26. 
Participants with DS-TB that are randomized to the HRZE/HR control arm in this trial will be 
given standard weight-adjusted doses of HRZE.   
Please see the HRZE and HR Package Inserts[22, 40] for known and potential risks and benefits. 
3.0 
Trial Objectives 
3.1 
Primary Endpoint 
To evaluate the time to culture negativity over 8 weeks from the start of the treatment regimens 
in participants with: 
• 
Drug Sensitive TB (DS-TB) 
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• 
Drug Resistant TB (DR-TB)  
 
DR-TB are defined as participants with: 
1. mono-resistance to rifampicin or isoniazid, OR 
2. resistance to both rifampicin and isoniazid (DR-TB) 
 
3.2 
Secondary Endpoints 
Efficacy: 
 
• 
Incidence of bacteriologic failure or relapse or clinical failure at 52 weeks (12 months) and 104 
weeks (or 24 months) weeks from the start of therapy.  
• 
Proportion of participants with sputum culture conversion to negative status in liquid culture 
(MGIT) at 4, 6, 12 and 17 weeks to be explored as a potential biomarker of outcome at 52 
weeks from start of therapy. 
• 
Change from baseline in weight. 
• 
Change from baseline in TB symptoms. 
• 
Change from baseline in Participant Reported Health Status. 
 
Safety and Tolerability: 
 
• 
Incidence of Treatment Emergent Adverse Events (TEAEs) presented by incidence, severity, 
drug relatedness, seriousness, leading to early withdrawal, and leading to death.  
 
Quantitative and qualitative clinical safety laboratory measurements, including observed 
and change from baseline. 
 
Quantitative and qualitative ECG results (heart rate, RR interval, PR interval, QRS 
interval, QT interval and QTc interval), including observed. QT/QTc intervals, change 
from baseline, will be categorized as these will be centrally read. 
• 
Changes in male reproductive hormones 
• 
Changes in lens opacities. 
 
These data will be presented as descriptive analyses, and no inferential tests will be carried out. 
Pharmacokinetics (PK) and Pharmacokinetics/Pharmacodynamics (PK/PD): 
 
Plasma concentrations from sparse sampling will be used to update existing population PK 
models and derive exposure metrics (e.g., minimum plasma concentration [Cmin], maximum 
plasma concentration [Cmax], area under curve over a dosing interval [AUC]) for bedaquiline and 
its M2 metabolite, pretomanid, moxifloxacin, and pyrazinamide. Effects of baseline covariates 
on exposure will be assessed; so too, will the effects of concomitant medications, including 
antiretroviral therapy (ART), where feasible.  
 
Data from other trials may be included to enhance the model-based analysis. Relationships will 
be explored between drug exposure and efficacy and safety endpoints. These exploratory 
PK/PD analyses may include HIV status as a covariate. 
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3.3 
Exploratory Objectives 
• 
Evaluate whether any of the secondary endpoints predicts relapse free cure. 
• 
Subgroup analysis of populations by HIV status.  
4.0 
Trial Design 
4.1 
Summary of Trial Design 
This is a Phase 2c, multi-centre, open-label, partially randomized clinical trial conducted in 3 
treatment groups.  Participants, trial Investigators and staff, including laboratory staff, will not be 
blinded to treatment randomisation and allocation during the treatment phase of the trial. 
The trial will be performed globally at multiple centres located throughout the world.    
A total of 300 DS-TB participants (150 per treatment arm) will be randomized and stratified for co-
infection with HIV and cavitation, with a target of 50% of the participants being HIV positive.  Up 
to 150 DR-TB participants will be enrolled and assigned to the treatment arm described in Table 
4 below.   
Refer to Section 3.0 Trial Objectives above and Section 9.3 Interim Analysis for details of the 
planned interim analysis and potential updates to the trial objectives and sample size. 
 
Participants with Drug Sensitive TB (DS-TB): 
 
Participants with DS-TB will be randomized to one of two treatment arms. These participants will 
receive either BPaMZ daily for 17 Weeks, or HRZE/HR combination tablets daily for 26 Weeks.  
Participants will be stratified for co-infection with human immunodeficiency virus (HIV) and 
cavitation. 
 
Participants with Drug Resistant TB (DR-TB): 
 
Participants with DR-TB will be assigned to receive BPaMZ daily for 26 weeks (6 months). 
Eligible participants who meet all the inclusion criteria and none of the exclusion criteria, aged 18 
and over, male or female will be assigned to one of the 3 treatment groups with a target of 50% 
of the participants being HIV positive.  
 
DR participants will be treated with 6 months of BPaMZ.  DS participants will be randomised using 
an interactive web response system (IWRS) stratifying for cavitation and HIV status to allocate 
participants evenly across the arms after they have given written, informed consent during the 
Screening visit (Days -9 to -1). 
4.2 
Treatment Plan: Schedule of Assessments 
• 
Screening Period (Day -9 to Day -1) 
• 
Treatment Period (Day 1 to Week 17 / Week 26) 
• 
Follow-Up Period (Week 39 to Week 104) 
Refer to: 
• 
Synopsis Flow Chart and Procedures (Section 1.2) for the timing of all procedures and 
laboratory samples to done at each visit.   
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• 
Trial Procedures (Section 7.0 Trial Variables and Procedures) for details regarding specific 
procedures or laboratory tests. 
Each participant will receive up to 26 weeks of treatment.  The trial IMP regimens may require 
interruptions/pauses due to toxicities. All dose interruptions/pauses should be discussed with the 
Sponsor’s Medical Monitor prior to implementation unless an interruption/pause is required 
urgently for a safety concern.  
 
All participants will enter post-treatment follow-up which continues until Week 104 after start of 
treatment / randomisation. 
 
Participants will receive daily dosing, orally. They will be randomized to one of the following arms: 
Table 4: Treatment Groups 
 
Treatment Group 
Treatment 
Duration 
No of 
Participants 
1 Bedaquiline 200 mg daily for 8 weeks  
then 100 mg daily for 9 weeks, together with pretomanid 
200 mg + moxifloxacin 400 mg + pyrazinamide 1500 mg 
daily 
17 weeks 
(4 months) 
150 DS-TB 
2 HRZE Tablets (Weeks 1-8): (isoniazid 75 mg plus 
rifampicin 150 mg plus pyrazinamide 400 mg plus 
ethambutol 275 mg combination tablets).  
 
Followed by, 
 
HR Tablets (Weeks 9-26): (isoniazid 75 mg plus 
rifampicin 150 mg combination tablets).   
First 8 weeks  
(2 months) 
 
 
then 
 
17 weeks  
(4 months) 
 
Total 6 months 
150 DS-TB 
3 Bedaquiline 200 mg daily for 8 weeks  
then 100 mg daily for 18 weeks, together with 
pretomanid 200 mg + moxifloxacin 400 mg + 
pyrazinamide 1500 mg daily. 
26 weeks 
(6 months) 
Up to 150 
DR-TB 
 
5.0 
Trial Population 
The participant must meet all inclusion and no exclusion criteria within the screening period.  
Retesting for any laboratory or ECG parameters is allowed within the screening period.  Sponsor 
may consider replacement of late exclusions. 
5.1 
Inclusion Criteria 
Participants are required to meet all the following inclusion criteria during the screening period to 
be randomized. 
1. Signed written consent prior to undertaking any trial-related procedures. 
2. Male or female, aged 18 years or over. 
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3. Body weight (in light clothing and no shoes) ≥ 30 kg. 
4. Sputum positive for tubercule bacilli (at least 1+ on the International Union Against 
Tuberculosis and Lung Disease [IUATLD]/WHO scale (Appendix 1) on smear microscopy) at 
the trial laboratory. 
5. Disease Characteristics - Participants with one of the following pulmonary TB conditions: 
 
DS-TB treatment arm participants should be: 
a. sensitive to rifampicin, isoniazid and fluoroquinolones by rapid sputum-based test 
AND 
b. either newly diagnosed for TB or have a history of being untreated for at least 3 
years after cure from a previous episode of TB. 
DR-TB treatment arm participants should be: 
a. Resistant to rifampicin and/or isoniazid; but sensitive to fluoroquinolones by rapid 
sputum-based test AND  
b. Should not have had previous treatment for DR-TB/MDR-TB, although may have 
been on a DR-TB/MDR-TB treatment regimen for no longer than 3 days at start of 
screening. 
c. Participants with resistance to injectables by rapid sputum-based test are allowed 
in the trial. 
When Phenotypic DST and whole genome sequencing (WGS) results on baseline 
samples become available, any results that are discordant with the screening molecular 
test results used to qualify a participant’s eligibility for the trial will be reviewed by the 
Sponsor Medical Monitor in consultation with the Investigator to determine whether that 
participant is unlikely to respond to treatment and should therefore be removed from the 
trial and given alternative treatment.  If a participant is removed from the trial for such a 
reason, they will be classified as a late exclusion. 
6. A chest x-ray, within 6 months prior to or during the Screening visit, which in the opinion of 
the Investigator is compatible with pulmonary TB.  
7. Contraception: 
Be of non-childbearing potential or using effective methods of birth control, as defined below: 
Non-childbearing potential: 
a. Participant - not heterosexually active or practice sexual abstinence; or  
b. Female participant or male participants female sexual partner - bilateral 
oophorectomy, 
bilateral 
tubal 
ligation 
and/or 
hysterectomy 
or has 
been 
postmenopausal with a history of no menses for at least 12 consecutive months; or  
c. Male participant or female participants male sexual partner - vasectomised or has had 
a bilateral orchidectomy at least three months prior to screening; 
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Effective birth control methods: 
a. Double barrier method which can include a male condom, diaphragm, cervical cap, or 
female condom; or  
b. Female participant: Barrier method combined with hormone-based contraceptives or 
an intra-uterine device.  
c. Male participants’ female sexual partner: Barrier method combined with hormone-
based contraceptives or an intra-uterine device.  
Both male and female participants must be willing to continue practicing birth control 
methods and are not planning to conceive throughout treatment and for 6 months after 
the last dose of trial IMP or discontinuation from trial IMP in case of premature 
discontinuation.  
Note: Hormone-based contraception alone may not be reliable when taking IMP; therefore, 
hormone-based contraceptives alone cannot be used by female participants to prevent 
pregnancy. 
 
5.2 
Exclusion Criteria 
Participants will be excluded from participation if they meet any of the following criteria: 
Medical History and Concurrent Conditions: 
1. Any non-TB related condition where participation in the trial, as judged by the Investigator, 
could compromise the well-being of the participant or prevent, limit or confound protocol 
specified assessments. 
2. Abuse of alcohol or illegal drugs that in the opinion of the Investigator would compromise 
the participants’ safety or ability to follow through with all protocol-specified restrictions, 
visits and evaluations. 
3. Historical and or current use of local traditional medications/herbs which in the opinion of 
the Investigator would compromise the participants’ safety or ability to follow through with 
all protocol-specified restrictions, visits and evaluations. 
4. Being, or about to be, treated for malaria. 
5. Is critically ill and, in the judgment of the Investigator, has a diagnosis likely to result in 
death during the trial or the follow-up period. 
6. TB meningitis or other forms of extrapulmonary tuberculosis with high risk of a poor 
outcome, or likely to require a longer course of therapy (such as TB of the bone or joint), 
as judged by the Investigator. 
7. History of allergy or hypersensitivity to any of the trial IMP or related substances, including 
known allergy to any fluoroquinolone antibiotic, history of tendinopathy associated with 
quinolones or suspected hypersensitivity to any rifampicin antibiotics. 
8. For HIV infected participants any of the following: 
 
a. CD4+ count <100 cells/µL  
b. Karnofsky score <60% (Appendix 5)   
c. Received intravenous antifungal medication within the last 90 days 
d. WHO Clinical Stage 4 HIV disease (Appendix 3) 
 
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9. Participants who recently started or expected to need to start ART within 1 month after 
randomization. Participants who have been on ARTs for more than 30 days prior to start 
of the Screening visit or expected to start ART greater than 30 days after randomization 
may be included.  
10. Having participated in other clinical trials with investigational agents within 8 weeks prior 
to start of trial IMP or currently enrolled in an investigational trial. 
11. Participants with any of the following at the Screening visit (per measurements and 
reading done by ECG): 
 
a. QTcF interval on ECG >500 msec.  Participants with QTcF > 450 must be 
discussed with the Sponsor Medical Monitor before enrolment. 
b. Heart failure 
c. A personal or family history of congenital QT prolongation 
d. A history of or known, untreated, ongoing hypothyroidism 
e. A history of or ongoing bradyarrhythmia 
f. 
A history of Torsade de Pointe 
 
12. Unstable Diabetes Mellitus which required hospitalization for hyper- or hypo-glycaemia 
within the past year prior to start of screening. 
13. Females who have a positive pregnancy test at the Screening visit or already known to be 
pregnant, breast-feeding, or planning to conceive a child during the trial or within 6 months 
of stopping treatment.  Males planning to conceive a child during the trial or within 6 
months of stopping treatment. 
Previous and Concomitant Therapy 
14. Previous treatment for TB: 
 
• 
For DS-TB participants: Previous treatment for tuberculosis within 3 years prior to the 
Screening visit. Participants who have previously received isoniazid prophylactically 
may be included in the trial if that treatment is/was discontinued at least 7 days at the 
start of the Screening visit. 
• 
For the DR-TB participants: Previous treatment for DR-TB/MDR-TB, although may 
have been on a DR-TB/MDR-TB treatment regimen for no longer than 3 days at the 
start of the Screening visit. 
 
15. Any diseases or conditions in which the use of the standard TB drugs or any of their 
components is contra-indicated, including but not limited to drug allergy. 
16. Use of any drug within 30 days prior to randomisation known to prolong QTc interval 
(including, but not limited to, amiodarone, amitriptyline, bepridil, chloroquine, 
chlorpromazine, cisapride, clarithromycin, disopyramide dofetilide, domperidone, 
droperidol, erythromycin, halofantrine, haloperidol, ibutilide, levomethadyl, mesoridazine, 
methadone, pentamidine, pimozide, procainamide, quinacrine, quinidine, sotalol, 
sparfloxacin, thioridazine). 
17. Use of systemic glucocorticoids within one year of the start of the Screening visit (topical, 
inhaled or intranasal glucocorticoids are allowed), as they can lead to visual opacities or 
cataracts. 
18. For HIV infected participants: 
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a. The following antiretroviral therapy (ART) should not be used with either (BPaMZ 
and HRZE/HR) trial regimen: 
 
1. Stavudine  
2. Didanosine  
3. Triple NRTI regimen is not considered optimal for HIV treatment (poor 
efficacy) 
 
b. In the case where participants are randomized to HRZE arm, rilpivirine and 
etravirine cannot be given with rifampicin due to drug-drug interactions. A 
standard NRTI backbone may be used in combination with one of the following: 
 
1. Efavirenz requires no dose adjustment  
2. Dolutegravir dose adjustment is required – double dose when co-
prescribed with rifampicin. 
3. Raltegravir requires no dose adjustment 
4. Lopinavir/r dose adjustment is required – double dose when co-
prescribed with rifampicin 
5. Nevirapine requires no dose adjustment, however, please note that 
nevirapine based regimens are associated with higher ART failure in 
participants having or known to have a previous viral load more than or 
equal to 100,000/ mL 
 
c. In the case where participants are randomized to the BPaMZ trial regimen, a 
standard NRTI backbone may be combined with the following:  
 
1. Rilpivirine 
2. Dolutegravir  
3. Raltegravir 
4. Nevirapine  
5. Lopinavir/r  
6. Participants who are on efavirenz, atazanavir/r or darunavir/r at the time 
of screening and have an undetectable viral load, should have their ART 
switched to one of the agents listed above (1-5). It would be preferable to 
switch to another permissible ARV within the same class accompanied by 
the same nucleoside backbone. 
 
d. ART regimen choice should be discussed with the Sponsor Medical Monitors if 
there are any concerns. 
 
Confirmed plans to use Isoniazid prophylaxis for HIV positive participants during the 
treatment and follow up period is not permitted. 
Diagnostic and Laboratory Abnormalities 
19. Participants with the following toxicities at screening as defined by the enhanced Division 
of Microbiology and Infectious Disease (DMID) adult toxicity table (Draft November 2007) 
(Appendix 2) where applicable: 
 
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a. platelets <75,000/mm3 
b. creatinine >1.5 times upper limit of normal (ULN)  
c. eGFR ≤ 60 mL/min 
d. haemoglobin <8.0 g/dL 
e. serum potassium less than the lower limit of normal for the laboratory. This may 
be repeated once 
f. GGT: greater than 3 x ULN 
g. AST: 
• 
≥3.0 x ULN to be excluded; 
• 
results between 1.5 x ULN and 3 x ULN must be discussed with and 
approved by the Sponsor Medical Monitor 
h. ALT: 
• 
≥3.0 x ULN to be excluded 
• 
greater than ULN must be discussed with and approved by the Sponsor 
Medical Monitor 
i. 
 ALP: 
• 
≥3.0 x ULN to be excluded 
• 
2.0 – <3.0 x ULN must be discussed with and approved by the Sponsor 
Medical Monitor 
j. 
Total bilirubin: 
• 
>1.5 x ULN to be excluded; 
• 
greater than 1 – 1.5 x ULN must be discussed with and approved by the 
Sponsor Medical Monitor 
k. Direct bilirubin: 
• 
greater than 1x ULN to be excluded 
All the inclusion and none of the exclusion criteria must be met. If no single variable/value is 
outside of the ranges of acceptability, but when multiple values are close to the limits and/or 
whenever the Investigator has reason to suspect that there might be a health problem (other than 
TB), enrolment should only be considered after discussing the case with the Sponsor Medical 
Monitor. 
 No protocol waivers will be granted by the TB Alliance. 
 
5.3 
Restrictions 
Concomitant medications should be kept to a minimum during the trial. However, if concomitant 
medications are necessary for the participant’s welfare, they may be given at the discretion of the 
Investigator. For any concomitant medications given as a treatment for a new condition or a 
worsening of an existing condition occurring after signing of the informed consent form, the 
condition must be documented on the Adverse Event pages of the electronic Case Report Form 
(eCRF). 
The prescribing information for all concomitant medication should be reviewed carefully. The 
determinations listed in the respective contraindicated, warning, and precaution sections must be 
respected to prevent any potentially serious and/or life-threatening drug interactions. 
The following recommendations should be followed with regards to concomitant medication to 
avoid possible drug interaction with the IMP: 
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Participants on a moxifloxacin containing treatment arm: The IMP should be taken either 
4 hours before or 8 hours after taking the following products: 
• 
An antacid, multivitamin, or other product that has magnesium, aluminium, iron or zinc 
• 
Sucralfate 
• 
Didanosine 
Participants on the HRZE/HR treatment arm: 
• 
Any aluminium-containing antacids should be taken at least one hour after the IMP 
dose. 
The following medicinal products are prohibited from the Screening visit and during the treatment 
period: 
• 
Quinolone antimalarial (e.g., chloroquine and quinacrine). Participants who have 
malaria at screening are to be excluded. However, if a participant develops malaria 
during the trial, the Investigator is advised to consult the Malaria Treatment Guidance 
document regarding the interaction between moxifloxacin and bedaquiline with anti-
malarial drugs. Investigators may also contact the Sponsor Medical Monitor for further 
guidance. 
• 
Chronic systemic glucocorticoids (topical, inhaled or intranasal glucocorticoids are 
allowed) due to their potential to cause visual opacities. Short term systemic 
glucocorticoids are allowed for emergency situations (e.g. for treatment of pulmonary 
exacerbation when inhaled glucocorticoids is inadequate). 
• 
Medicinal products used to treat pulmonary TB: including but not limited to gatifloxacin, 
amikacin, cycloserine, rifabutin, kanamycin, para-aminosalicylic acid, rifapentine, 
thioacetazone, capreomycin, other quinolones, thioamides, and metronidazole. 
The following medicinal products should be avoided from Day 1 (Baseline visit) and during the 
treatment period as much as possible (unless this is required for emergency management of the 
participant). Investigators may also contact the Sponsor Medical Monitor for further guidance. 
• 
Any drug known to prolong QTc interval (including but not limited to amiodarone, 
bepridil, chloroquine, chlorpromazine, cisapride, clarithromycin, disopyramide 
dofetilide, domperidone, droperidol, erythromycin, halofantrine, haloperidol, ibutilide, 
levomethadyl, mesoridazine, methadone, pentamidine, pimozide, procainamide, 
quinidine, sotalol, sparfloxacin, thioridazine). The exception is moxifloxacin and 
bedaquiline administered as part of the trial IMP, with ECG monitoring, to help ensure 
participant safety. 
• 
Any 
drug 
known 
to 
be 
hepatotoxic 
(including 
but 
not 
limited 
to 
acetaminophen/paracetamol, acetazolamide, allopurinol, amiodarone, amitriptyline, 
amoxicillin, amprenavir, atorvastatin, augmentin/co-amoxiclav, azathioprine, baclofen, 
bumetanide, captopril, carbamazepine, celecoxib, chlorpromazine, chlorpromazine, 
clindamycin, 
clopidogrel, 
co-trimoxazole, 
darunavir, 
delavirdine, 
diclofenac, 
doxycycline, enalapril, fluconazole, fluoxetine, fosamprenavir, furosemide, gliclazide, 
glimeperide, glipizide, ibuprofen, irbesartan, ketoconazole, lisinopril, loperamide, 
losartan, methotrexate, metolazone, mirtazepine, nitrofurantoin, omeprazole, other 
non-steroidal anti-inflammatory drugs, paroxetine, phenobarbital, phenothiazines, 
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phenytoin, pravastatin, probenecid, prochlorperazine, risperidone, rosuvastatin, 
sertraline, simeprevir, simvastatin, sodium valproate, sotalol, sulfasalazine, 
sumatriptan, tamsulosin, terbinafine, tetracycline, theophyllin/uniphyllin, tipranavir, 
tolazamide, 
tolbutamide, 
topiramate, 
trazodone, 
tricyclic 
antidepressants, 
trimethoprim, verapamil).  
5.4 
Treatment Discontinuation and/or Early Withdrawal  
Any participant for whom the Investigator decides to temporarily discontinue their IMP is to be 
discussed with the Sponsor Medical Monitor and, if applicable, be restarted on IMP as soon as 
possible.  
A participant must be prematurely withdrawn from the trial (during the trial treatment or follow-up 
periods) because of the following: 
• 
Withdrawal of informed consent 
• 
Investigator considers that for safety reasons it is in the best interest of the participant that 
he/she be withdrawn, including a concern that the participant has symptomatic TB and/or 
bacteriological failure/relapse and requires a change in TB treatment 
• 
Pregnancy 
• 
At the specific request of the Sponsor or termination of the trial by the Sponsor 
• 
Lost to follow-up 
• 
When Phenotypic DST and whole genome sequencing (WGS) results on baseline 
samples become available, any results that are discordant with the screening molecular 
test results used to qualify a participant’s eligibility for the trial will be reviewed by the 
Sponsor Medical Monitor in consultation with the Investigator to determine whether that 
participant is unlikely to respond to treatment and should therefore be removed from the 
trial and given alternative treatment.  If a participant is removed from the trial for such a 
reason, they will be classified as a late exclusion. 
A participant may withdraw from the trial at any time at his/her request (withdrawal of consent) or 
may be withdrawn at any time at the discretion of the Investigator for safety, behavioural, 
compliance or administrative issues.  
When a participant withdraws consent from the trial, no additional follow-up visits will be 
performed. 
Participants who withdraw from the trial after having received IMP will not be replaced.  
All participants withdrawn from trial and who received at least one dose of IMP will be requested 
to return for an Early Withdrawal visit and the applicable safety Follow-Up visits, as per the 
Synopsis Flow Chart and Procedures (Section 1.2 footnote c), as well as Table 5. 
5.4.1 
Early Withdrawal 
In case of early withdrawal during the treatment or follow-up period, all efforts shall be made to 
complete the Early Withdrawal assessments.  At the Early Withdrawal visit the following 
information will be collected and procedures performed: 
• 
Sputum sample collection x 2 (one EMS brought from home and one spot at the research 
site under the coaching and observation of the trial staff).  If no EMS was provided by the 
participant, 2 spot samples may be collected at the site, at least 30 minutes apart. 
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• 
Urine pregnancy test (women of child bearing potential, whether they are sexually active or 
not) 
• 
Laboratory safety sampling (including male reproductive hormone tests); 
• 
Single 12-lead ECG 
• 
TB Symptoms Profile 
• 
Patient Reported Health Status Questionnaire 
• 
Vital signs 
• 
Full physical examination, including weight 
• 
Ophthalmology examination, if required as described in Table 5 
• 
IMP compliance check (if participant on IMP) 
• 
Concomitant medications 
• 
Adverse events 
Once a participant has been withdrawn early from the trial, they will be requested to attend follow-
up visits as described in Table 5: 
Table 5: Follow-up Visits Required for Early Withdrawal Participants 
Treatment 
Duration at 
EWD visit 
Ophthalmology 
Examination at 
EWDa 
Ophthalmology 
Examination  
 
Visit 3 months 
after EWD Visita 
Week 52  
(Month12) 
Follow-up 
Visit 
Week 104 
(Month 24) 
Follow-up 
Visit 
≤ 14 days 
Not required 
Not required 
Required 
Required 
15 days to      ≤ 
12 weeks 
Not required 
Required 
Required 
Required 
> 12 weeks  
Required 
Required 
Required, if not 
already 
performed 
Required 
a. If an additional visit is required for an ophthalmology examination after EWD, only the 
ophthalmology examination will be performed at this visit, and it will occur 3 months after the 
EWD visit date. 
The Weeks 52 and 104 visits will be performed to collect SAE information (including verification 
of survival) and participant reported TB outcome information.  This visit may be telephonic, a 
home or a site visit at Weeks 52) and/or Week 104 after the participants’ start of treatment date. 
5.4.2 
Unscheduled Visits 
Any visit which is conducted in addition to those required by the Synopsis Flow Chart and 
Procedures (Section 1.2), should be considered unscheduled regardless of the reason for the 
visit. The assessments which are undertaken as part of an Unscheduled visit should be as 
clinically indicated.  
The following situation/s require an unscheduled visit/s: 
• 
For any medical reason, as determined by the Investigator or participant. 
• 
If both sputum samples (EMS and spot) at Week 8 or later are contaminated, the 
participant should return for an unscheduled visit/s to give additional sputum samples or 
to document that the participant is not able to produce sputum.  
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• 
If after having converted to culture negative, the participant has a MTB confirmed 
positive culture at or after the last visit of the treatment period (Week 17 or Week 26), 
the participant should return for unscheduled visit/s to provide additional sputum 
samples, at a minimum of 7 days apart, or to document that the participant is not able to 
produce a sputum sample. 
Determination of the participant’s primary outcome status requires sputum culture results at the 
following time-points during the trial: 
o End of Follow-up Period (Week 52 and 104) 
o Early Withdrawal, if applicable 
At least one of the following criteria should be met at these time-points to confirm a participant’s 
primary outcome status: 
o two sequential negative sputum culture results; or  
o two sequential positive sputum culture results; or  
o has been unable to produce sputum after documentation of two negative sputum 
cultures with no intervening positive and the participant is clinically asymptomatic 
Should the participant’s primary outcome not meet any of the above criteria, the Investigator 
should continue to recall the participant for an Unscheduled visit to collect sputum samples until 
the criteria is met and the primary outcome can be determined. 
Additional sputum samples: Two samples at each visit – ideally, one EMS and one spot sputum 
sample at the research site under the coaching and observation of the trial staff). If no EMS was 
provided by the participant, 2 spot sputum samples may be collected on site, at least 30 minutes 
apart. Additional sputum samples should be collected at least 7 days after the previous sample. 
Table 6: Summary of Scenarios Requiring Unscheduled Visits for 
Mycobacteriology Testing 
Time-point 
Scenario 
Unscheduled 
Visit/s 
Required? 
Comment 
Week 8 or later 
Both sputum cultures are 
contaminated 
Yes 
Provide additional samples 
until a positive or negative 
result is reported, or it is 
confirmed that the participant 
is unable to produce sputum 
At or after the last 
treatment visit 
(Week 17 or Week 
26) 
Previously converted to 
culture negative but now 
has an MTB-positive 
culture 
Yes 
Provide additional samples at 
least 7 days after the 
previous sample until the 
result is confirmed, or it is 
confirmed that the participant 
is unable to produce sputum.  
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End of Follow-up 
Period (Week 52 
and 104)  
Early 
Withdrawal, if 
applicable 
Participant’s primary 
outcome status cannot be 
confirmed by: 
Two sequential negative 
sputum culture results; or   
two sequential positive 
sputum culture results; 
or has been unable to 
produce sputum after 
documentation of two 
negative sputum cultures 
with no intervening positive 
and are clinically 
asymptomatic 
Yes 
Provide additional samples at 
least 7 days after the 
previous sample until one of 
the criteria is met and the 
primary outcome status can 
be determined.  
 
If the Investigator is unsure of the outcome in any of the above scenarios, the Investigator should 
contact the Sponsor Medical Monitor to discuss and agree on how the participant is to be 
managed. 
5.4.3 
Lost-to-Follow-up 
Every reasonable attempt must be made to minimise Lost-to-Follow-up (LTFU) participants.  A 
minimum of three contact attempts (telephonic/home visit) will be made for participants who do 
not arrive for their scheduled trial visits. If these attempts are unsuccessful the participant will be 
considered LTFU.  All attempts to contact the participant must be clearly documented in the 
participant’s source documents. 
5.4.4 
Early Withdrawal due to TB 
Ultimately it is the Investigator’s decision whether a participant requires early withdrawal from the 
trial due to a concern that the participant has symptomatic worsening of TB and/or bacteriological 
failure/relapse.  
Early withdrawal is usually not indicated for a single positive culture.  Should a participant have a 
single positive culture result after being culture negative, the Investigator is to evaluate whether 
the participant has signs and symptoms suggestive of active inadequately treated TB and whether 
it is in the participants best interest that he/she be withdrawn. Prior to early withdrawal of a 
participant due to TB, the Investigator must discuss the participant with the Sponsor Medical 
Monitor, unless the Investigator cannot contact the Sponsor Medical Monitor and considers that 
early withdrawal must occur immediately due to immediate safety concerns with respect to the 
participant. 
If the Investigator decides to withdraw a participant due to TB, additional sputum samples may 
need to be collected to ensure the participant’s outcome status as determined in Section 5.5. 
All early withdrawn participants who are confirmed sputum positive (two sequential sputum 
positive cultures) and/or have symptomatic TB will require further TB treatment. These 
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participants will be referred to their applicable DS/DR local community TB clinics for standard anti-
tuberculosis chemotherapy according to National TB Treatment Guidelines.  
The participant will be provided with a referral letter from the Investigator to take with them to their 
National Treatment Program (NTP) clinic and the referral letter, at a minimum, should include all 
treatment received by the participant and information about any suspected/confirmed adverse 
event/reaction related to any of the trial IMP’s and or concomitant medications.  A follow-up call 
should be made by the trial site staff to the clinic to ensure the participant attended the NTP clinic.  
5.5 
Participant Progress Definitions  
Table 7: Participant Progress Definitions 
Status 
Treatment 
Follow-Up 
Screen Failure 
Participants from whom informed consent is obtained and is 
documented in writing (i.e., participant signs an informed consent form) 
but who are not randomized 
Completed 
Treatment / 
Completed 
Follow-Up* 
Participants who complete 
the full course of IMP 
Participants who complete all follow-up 
visits 
Completed 
Treatment / 
Discontinued 
Follow-Up 
Participants who complete 
the full course of IMP 
Participants who do not complete all 
applicable follow-up visits, regardless of 
the reason (excluding LTFU) 
Completed 
Treatment / Lost 
to Follow-Up 
Participants who complete 
the full course of IMP 
Participants who are unable to be 
contacted on or before their final visit 
Discontinued 
Treatment / 
Completed FU 
Participants who discontinue 
IMP prior to completion of 
the protocol-defined 
treatment course 
Participants who complete all applicable 
follow-up visits 
Discontinued 
Treatment / 
Discontinued 
Follow-Up** 
Participants who discontinue 
IMP prior to completion of 
the protocol-defined 
treatment course 
Participants who do not complete all 
applicable follow-up visits, regardless of 
the reason (excluding LTFU) 
Lost to Follow-Up 
Participants who are unable to be contacted on or before their final 
treatment visit and it cannot be confirmed whether treatment was 
completed 
* 
Note that this includes treatment failures who complete all applicable follow-up visits 
** 
Early Withdrawal 
5.6 
Trial Stopping Rules 
There are no trial specific stopping rules.  
The trial or parts of the trial can be stopped by the Sponsor on advice from the Data Safety and 
Monitoring Committee (DSMC) after their review of applicable trial data.  In addition, the Sponsor 
has the right to stop the trial or a specific trial site at any time, although this should only occur 
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after consultation between the involved parties.  Should this occur, the local and central Ethics 
Committee/Institutional Review Board (EC/IRB) and Regulatory Authorities will be informed.   
Should a trial site be closed prematurely, all trial materials (except source documentation that 
must remain at the site) will be returned to the Sponsor or applicable vendor.   The Investigator 
will retain all other documents until notification given by the Sponsor for destruction.  Participants 
currently on trial IMP will receive an appropriate regimen and all participants will be referred to 
their applicable DS-TB/DR-TB NTP clinic. 
6.0 
Treatment 
6.1 
IMP Administration  
6.1.1 
Instructions for Dosing of Test Regimen (BPaMZ) 
• 
Treatment will be orally administered once daily, to be taken during breakfast, with a full 
glass of water (approximately 240 ml), for 17 weeks (4 months) or 26 weeks (6 months). 
 
6.1.2 
Instructions for Dosing Control Treatment Regimen (HRZE/HR) 
• 
To be taken with a glass of water (approximately 240 ml). 
• 
HRZE or HR should not be taken with a meal (generally, no closer to meals than 1 hour 
before or 2 hours after a meal) in the following dosing schemes. 
HRZE/HR treatment will be administered orally once daily to DS-TB participants as follows: 
Weight Band 
Weight Range 
Number of tablets 
per weight band 
1 
30-39 kg 
2 
2 
40-54 kg 
3 
3 
55-70 kg 
4 
4 
≥ 71 kg 
5 
 
The participant’s weight at the Screening (HRZE) and Week 8 (HR) visits will be used to determine 
which weight band and dose to administer. 
 
A daily supplement of Vitamin B6 will be provided by the trial site to participants randomised to 
the HRZE/HR treatment arm, per each country’s National TB Treatment Guideline.   
6.2 
Participant Compliance 
During site clinic visits, the IMP will be administered by the Investigator(s)/designated site 
personnel and when possible, the check for IMP compliance via the hand-and-mouth procedure 
(both the hand and the mouth of the participant will be checked to ensure that the participant has 
swallowed the IMP). During the trial, sites will be responsible for ensuring participants are taking 
IMP correctly and are fully trained on how the IMP is to be taken, as well as to check the IMP 
cards for unused tablets in the containers at each visit during the treatment phase.  
6.3 
Treatment Modification(s) 
The importance of adherence to the treatment schedule will be reinforced at each visit.  Non-
adherence should prompt the Investigator to identify and address the cause(s) (e.g. side effects).  
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Participants that do not take: 
 
• 
Up to 7 consecutive doses of IMP doses: restart IMP, no extension of IMP required. 
• 
If more than 7 to ≤ 35 consecutive doses of IMP: restart IMP and extend the IMP 
treatment by the number of consecutive doses missed. The final treatment visit should 
also be pushed out to the date of last dose. It is not necessary to have an unscheduled 
visit at the time when the end of treatment visit would have been.   
• 
If more than 35 consecutive doses of IMP, discontinue IMP and withdraw participant 
from the trial. 
• 
If the participant misses a total (sum) of 56 cumulative missed doses, discontinue the 
IMP and withdraw the participant from the trial. 
• 
If more than 7 to ≤ 35 consecutive doses are missed, these must be made up with the 
same treatment combination or dose that was missed.  
Any participant for whom the trial IMP is discontinued (including for non-adherence) will be 
discussed with the Sponsor Medical Monitor and, if applicable, the participant will be restarted on 
trial IMP as soon as possible.  
6.4 
IMP Packaging and Labelling 
The complete formulations of the IMP, bedaquiline and pretomanid, are found in the respective 
Investigator Brochures.[8, 15] The complete formulations of moxifloxacin, pyrazinamide, HRZE/HR 
are found in the Package Inserts.[19, 20, 22, 40]  
The IMP will be packaged in weekly or bi-weekly cards as follows: 
Week 1 to 8 Cards: Dispensed Weekly 
IMP 
Strength 
Number of tablets 
Abbreviation 
Bedaquiline 
100 mg 
14 
B 
Pretomanid 
200 mg 
7 
Pa 
Moxifloxacin 
400 mg 
7 
M 
Pyrazinamide 
500 mg 
21 
Z 
 
Week 9 to 17/26 Cards: Dispensed Weekly 
IMP 
Strength 
Number of tablets 
Abbreviation 
Bedaquiline 
100 mg 
7 
B 
Pretomanid 
200 mg 
7 
Pa 
Moxifloxacin 
400 mg 
7 
M 
Pyrazinamide 
500 mg 
21 
Z 
 
Control (HRZE/HR) Group: Dispensed Bi-weekly 
Weight Band 
Weight Range 
Number of tablets 
per weight band 
Number of tablets 
in each card 
1 
30-39 kg 
2 
28 
2 
40-54 kg 
3 
42 
3 
55-70 kg 
4 
56 
4 
≥71 kg 
5 
70 
 
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A daily supplement of Vitamin B6 will be provided by the trial site to participants randomised to 
the HRZE/HR treatment arm, per each country’s National TB Treatment Guideline. 
The packaging of each weekly and biweekly cards will be labelled with, at a minimum, the 
following information: 
• 
Name of Sponsor 
• 
Name of medication 
• 
Dosage, quantity and method of administration  
• 
Reference/lot number 
• 
The statement “For Clinical Trial Use Only” 
• 
Space for completion of name of Investigator and site number 
• 
MedID: medication identification number 
• 
Storage conditions 
• 
Period of use 
• 
The statement “Keep out of reach of children” 
• 
Expiry date 
• 
Directions for use 
• 
Space for completion of participant number and visit/date dispensed 
6.5 
Blinding and Procedures for Breaking the Blind 
As this is an open label trial there is no need for blinding or procedures to break the blind. The 
trial participants, the site staff, Sponsor, and CROs will not be blinded to treatment assignment.  
6.6 
Handling, Storage and Accountability  
The Investigator or designee must confirm that the appropriate temperature conditions as per 
details on IMP labelling, have been maintained during transit for all trial IMP received, and any 
discrepancies are reported and resolved before use of the trial IMP. 
Only participants randomised in the trial may receive trial IMP and only authorized site staff may 
supply or administer trial IMP. All trial IMP’s must be stored in a secure, environmentally 
controlled, and monitored (manual or automated) area in accordance with the labelled storage 
conditions with access limited to the Investigator and authorized site staff. 
The Investigator, institution, or the head of the medical institution (where applicable) is responsible 
for trial IMP accountability, reconciliation, and record maintenance (i.e., receipt, reconciliation, 
and final disposition records).  Upon completion or termination of the trial, all unused and/or 
partially used IMPs must either be returned to Sponsor (or designated vendor: who will arrange 
for destruction) or destroyed at site as agreed by the Sponsor, after final accountability has been 
confirmed. 
The Investigator/designee will immediately inform the Sponsor of any quality issues arising with 
respect to the trial IMP. The Sponsor will take whatever action is required should such a situation 
arise. 
Further guidance and information for the handling, storage, accountability and final disposition of 
unused trial IMPs are provided in the Pharmacy Manual. 
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7.0 
Trial Variables and Procedures 
The Synopsis Flowchart and Procedures (Section 1.2)  should be referenced for timing, 
sequence of assessments, and specific procedures. 
7.1 
Demographic and Background Variables and Procedures 
The following demographic and background variables will be collected: 
• 
Written Informed Consent 
• 
Visit dates 
• 
Participant disposition 
• 
Demography (date of birth, race and gender) 
• 
Inclusion and exclusion criteria 
• 
Clinically significant medical and TB treatment history (including past and current TB 
diagnosis, smoking and alcohol use) 
• 
Screening coached spot sputum samples: 
o Smear microscopy for acid-fast bacilli  
o Rapid molecular tests for isoniazid, rifampicin, fluoroquinolones resistance (Hain 
MTBDRplus and HainMTBRsl) 
o Liquid Culture (MGIT) for Mycobacterium tuberculosis (MTB), followed by a speciation 
test to detect presence or absence of MTB and obtain time to positivity (TTP) when 
positive. 
• 
Urine pregnancy test: women of childbearing potential only, whether they are sexually 
active or not (non-childbearing potential for a female participant is defined as having 
bilateral oophorectomy, bilateral tubal ligation and/or hysterectomy or has been 
postmenopausal with a history of no menses for at least 12 consecutive months). 
• 
Serology: HIV and CD4 count.  Where required by regulatory authorities or ethics 
committees, a separate (EC/IRB approved) HIV informed consent form will be obtained 
from participants: 
o Prior to HIV testing and on receipt of the results, participants will be counselled on HIV by 
trained counsellors if they have indicated as such on the HIV consent form. If requested 
by the participant, HIV counselling that is provided to the participant by the trial site should 
be clearly documented in the participant’s medical records/source.  Participants have the 
right to decline to know or receive their HIV test results. This decision should be clearly 
documented in the participant’s medical records/source.   
• 
Karnofsky Score (Appendix 5). Only for HIV positive participants. 
• 
Chest X-Ray: A chest X-ray digital image within 6 months prior to or during the Screening 
visit, will be obtained and read locally by the Investigator or designee.  Digital images will 
be provided to the Sponsor; this process will be documented in the Chest X-Ray / 
Radiology Manual.  The investigator is responsible for review and analysis of the chest X-
ray for participant’s inclusion. 
• 
Method of birth control: male and female participants and their sexual partners 
• 
IMP details: randomization 
• 
IMP compliance and actual dosing 
• 
Concomitant medications 
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7.2 
Efficacy Variables and Procedures 
Two spot sputum samples are collected, one EMS brought from home or collected in the hospital 
ward (only if the participant is hospitalised) and one spot sputum sample collected at the research 
site under the coaching and observation of the trial staff or, if no EMS sample was provided by 
the participant, 2 samples may be collected on site at least 30 minutes apart. The 
mycobacteriology sampling methodology and requirements will be described in a separate 
document, the Mycobacteriology Laboratory Manual, which will be provided prior to the trial start. 
Sputum samples may not be obtained by induction. 
The following analyses will be performed: 
• 
Liquid culture (MGIT), to detect presence or absence of MTB and obtain the TTP followed 
by a speciation test when applicable, to confirm MTB. 
 
Using these observed variables, the following derived variables will be assessed for evaluation of 
the efficacy endpoints: 
• 
Bacteriologic failure/relapse 
• 
Time to sputum culture conversion 
• 
Number of participants with sputum culture conversion 
 
Every effort must be made to collect sputum samples. However, in general, the inability to produce 
sputum is treated as being equivalent to having a negative culture (favourable) result.  A 
participant who never achieves culture negative status due to the inability to produce sputum but 
has completed Week 17 or Week 26 and post treatment follow-up (Weeks 39 to 104) and is 
without clinical or biological evidence of relapse, will be considered to have a favourable outcome. 
TB Symptoms Profile:  
• 
The TB Symptoms Profile will record participants’ ratings of the severity of common TB 
symptoms.  
 
Patient Reported Health Status Variables and Procedures:  
• 
The Patient Reported Health Status variables will be collected at the time points described 
in the Synopsis Flow Chart and Procedures (Section 1.2). Patient Reported Health Status 
will be collected using the EQ-5D-5L Health Questionnaire. This descriptive system consists 
of five health-related quality of life dimensions, each of which will be recorded using five 
levels of severity.  
 
Methodology: The Patient Reported Health Status methodology and requirements will be 
described in a separate trial Participant Questionnaires Guideline, which will be provided prior to 
the trial start. 
7.3 
Safety and Tolerability Assessments 
The following safety and tolerability variables will be collected at the time points described in the 
Synopsis Flow Chart and Procedures (Section 1.2) and assessed for evaluation of the safety 
endpoints: 
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• 
The safety laboratory sampling methodology and requirements will be described in a 
separate document, the Safety Laboratory Manual, which will be provided prior to the trial 
start. The following analyses will be performed: 
o Full Blood Count (haemoglobin, haematocrit, red blood cell count, white blood cell 
count with differential, platelet count) 
o Clinical Chemistry (albumin, serum urea, creatinine, direct, indirect and total bilirubin, 
uric acid, total protein, ALP, AST, ALT, lipase, phosphate, sodium, potassium, calcium 
(corrected for albumin), chloride, magnesium, glucose, bicarbonate/CO2, creatine 
phosphokinase (CPK). GGT is only routinely included at the Screening visit (Day -9 to 
-1).  
o When managing participants with elevated liver enzymes at an Unscheduled visit, the 
investigator can request additional tests, in addition to the repeat LFT [e.g. Gamma 
Glutamyl Transferase (GGT), screening for Hepatitis A, B, C; to assist in ruling out 
other causes of a dysfunctional liver test (e.g. alcohol induced hepatic cell injury, 
hepatobiliary disease, hepatic viral infection)]. 
o Urinalysis (pH, specific gravity, protein, glucose, micro-albumin, ketones, bilirubin, 
creatinine, nitrite, sodium, urobilinogen, blood, leukocytes). Microscopy will be 
completed as follow up to abnormal urinalysis per discretion of Investigator 
• 
12-lead ECG: 
o Investigator assessment: normal or abnormal 
o Central cardiologist assessment: heart rate, PR interval, RR interval, QT, corrected 
QT Interval (QTc) (QTcB and QTcF), QRS. 
o Methodology: 
 
Timing (Synopsis Flow Chart and Procedures, Section 1.2) and registration 
technique for ECGs will be standardized for all participants and will be 
described in a separate document which will be provided prior to the trial start 
 
ECGs are to be recorded for 10 seconds 
 
ECGs are to be performed during a single visit 
 
ECGs should be done before any phlebotomy when both included in a visit 
 
For each participant, the ECGs should, to every extent possible, be collected 
at approximately the same time of day (+/- 1 hours) and in the same fed/fast 
state throughout the trial (e.g. 4 hours after lunch) 
o ECGs to be performed prior to pre- and post-dose PK sampling as described below: 
 
Day 1: pre-dose (within 2 hours prior to dosing) 
 
Week 2: pre-dose (within 2 hours prior to dosing), 1.5–3 hours post-dose and 
4-6 hours post-dose 
 
Week 8: pre-dose (within 2 hours prior to dosing), 1.5–3 hours post-dose and 
4-6 hours post-dose 
 
Week 12: pre-dose (within 2 hours prior to dosing)  
 
Week 17 or at early withdrawal if prior to week 17: pre-dose (within 2 hours 
prior to dosing) and 1.5–3 hours post-dose 
• 
Vital signs: 
o Vital signs (should be done before any phlebotomy in light clothing and with no 
shoes) 
o Systolic and diastolic blood pressure (mmHg) to be measured in a supine position 
(after 5 minutes of rest) using an appropriately sized cuff, and using the same type of 
sphygmomanometer, if possible, by the same observer, at each relevant visit 
o Heart rate (beats per minute) 
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o Respiratory rate (breaths per minute)  
o Axillary body temperature (°C) 
• 
Physical Examination:  
o Height (m) is measured at the screening visit only 
o Full (complete) and limited (gross neurological, pulmonary, cardiovascular and 
abdominal) examinations will be performed and any clinically significant findings will 
be recorded 
o Weight (kg) (in light clothing and with no shoes) 
o Using the variables of weight and height, the body mass index (BMI) will be 
calculated 
• 
Ophthalmology Slit Lamp Examination: 
o To be done by an Ophthalmologist trained on Age-Related Eye Disease Scale 2 
(AREDS2) assessment. The ophthalmology slit lamp methodology and requirements 
will be described in a separate document, the Ophthalmology Guideline. The 
following analyses will be performed: AREDS2 opacity typing and grading. 
• 
Adverse events 
• 
Investigator assessment:  
o The Investigator will review the participant status at specified visits in the Synopsis 
Flow Chart and Procedures (Section 1.2), including any time the Investigator 
determines that the participant fulfils the criteria for the primary outcome of treatment 
failure. The Investigator will assess whether TB treatment is considered a “success” 
or “failure”.  If it is considered a failure, the Investigator should specify if the 
assessment is based on bacteriology and/or clinical deterioration and/or radiological 
deterioration. 
7.4 
PK Variables and Procedures 
Plasma concentrations from sparse sampling (Synopsis Flow Chart and Procedures, Section 1.2) 
will be used to update population PK models for bedaquiline and its M2 metabolite, pretomanid 
to further evaluate the effects of covariates on model parameters in this trial population.   
 
PK data from the current trial may be combined with prior data to enhance this population PK 
analysis. The models will be used to estimate individual exposure metrics (e.g., Cmin, Cmax, AUCτ, 
Cmean, and time above minimum inhibitory concentration) for subsequent analyses exploring 
relationships between drug exposure and efficacy and safety endpoints. 
 
If IMP is not administered during Week 2, 8 and or 17, then only a single PK sample is required 
to be obtained at any time during the visit assessment. 
7.5 
Mycobacteriology Characterization Variable and Procedures 
 
• 
Day 1 (Baseline) sputum sample (or any positive sample from Screening to Week 4, if 
the baseline cultures are contaminated or negative); 
• 
MTB confirmed positive cultures (after the participant has previously converted to 
negative) at or after the last visit of the treatment period (Week 17 or Week 26) or visits 
with positive cultures, during the post-treatment follow-up period. 
• 
Refer to the Mycobacteriology Laboratory Manual for full details. 
Mycobacterial Characterization - MTB isolates (from the first MTB positive culture) will be 
processed for: 
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• 
Rapid molecular tests for fluoroquinolones, injectables, isoniazid and rifampicin 
resistance (only on MTB positive cultures in the follow-up period); 
• 
Minimum Inhibitory Concentration (MIC) against bedaquiline, pretomanid, and 
moxifloxacin;  
• 
Drug Susceptibility Testing for streptomycin, rifampicin, isoniazid, ethambutol, 
moxifloxacin, and pyrazinamide in liquid culture;  
• 
Extraction of organismal (MTB) DNA for whole genome sequencing (WGS), and 
comparison of sequences from baseline and relapse isolates. 
 
If the participant’s culture converts to negative and has a MTB positive culture at or after the last 
visit of the treatment period (Week 17 and Week 26), the MTB cultures will be tested at the trial 
mycobacteriology laboratories using Hain MTBDRplus and HainMTBRsl to detect resistance to 
isoniazid, rifampicin, fluoroquinolones and injectables. 
 
All MTB isolates must be stored at the local mycobacteriology laboratories, until trial closure.  In 
addition, MTB isolates as well as extracted MTB DNA from the applicable baseline and follow-up 
cultures will be stored at the central mycobacteriology laboratory for potential further work to 
advance new assay tools and understanding of MTB as a pathogen for a maximum of 5 years 
after trial closure.  
8.0 
Adverse Events 
8.1 
Definitions 
8.1.1 
Adverse Event (AE) 
Any untoward medical occurrence in a clinical investigation participant, temporally associated with 
the use of a trial treatment whether or not considered related to trial treatment. An AE can 
therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease (new or exacerbated) temporally associated with the use of a trial treatment, 
whether or not related to the trial treatment. 
8.1.2 
Serious Adverse Event (SAE) 
Any untoward medical occurrence that at any dose: 
• 
Results in death 
• 
Is life threatening (any event in which the participant was at risk of death at the time of the 
event; it does not refer to an event, which hypothetically might have caused death if it were 
more severe) 
• 
Requires inpatient hospitalisation or prolongation of existing hospitalisation; in general, 
hospitalisation signifies that the participant has been detained (usually involving at least 
an overnight stay) at the hospital or emergency ward for observation and/or treatment that 
would not have been appropriate in the physician’s office or outpatient setting. 
Complications that occur during hospitalisation are AEs. If a complication prolongs 
hospitalisation or fulfils any other serious criteria, the event is serious. When in doubt as 
to whether “hospitalisation” occurred, or was necessary, the AE should be considered 
serious. Hospitalisation for elective treatment of a pre-existing condition that did not 
worsen from baseline is not considered an AE. 
• 
Results in persistent or significant disability/incapacity; the term disability means a 
substantial disruption of a person’s ability to conduct normal life functions. This definition 
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is not intended to include experiences of relatively minor medical significance such as 
uncomplicated headache, nausea, vomiting, diarrhoea, influenza, and accidental trauma 
(e.g., sprained ankle) which may interfere with or prevent everyday life functions but do 
not constitute a substantial disruption. 
• 
Is a congenital anomaly/birth defect; or 
• 
Is a medically important event 
Note:  Medical and scientific judgment should be exercised in deciding which is a medically 
important event that may not be immediately life-threatening or result in death or hospitalisation 
but may jeopardize the participant or may require medical or surgical intervention to prevent one 
of the outcomes listed above.   
Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias or convulsions that do not result in hospitalisation, or the 
development of drug dependency or drug abuse. A “suspected transmission of infectious agent 
by a medicinal product” is also considered a serious adverse event under the SAE criterion “Other 
medically important condition”.     
8.1.3 
Attribution/Causality 
• 
The Investigator is obligated to assess the relationship between trial treatment and each 
occurrence of each AE/SAE 
• 
The Investigator will use clinical judgment to determine the relationship 
• 
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to trial IMP administration will be 
considered and investigated 
• 
The Investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment 
• 
For each AE/SAE, the Investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality 
• 
There may be situations in which an SAE has occurred, and the Investigator has minimal 
information to include in the initial report to the Sponsor/designee. However, it is very 
important that the Investigator always assesses causality for every event before the initial 
transmission of the SAE data to the Sponsor/designee. 
• 
The Investigator may change his/her opinion of causality in light of follow-up information 
and send a SAE follow-up report with the updated causality assessment 
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Table 8: Adverse Events Attribution/Causality Ratings 
Relatedness Rating 
Definition 
Not Related 
An AE, which is not related to the use of the drug. 
Unlikely 
An AE for which an alternative explanation is more likely, e.g., 
concomitant drug(s) or concomitant disease(s), and/or the 
relationship in time suggests that a causal relationship is unlikely. 
Possible 
An AE, which might be due to the use of the drug.  An alternative 
explanation, e.g., concomitant drug(s) or concomitant disease(s), is 
inconclusive.  The relationship in time is reasonable; therefore, the 
causal relationship cannot be excluded. 
Probable 
An AE, which might be due to the use of the drug.  The relationship 
in time is suggestive, e.g., confirmed by de-challenge.  An alternative 
explanation is less likely, e.g., concomitant drug(s) or concomitant 
disease(s). 
Certain 
An AE, which is listed as a possible adverse reaction and cannot be 
reasonably explained by an alternative explanation, e.g., concomitant 
drug(s) or concomitant disease(s).   
8.1.4 
Severity 
Table 9: Definitions for Adverse Event Severity Gradings 
Grade 
Severity Rating 
Definition 
GRADE 1 
Mild 
Transient or mild discomfort (< 48 hours); no medical 
intervention/therapy required. 
GRADE 2 
Moderate 
Mild to moderate limitation in activity - some assistance 
may be needed; no or minimal medical intervention/therapy 
required. 
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. 
 
See Appendix 2 for full DMID Toxicity Tables. Above ratings should be used to estimate the grade 
for abnormalities NOT found elsewhere in the Toxicity Tables. 
8.2 
Reporting 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and non-
leading verbal questioning of the participant is the preferred method to inquire about AE 
occurrences. 
All AEs will be collected by the Investigator from the time a participant signs the Informed Consent 
Form through to their Week 104 follow-up visit. The exception to this is early withdrawal 
participants who will only have SAEs collected from their time of early withdrawal to their Week 
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104 follow-up visit at the timepoints specified in the Synopsis Flow Chart and Procedures (Section 
1.2) and recorded in the CRF.   
Medical occurrences that begin after obtaining informed consent will be recorded as AEs. If an 
AE started before signing of the informed consent, but is ongoing at trial start, it should be 
recorded as medical history.  If the pre-existing medical occurrence worsens during the trial, an 
AE will be recorded. 
All SAEs will be recorded and reported to the Sponsor or designee within 24 hours of the 
information becoming known to the Investigator, as noted in the SAE reporting guidelines. The 
Investigator will submit any updated SAE data to the Sponsor within 24 hours of information 
becoming known to the Investigator.  
The Sponsor/Investigator/designee will inform Regulatory Authorities and/or EC/IRB of all SAEs 
in accordance with local requirements and ICH guidelines for GCP. 
The Sponsor/designee will forward Safety Notification letters to the Investigator for submission to 
the EC/IRB. 
Investigators are not obligated to actively seek AE or SAE information in former trial participants. 
However, if the Investigator learns of any SAE, including a death, at any time after a participant 
has been discharged from the trial, and he/she considers the event to be reasonably related to 
the trial IMP or trial participation, the Investigator must promptly notify the Sponsor, EC/IRB and 
regulatory authorities in an expedited basis, in accordance with local requirements and ICH GCP 
Guidelines. 
8.2.1 
Follow up of Adverse Events 
All AEs will be followed until: 
• 
Satisfactory clinical resolution or stabilization; or 
• 
The end of the follow-up period; and  
• 
All queries on these AEs have been resolved.   
Certain long-term AEs cannot be followed until resolution within the setting of this protocol. In 
these cases, follow-up will be the responsibility of the Investigator.  However, this will have to be 
agreed upon with the Sponsor Medical Monitor. 
The Investigator is obligated to perform or arrange for the conduct of supplemental measurements 
and/or evaluations as medically indicated or as requested by Sponsor or representative to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may include 
additional laboratory tests or investigations, histopathological examinations, or consultation with 
other health care professionals.  The Investigator should contact the Sponsor/designee to discuss 
appropriate medical follow-up if consultation is required.  
If a participant dies during participation in the trial or during a recognized follow-up period, the 
Investigator will provide the Sponsor/representative with a copy of any post-mortem findings, 
including histopathology. 
New or updated SAE information will be recorded in the originally completed CRF and submitted 
to the Sponsor within 24 hours of receipt, per the eCRF completion guideline. 
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8.2.2 
Clinical Laboratory Adverse Events 
Changes in the results of the clinical laboratory assessment results and which the Investigator 
determines are clinically significant will be reported as AEs.  It is the Investigators’ responsibility 
to review the results of all laboratory tests as they become available.  This review must be 
documented by the Investigators’ dated signature on the laboratory report.  For each abnormal 
laboratory test result, the Investigator needs to ascertain and document if this is a clinically 
significant change from baseline for that individual participant.  This determination, however, does 
not necessarily need to be made the first time an abnormal value is observed.  The Investigator 
may repeat the laboratory test or request additional tests to verify the results of the original 
laboratory tests.  If this laboratory value is determined by the Investigator to be a clinically 
significant change from baseline for that participant, it is considered to be an AE. 
8.2.3 
Disease Symptoms During Trial 
Symptoms of the disease under trial (Tuberculosis) experienced by the participant while on the 
trial will be assessed by the Investigator.  If the symptom has: 
• 
worsened while the participant is in the trial; and  
• 
the Investigator assesses it as clinically significant; 
it will be recorded as an adverse event. If there is: 
• 
no change; and  
• 
the Investigator assesses the symptom as due to the participant’s TB; and  
• 
not clinically significant; 
it will not be recorded as an AE and this will be noted in the participant’s source documentation. 
All TB related symptoms that meet SAE criteria will be recorded and reported as a SAE. 
8.2.4 
Overdose 
Overdose of the IMP experienced by the participant while on the trial, will be assessed by the 
Investigator to determine whether the overdose led to an adverse event, including if the taking of 
the suspected medicine led to suicidal intention and subsequent overdose of the suspected 
medicine, or other medication. In this case it will be recorded as an adverse event. If it does not 
lead to an adverse event, it will not be recorded as an AE and this will be noted in the participant’s 
source documentation. 
8.2.5 
Drug Interaction 
If the Investigator becomes aware that the participant has experienced a drug interaction which 
has resulted in an adverse event, it will be recorded as an adverse event. 
8.2.6 
Pregnancy 
The Investigator will immediately notify the Sponsor of any pregnancy that is discovered during 
IMP administration or which started during IMP administration.  Pregnancy forms will be 
completed for all pregnancies reported during the clinical trial, as defined below. In addition, the 
Investigator will report to the Sponsor any follow up information regarding the outcome of the 
pregnancy, including perinatal and neonatal outcome.  Infants will be followed-up for 6 months.   
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All women of childbearing potential will be instructed to contact the Investigator immediately if 
they suspect they might be pregnant (for example, missed or late menses) at any time during the 
trial. 
If a pregnancy is suspected while the participant is receiving IMP, the IMP will be withheld 
immediately until the result of the pregnancy test is known.  If pregnancy is confirmed, the IMP 
will be permanently discontinued in an appropriate manner, the participant withdrawn from the 
trial and referred to the NTP for further management.  
Protocol-required procedures for trial discontinuation and follow-up will be performed unless 
contraindicated by the pregnancy. 
Pregnancy reporting will follow the same timelines for a SAE (see above). Instructions and 
forms will be provided separately. SAE reporting will also occur if the pregnancy outcome is a 
congenital anomaly.  This will follow the reporting procedures described above for SAE reporting. 
8.3 
Monitoring for Specific Toxicities  
Monitoring for specific toxicities is based upon target organs as defined in the preclinical toxicity 
studies of the Investigator’s Brochures[8, 15] and Package Inserts.[19, 20, 22, 40] 
AEs still ongoing at the end of the treatment period in the trial will be followed until satisfactory 
clinical resolution or stabilization, or until the end of the follow-up period and until all queries on 
these AEs have been resolved.   
Grade 3 and Grade 4 laboratory abnormalities, and laboratory abnormalities considered clinically 
significant should be followed until satisfactory resolution or stabilization. 
Note: For Grade 3 or 4 laboratory toxicities, participants should have a confirmatory 
measurement within 48 hours, where possible. The recommendations for managing 
participants below assumes that the laboratory abnormalities of concern have been confirmed. 
 
8.3.1 
ALT, AST and Bilirubin Elevations 
The Investigator should refer to the Hepatoxicity Management Guideline, to appropriately monitor 
significant elevations of AST, ALT or Bilirubin. A separate Hepatoxicity Management Guideline 
document has been developed to aid investigators in the management of participants. 
When managing participants with elevated liver enzymes at an Unscheduled visit, the Investigator 
can request additional tests, in addition to the repeat LFT [e.g. Gamma Glutamyl Transferase 
(GGT), screening for Hepatitis A, B, C; to assist in ruling out other causes of a dysfunctional liver 
test (e.g. alcohol induced hepatic cell injury, hepatobiliary disease, hepatic viral infection)]. 
8.3.2 
Lipase 
Grade 3 (> 2.0 to ≤ 5.0 x ULN) or Grade 4 (> 5.0 x ULN): 
• 
Contact the Sponsor Medical Monitor to review. Participants with confirmed Grade 3 or 
4 elevations of lipase, the Investigator should consider pausing the full regimen, pending 
further evaluation. 
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8.3.3 
Musculoskeletal System and Cardiac Muscle Myalgia 
Grade 2 (muscle tenderness at a site other than sites of injection and/or venepuncture or with 
moderate impairment of activity) or Grade 3 (severe muscle tenderness with marked impairment 
of activity) or Grade 4 (frank myonecrosis): 
• 
Participants with Grade 2 signs and symptoms should be followed closely. Participants 
with Grade 3 or 4 signs and symptoms should be discussed with the Sponsor Medical 
Monitor to consider pausing trial IMP, pending further evaluation. 
8.3.4 
Cardiac Rhythm Disturbances 
Cardiac rhythm disturbances that are Grade 3 (recurrent, persistent, symptomatic arrhythmia 
requiring treatment) or Grade 4 (unstable dysrhythmia requiring treatment): 
• 
Participants should be monitored closely.  The Investigator should discuss with the 
Sponsor Medical Monitor to consider pausing the full regimen, pending further evaluation. 
QTc prolongation  
If QTcF is equal to or greater than 500 msec, the ECG should be repeated, and serum electrolytes 
should be evaluated. If the second ECG also has a QTcF of > 500 msec, the Sponsor Medical 
Monitor should be consulted to consider pausing the full regimen, pending further evaluation. 
New left bundle branch block (LBBB) or Mobitz type 2 or complete heart block. Recordings with 
artefacts that interfere with the interpretation of the ECG should be repeated to confirm the 
findings. If the finding is from the centralized ECG machine reading the result is to be checked 
and confirmed by the Investigator.  If this is confirmed by the Investigator, dosing is to be paused 
until the reading has been confirmed by the central cardiologist and the participant is to be treated 
per the Investigator’s clinical judgment. If it is confirmed by the central cardiologist, the participant 
is to be withdrawn from the full regimen.  Contact Sponsor Medical Monitor to review.  
8.4 
Safety Monitoring by Data Monitoring Committee 
A Data Safety Monitoring Committee (DSMC) will be appointed for the trial. The primary 
responsibility of the DSMC will be to act in an advisory capacity to the Sponsor to safeguard the 
interests of trial participants by monitoring participant safety, assess participant risk versus 
benefit, and assess data quality and general evaluation of the trial progress. Its activities will be 
delineated in a DSMC Charter that will define the membership, responsibilities and the scope and 
frequency of data reviews.  
The DSMC will operate on a conflict-free basis independently of the Sponsor and the trial team. 
It will comprise at least 3 voting members that include at least 2 clinicians and one statistician.   
The DSMC may have an organizational meeting prior to commencement of the trial. The DSMC 
will have meetings where it will review unblinded data during a closed session. These meetings 
will be planned at regular intervals.  
The Sponsor or the DSMC may convene ad hoc meetings based on rates of SAEs and/or to 
review results of the futility analysis, or if safety concerns arise during the trial.  After its 
assessment, the DSMC will recommend to the Sponsor continuation, modification or termination 
of the clinical trial.  
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9.0 
Statistical Analysis 
The statistical analysis plan (SAP), which will contain details of the analyses specified in this 
section, will be written and signed off prior to the interim analysis. 
There will be 3 data analyses and trial reports generated for this trial:  
 
1. When all participants have completed 8 weeks (2 months) of treatment from baseline.  
2. When all participants have completed 52 weeks (12 months) follow-up from start of 
therapy. 
3. When all participants have completed 104 weeks (24 months) follow-up from start of 
therapy.  
9.1 
Analysis Populations 
There will be three main analyses of the primary efficacy endpoint: An intent to treat (ITT) analysis; 
a modified intent to treat (mITT) analysis and a per protocol (PP) analysis: 
• 
The ITT population is defined as all randomized participants excluding late screening 
failures. Late screening failures are participants withdrawn from treatment because they 
were found to be ineligible (late exclusions from the trial), based on data collected prior to 
randomization. 
• 
The mITT population is defined as the ITT population with extra exclusions (described in 
the SAP). 
• 
The PP population is defined as the mITT population with extra exclusions (described in 
the SAP). 
• 
The mITT analysis will be considered primary, with consistent findings required from the 
other main analysis populations to support the primary conclusion. 
9.2 
Sample Size 
For the primary endpoint, time-to-culture conversion at 8 weeks,150 participants per arm (DS-TB 
participants) will provide at more than 90% power (5% 2-sided significance) to detect a hazard 
ratio (HR) of at least 2 assuming 50% of control participants are culture negative by 8 weeks. If 
only 25% of the control arm remain culture positive at 8 weeks, then this sample size will still 
retain more than 90% power to detect a HR of least 2.  This sample size also allows for one 
planned interim analysis of the primary endpoint (See Section 9.4.1) 
For the key secondary endpoint of clinical outcome at 12 months from randomization, 150 patients 
per arm will provide 74% power based on assumptions using data from the largest most recent 
and completed phase 3 TB treatment trial which used the same control arm.[41]  That is, assuming 
16% unfavourable (see Section 9.4.2) in the control arm and 13% unassessable (see Section 9.6) 
at 52 weeks post randomization. A 12% margin of non-inferiority was chosen to preserve at least 
75% of the estimated control arm effect against placebo (estimated to be 54%)[41, 42] which is 
considered an acceptable proportion on which to declare non-inferiority of the test regimen. 
9.3 
Interim Analyses 
There is one planned interim efficacy analysis which will occur after approximately 60 assessable 
participants have been randomised to the control arm and have reached the 8-week primary 
endpoint. Time to culture negative status in liquid media up to 8 weeks will be analysed using a 
Cox regression model, censoring for death and lost to follow up/withdrawal to estimate the hazard 
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ratio (HR). Following a review of these interim findings, the following considerations will be given 
to modify the trial objectives and sample size: 
If the observed HR (time to culture negativity, experimental arm vs. HRZE control arm) is >2, the 
sample size may be increased to adequately power the trial on the key secondary efficacy 
endpoint (clinical and microbiological outcome at 52 weeks from randomization), which will then 
become the primary efficacy endpoint. The trial efficacy objectives will be updated as follows: 
- 
Primary Objective 
To determine the incidence of bacteriologic failure or relapse or clinical failure at 52 weeks 
from the start of treatment / randomisation.  
- 
Secondary Objectives 
To evaluate the time to culture negativity over 8 weeks, from the start of treatment / 
randomisation. 
All other trial objectives will remain unchanged. 
To achieve 90% power and overall 5% 2-sided significance after adjusting for the interim analysis, 
this will mean increasing the sample size to 225 participants per randomised arm, i.e., to a total 
of 450 DS-TB participants (and up to 225 DR-TB participants). This adaptation is based on the 
Multi-arm Multi-stage (MAMS) framework [46, 47, 48] and full details are provided in the Statistical 
Analysis Plan.  
9.4 
Primary and Secondary Efficacy Endpoint Analysis 
9.4.1 
Primary Efficacy Endpoint, Time to Culture Conversion at 8 Weeks 
The primary analysis will be conducted using culture results from liquid culture (MGIT) media. 
Participants will be classified as being culture positive, culture negative, dead or unassessable at 
8 weeks.  The proportion culture negative will be those classified as being culture negative divided 
by the total considered culture negative, culture positive or have died. This proportion will be 
estimated from the Kaplan Meier estimates from the time to culture conversion to negative status 
analysis and groups compared using a hazard ratio and 95% confidence interval. 
Non-inferiority of the key secondary endpoint of clinical outcome will be assessed using the upper 
bound of the one-sided 97.5% confidence interval for the difference between the proportion of 
participants who are classified as having an unfavourable status on the intervention less the 
control regimen.  If the upper bound of the one-sided 97.5% confidence limit for this difference in 
proportions is less than 12% (the margin of inferiority) the intervention will be non-inferior to the 
control arm. 
9.4.2 
Key Secondary Efficacy Endpoint, Clinical Outcome at 52 Weeks from 
Randomization  
For the key secondary endpoint of clinical outcome (bacteriologic failure or relapse or clinical 
failure), participants will be classified as having a favourable, unfavourable or unassessable 
outcome status which will be defined in detail in the SAP.  In general, participants achieving and 
maintaining culture negative status without any additional treatment will be considered favourable; 
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participants who fail on treatment or relapse in follow-up will be considered unfavourable and 
participants who are not assessable (and who have not already been declared as unfavourable) 
will be considered unassessable and excluded from the analysis. 
9.4.3 
Other Secondary Efficacy Endpoints 
The secondary efficacy endpoints and analyses are as follows are: 
• 
Clinical outcome (bacteriologic failure or relapse or clinical failure) at 104 weeks from the 
start of therapy.  
• 
Proportion of participants with sputum culture conversion to negative status in liquid 
culture (MGIT) at 4, 6, 12 and 17 weeks to be explored as a potential biomarker of outcome 
at 52 weeks from start of therapy. 
• 
Change from baseline in weight will be summarised and presented. 
• 
Proportion of participants experiencing a change from baseline in TB symptoms. 
• 
Change from baseline in Patient Reported Health Status will be summarised and 
presented. 
9.5 
Safety and Tolerability Assessments 
The incidence of all-cause mortality will be summarized.  All adverse events will be coded using 
the Medical Dictionary for Regulatory Activities (MedDRA) and will be presented by Preferred 
Term within each MedDRA System Organ Class (SOC).  
Treatment-emergent adverse events (TEAEs) are defined as AEs which started at or after the 
first administration of IMP and includes those events started prior to the first administration of IMP 
but which worsened after the first intake.  Adverse events starting after the last administration of 
IMP until the last scheduled visit/assessment/measurement will be regarded as treatment-
emergent. 
The incidence of the following events will be summarized for further medical analysis: 
• 
Incidence of TEAEs; 
• 
Incidence of TEAEs by Severity; 
• 
Incidence of TEAEs by DMID toxicity grade; 
• 
Incidence of Drug-Related TEAEs; 
• 
Incidence of Serious TEAEs; 
• 
Incidence of TEAEs Leading to Early Withdrawal; 
• 
Incidence of TEAEs leading to Death. 
9.6 
Pharmacokinetics 
For each analyte and each scheduled sampling time/window, the plasma concentration will be 
summarized by descriptive statistics including the mean, SD, coefficient of variation (CV), median, 
minimum, maximum, geometric mean and geometric CV (%). 
In addition, mean and/or median concentration-versus-time graphs will be provided, with error 
bars and/or scatter plots as appropriate. 
Plasma concentrations from sparse sampling will be used to update existing population PK 
models and derive exposure metrics (e.g., Cmin, Cmax, AUC) for bedaquiline and its M2 metabolite, 
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pretomanid, moxifloxacin, and pyrazinamide. Effects of baseline covariates on exposure will be 
assessed; so, too, will the effects of concomitant medications including ART, as feasible. Data 
from other trials may be included to enhance the model-based analysis.  
Detailed plans for the PopPK analysis will be outlined in a separate modelling plan, and results 
will be reported in separate modelling report. 
9.7 
Pharmacokinetics/Pharmacodynamics 
Relationships will be explored between drug exposure and efficacy and safety endpoints. These 
exploratory PK/PD analyses may include HIV status as a covariate. Planning details and results 
will be included in the separate modelling plan and report. 
10.0 Records Management 
10.1 Data Collection 
All relevant CRF/eCRF pages will be completed for each participant who receives any amount of 
IMP, depending on visits attended.  For screening failure participants, specific eCRF pages will 
be completed as described in the eCRF Completion Guidelines. For participants who are 
prematurely withdrawn, all the visits the participant attended including withdrawal and follow-up 
visits need to be completed. 
10.2 Source Documents 
Source documents are defined as all information in original records and certified copies of original 
records of clinical findings, observations, or other activities in a clinical trial necessary for the 
reconstruction and evaluation of the trial.  Source documents will include, but are not limited to, 
progress notes, in-patient hospital records, electronic data, screening logs, and recorded data 
from automated instruments. 
All source documents pertaining to this trial will be maintained by the Investigators.  The 
Investigator 
must 
permit 
trial 
related 
monitoring, 
audits, 
Independent 
Ethics 
Committee/Institutional Review Board (EC/IRB) review and regulatory inspections providing 
authorized personnel direct access to source documents, including documents required to confirm 
inclusion/exclusion and relevant in-patient records while participants are on trial treatment. 
10.3 File Management at the Trial Centre 
It is the responsibility of the Investigators to ensure that the trial centre files are maintained in 
accordance with International Good Clinical Practice Guidelines and the ethical principles that 
have their origin in the Declaration of Helsinki. 
10.4 Records Retention at the Trial Centre 
The Investigator is obliged to retain records and data from the trial for safety reasons and for audit 
and inspection after trial completion.  The essential documents should be retained for not less 
than 2 years after the last approval of a marketing application and until there are no pending or 
contemplated marketing applications or at least 2 years have elapsed since the formal 
discontinuation of clinical development of the IMP.  Investigator should notify the 
Sponsor/designees prior to destroying any records pertaining to the trial. 
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11.0 Quality Control and Assurance  
11.1 Site Procedures 
The Investigator undertakes to perform the clinical trial in accordance with this protocol, local 
regulations, International GCP, and the ethical principles that have their origin in the Declaration 
of Helsinki. 
The Investigator undertakes to complete the CRFs according to the Sponsor’s requirements, in a 
timely, accurate and legible manner. CRF entries will be verifiable to source documentation other 
than the CRF. 
Site Standard Operating Procedures (SOPs), where available, will be adhered to for all clinical 
and bioanalytical activities relevant to the quality of the trial.  Participant compliance will be 
monitored throughout the trial. 
The Investigator will sign and date any analysis results (e.g., laboratory, ECG, etc.) to verify that 
the results have been reviewed. 
The Investigator may appoint other sub-Investigators to assist with the trial. However, the 
Investigator maintains responsibility for the trial and will supervise the sub-Investigators. Written 
EC/IRB approval of the trial will be obtained prior to involvement in the trial. 
The Investigator will ensure that all site personnel are adequately trained in GCP, local 
regulations, the protocol, IBs/package inserts and all trial procedures and requirements. 
11.2 Monitoring 
The Investigator is responsible for the validity of all data collected at the clinical site and must 
accept the various monitoring procedures employed by the Sponsor.  The purpose of monitoring 
is to verify that the rights and well-being of human participants are protected; that trial data are 
accurate, complete and verifiable with source data; and that the trial is conducted in compliance 
with the protocol, International GCP, the ethical principles that have their origin in the Declaration 
of Helsinki and the applicable regulatory requirements.  
Monitors assigned by the Sponsor will conduct regular site visits before, during and after the trial 
for monitoring various aspects of the trial, and to assure appropriate conduct of the trial in 
accordance with ICH GCP.  Visits will take place usually within a predetermined interval, but this 
may vary during the trial.  The Investigator and site staff will allow the trial monitor and authorized 
representatives of the Sponsor to (1) inspect all CRFs, written informed consent documents and 
corresponding source documents (e.g., original medical records), patient records and laboratory 
raw data, site SOPs, training records, facilities and other trial related systems/processes, and (2) 
access clinical supplies, dispensing and storage areas.  The Investigator and site staff should 
also (1) agree to assist with monitoring activities if requested and (2) provide adequate time and 
space for monitoring visits.  
The monitor will query any missing, confusing, spurious, or otherwise ambiguous data with the 
Investigator.  All queries should be resolved in a timely manner.  A monitoring log will be 
maintained recording each visit, the reason for the visit, the monitor’s signature and Investigator 
or designee’s confirmation signature. 
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11.3 Protocol Deviations 
A protocol deviation is any noncompliance with the clinical trial protocol and GCP requirements. 
The noncompliance may be either on the part of the participant, the Investigator, or the trial site 
staff. Because of deviations, corrective actions are to be developed by the site and implemented 
promptly.  
It is the responsibility of the site to use continuous vigilance to identify and report deviations. All 
deviations must be addressed in trial source documents and reported to Sponsor/designee. 
Protocol deviations must be sent to the local IRB per their guidelines. The site PI/trial staff is 
responsible for knowing and adhering to their IRB requirements. 
11.4 Auditing 
For compliance with International GCP and regulatory agency guidelines, it may be necessary for 
Sponsor-authorized Quality Assurance personnel and/or authorized personnel from an external 
regulatory agency to conduct an audit or inspection of the investigational site.  The purpose of an 
audit is to assess the quality of data about accuracy, adequacy and consistency, and to assure 
that trials are in accordance with the guidelines.  Having the highest quality data from trials is an 
essential aspect of drug development.  
The Investigator and site staff will be given sufficient notice to prepare for such visits, which will 
usually last between one and two days and may be conducted at any stage during the trial.  The 
audit will involve the review of all trial-related documentation required by GCP to be maintained 
by each site; drug storage, dispensing and return; all trial-related supplies; and source documents 
against the CRFs to assure the adequacy and accuracy of the information which has been 
recorded, including the verification of any AEs which have occurred. The auditors or inspectors 
may also review site SOPs, training records, site facilities and other trial related 
systems/processes. 
In the event of the site being notified of a Regulatory Inspection, the Sponsor will help with 
preparation.  It is essential that the Sponsor be notified of the inspection as soon as possible. 
12.0 Ethics and Regulatory 
12.1 Basic Principles 
This research will be carried out in accordance with International GCP, the ethical principles that 
have their origin in the Declaration of Helsinki and the applicable regulatory requirements. 
12.2 Independent Ethics Committee/Institutional Review Board (EC/IRB) Review 
The protocol and required trial related documents will be reviewed by the sites respective EC/IRB.  
The trial will not start until the EC/IRB has approved the protocol, written informed consent, any 
written information to be provided to the participant or any modification thereof, plus any other 
trial related documents required for review.  The EC/IRB shall be constituted and shall operate in 
accordance with International GCP, the ethical principles that have their origin in the Declaration 
of Helsinki. The Investigator will maintain an accurate and complete record of all submissions 
made to, and responses from the IRB/EC.  The records should be filed in the Investigator’s Trial 
File, and copies will be sent to the Sponsor. 
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12.3 Regulatory Authorities 
The Regulatory Authorities will receive the protocol, amendments, reports on SAEs, and the 
Integrated Clinical Trial Report according to national regulations.  As required by local legislation, 
written approval will be obtained from the Regulatory Authorities prior to commencement of the 
trial and implementation of e.g. amendments as applicable. 
12.4 Informed Consent 
Written informed consent will be obtained from all participants (or legally acceptable 
representative) before any trial-related procedures (including any screening or pre-treatment 
procedures) are performed.  Investigators may discuss the availability of the trial and the 
opportunity for entry with a potential participant without first obtaining consent.  However, informed 
consent must be obtained and documented prior to initiation of any procedures that are performed 
solely for determining eligibility for research, including withdrawal from current medication(s).  
When this is done in anticipation of, or in preparation for, the research, it is part of the research. 
The Investigators have both ethical and legal responsibility to ensure that each participant being 
considered for inclusion in this trial is given a full explanation of the protocol.  Participants must 
be informed that their participation is voluntary.  The Investigator or his/her representative will 
explain the nature of the trial to the participant or his/her legally authorized representative and 
answer all questions regarding the trial. This shall be documented on a written informed consent 
form that shall be approved by the same EC/IRB responsible for approval of this protocol.  Each 
informed consent form shall include the elements required by the international GCP and must 
adhere to the ethical principles that have their origin in the Declaration of Helsinki.  
The trial will be included and updated in the appropriate Country registry and referenced in the 
informed consent forms (ICF). 
Once the appropriate essential information has been provided to the participant and fully 
explained by the Investigators (or qualified designees) and it is felt that the participant 
understands the implications of participating, the EC/IRB approved written ICF will be signed and 
dated by both the participant and the person obtaining consent (Investigators or designees), and 
by any other parties required by the EC/IRB. Ongoing participants must be re-consented to the 
most current version of the ICF(s) during their participation in the trial. 
The original signed ICFs will be kept with the trial records and a copy of signed ICF will be provided 
to the participant or the participant’s legally authorized representative.  Another copy of the signed 
ICF and a source document identifying the trial and recording the dates of participation will be 
placed in the participant’s medical record. 
The monitor will inspect the original completed ICFs for all participants. 
12.5 Confidentiality 
All site staff, the Sponsor, and any Sponsor representatives will preserve the confidentiality of all 
participants taking part in the trial, in accordance with International GCP, applicable local 
legislation/regulations. Subject to the requirement for source data verification by the trial 
personnel by reference to the participant’s notes, confidentiality of all participant identities will be 
maintained.  Unique identifiers will be used on the CRF and in all trial correspondence, as 
permitted.  No material bearing a participant’s name will be kept on file by the Sponsor. The written 
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informed consent will contain a clause granting permission for review of the participants’ source 
data by the Sponsor or designees. 
13.0 Publication Policy 
The definition of publication for this purpose is any public presentation of the data emerging from 
this trial.  
All unpublished information given to the Investigator by the Sponsor shall not be published or 
disclosed to a third party, other than to the responsible EC/IRB, within the understanding of the 
confidentiality of their nature, without the prior written consent of the Sponsor. 
Results of this research will be submitted for publication as soon as feasible upon completion of 
the trial in the form of a joint publication(s) between Sponsor and Investigator(s), including site 
clinical and laboratory Investigators, as appropriate. Publication and authorship will be in accord 
with the International Association of Journal Editors.[43]  
Because the trial is funded, in whole or in part, by the Bill and Melinda Gates Foundation (the 
“Foundation”), all peer-reviewed published research relating to the Trial must comply with the 
Foundation’s 
Open 
Access 
Policy 
as 
described 
from 
time 
to 
time 
at 
http://www.gatesfoundation.org/How-We-Work/General-Information/Open-Access-Policy. 
Specifically, (a) all peer-reviewed published research relating to the trial must be submitted for 
publication by TB Alliance through the Chronos Open Access Publishing Service established by 
the Foundation to ensure the immediate and unrestricted access and reuse of all peer-reviewed 
published research funded, in whole or in part, by the Foundation without any embargo period, 
and (b) all data underlying the peer-reviewed published research results must be immediately 
made accessible and open to the public in accordance with the Foundation’s Open Access Policy. 
14.0 Protocol Amendment Policy 
Any change to the protocol will be affected by means of a protocol amendment.  Any changes 
which affect participant safety or welfare will be submitted to the EC/IRB and Regulatory 
Authorities prior to implementation.  The Investigator, EC/IRB, and Sponsor must agree on all 
amendments.  No amendment will be implemented until approved by the relevant authorities 
and/or EC/IRB and signed by all required parties.  Exceptions to this are when the Investigator 
considers that the participant’s safety is compromised.  
Protocol amendments detailing minor administrative changes should be submitted by the 
Investigator to the EC/IRB and Regulatory Authorities, either for notification purposes or approval 
as appropriate. 
15.0 Sponsor, Financial Aspects, Insurance and Indemnity 
The trial Sponsor is the TB Alliance (TBA).  The TB Alliance is a not for profit, product development 
partnership accelerating the discovery and development of new TB drugs that will shorten 
treatment, be effective against susceptible and resistant strains, be compatible with antiretroviral 
therapies for those HIV-TB participants currently on such therapies and improve treatment of 
latent infection. 
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The TB Alliance works with public and private partners worldwide.  It is committed to ensuring 
that approved new regimens are affordable, adopted and available to those who need them. 
The TB Alliance operates with funding mainly from the Bill & Melinda Gates Foundation, the 
Netherlands Ministry of Foreign Affairs (DGIS), the United Kingdom Department for International 
Development (DFID), and the United States Agency for International Development (USAID). 
The participants will not receive any incentives for their involvement in the trial.  The Sponsor has 
made provision to reimburse the participants for out-of-pocket expenses such as travelling to and 
from the trial site and other miscellaneous costs as a result of their trial participation. 
The Sponsor certifies that it has liability insurance coverage for itself and will provide an 
associated certificate upon request.  The insurance does not relieve the Investigators of the 
obligation to maintain their own liability insurance as required by applicable law. The Sponsor 
does not assume any obligation for the medical treatment of other injuries and illnesses.
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16.0 References 
1. 
Maggi N, Pasqualucci CR, Ballotta R, Sensi P. Rifampicin: a new orally active rifamycin. 
Chemotherapy. 1966;11(5):285-292. 
2. 
Jindani A, Aber VR, Edwards EA, Mitchison DA. The early bactericidal activity of drugs in 
patients with pulmonary tuberculosis. Am Rev Respir Dis. 1980;121(6):939-949. 
3. 
Dietze R, Teixeira L, Rocha LM, Palaci M, Johnson JL, Wells C, et al. Safety and 
bactericidal activity of rifalazil in patients with pulmonary tuberculosis. Antimicrob Agents 
Chemother. 2001;45(7):1972-1976. 
4. 
Donald PR, Sirgel FA, Venter A, Parkin DP, Seifart HI, van de Wal BW, et al. Early 
bactericidal activity of antituberculosis agents. Expert Rev Anti Infect Ther. 2003;1(1):141-
155. 
5. 
Johnson JL, Hadad DJ, Boom WH, Daley CL, Peloquin CA, Eisenach KD, et al. Early and 
extended early bactericidal activity of levofloxacin, gatifloxacin and moxifloxacin in 
pulmonary tuberculosis. Int J Tuberc Lung Dis. 2006;10(6):605-612. 
6. 
Rustomjee R, Diacon AH, Allen J, Venter A, Reddy C, Patientia RF, et al. Early bactericidal 
activity and pharmacokinetics of the diarylquinoline TMC207 in treatment of pulmonary 
tuberculosis. Antimicrob Agents Chemother. 2008;52(8):2831-2835. 
7. 
Package insert: Sirturo.  Janssen Therapeutics, September 2014 Available at: 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/204384s000lbl.pdf. 
8. 
Investigator’s Brochure: TMC207 (bedaquiline).  Edition 10. Janssen Research and 
Development, 02 Dec 2016. 
9. 
Koul A, Dendouga N, Vergauwen K, Molenberghs B, Vranckx L, Willebrords R, et al. 
Diarylquinolines target subunit c of mycobacterial ATP synthase. Nat Chem Biol. 
2007;3(6):323-324. 
10. 
Andries K, Verhasselt P, Guillemont J, Gohlmann HW, Neefs JM, Winkler H, et al. A 
diarylquinoline drug active on the ATP synthase of Mycobacterium tuberculosis. Science. 
2005;307(5707):223-227. 
11. 
Huitric E, Verhasselt P, Andries K, Hoffner SE. In vitro antimycobacterial spectrum of a 
diarylquinoline ATP synthase inhibitor. Antimicrob Agents Chemother. 2007;51(11):4202-
4204. 
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12. 
Koul A, Vranckx L, Dendouga N, Balemans W, Van den Wyngaert I, Vergauwen K, et al. 
Diarylquinolines are bactericidal for dormant mycobacteria as a result of disturbed ATP 
homeostasis. J Biol Chem. 2008;283(37):25273-25280. 
13. 
Nuermberger E, Rosenthal I, Tyagi S, Williams KN, Almeida D, Peloquin CA, et al. 
Combination chemotherapy with the nitroimidazopyran PA-824 and first-line drugs in a 
murine model of tuberculosis. Antimicrob Agents Chemother. 2006;50(8):2621-2625. 
14. 
Nuermberger E, Tyagi S, Tasneen R, Williams KN, Almeida D, Rosenthal I, et al. Powerful 
bactericidal and sterilizing activity of a regimen containing PA-824, moxifloxacin, and 
pyrazinamide in a murine model of tuberculosis. Antimicrob Agents Chemother. 
2008;52(4):1522-1524. 
15. 
Investigator's Brochure: Pretomanid (PA-824).  Global Alliance for TB Drug Development, 
22 December 2016. 
16. 
Stover CK, Warrener P, VanDevanter DR, Sherman DR, Arain TM, Langhorne MH, et al. 
A small-molecule nitroimidazopyran drug candidate for the treatment of tuberculosis. 
Nature. 2000;405(6789):962-966. 
17. 
Lenaerts AJ, Gruppo V, Marietta KS, Johnson CM, Driscoll DK, Tompkins NM, et al. 
Preclinical testing of the nitroimidazopyran PA-824 for activity against Mycobacterium 
tuberculosis in a series of in vitro and in vivo models. Antimicrob Agents Chemother. 
2005;49(6):2294-2301. 
18. 
Tyagi S, Nuermberger E, Yoshimatsu T, Williams K, Rosenthal I, Lounis N, et al. 
Bactericidal activity of the nitroimidazopyran PA-824 in a murine model of tuberculosis. 
Antimicrob Agents Chemother. 2005;49(6):2289-2293. 
19. 
Package insert: Moxifloxacin.  MacLeods Pharmaceuticals Ltd., January 2014. 
20. 
Package insert: Pyrazinamide.  MacLeods Pharmaceuticals Ltd., November 2012. 
21. 
Zhang Y, Mitchison D. The curious characteristics of pyrazinamide: a review. Int J Tuberc 
Lung Dis. 2003;7(1):6-21. 
22. 
Package insert: HRZE Combination Tablets.  MacLeods Pharmaceuticals Ltd., September 
2011. 
23. 
World Health Organization. Global tuberculosis report 2012.  2015. WHO Press, Geneva, 
Switzerland. 
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24. 
Pym AS, Diacon AH, Tang S-J, Conradie F, Danilovits M, Chuchottaworn C, et al. 
Bedaquiline safety data in a broad patient population treated for drug-resistant TB 
including XDR-TB (C209 trial). Tuberculosis. 2016;47:394-402. 
25. 
Lee M, Lee J, Carroll MW, Choi H, Min S, Song T, et al. Linezolid for treatment of chronic 
extensively drug-resistant tuberculosis. N Engl J Med. 2012;367(16):1508-1518. 
26. 
A Phase 3 Trial Assessing the Safety and Efficacy of Bedaquiline Plus PA-824 Plus 
Linezolid in Subjects With Drug Resistant Pulmonary Tuberculosis. ClinicalTrials.gov,  
Available at: https://www.clinicaltrials.gov/ct2/show/NCT02333799, Updated 28 February 
2017. 
27. 
Mdluli K, Nuermberger E. Pre-Clinical Drug Combination Trials to Identify Novel Regimens 
for TB.  2009. in Recent Advances in TB Drug Development Symposium. 40th Union World 
Conference, International Union Against TB and Lung Disease. Cancun, Mexico. 
28. 
Tasneen R, Li SY, Peloquin CA, Taylor D, Williams KN, Andries K, et al. Sterilizing activity 
of novel TMC207- and PA-824-containing regimens in a murine model of tuberculosis. 
Antimicrob Agents Chemother. 2011;55(12):5485-5492. 
29. 
Singh R, Manjunatha U, Boshoff HI, Ha YH, Niyomrattanakit P, Ledwidge R, et al. PA-824 
kills nonreplicating Mycobacterium tuberculosis by intracellular NO release. Science. 
2008;322(5906):1392-1395. 
30. 
Manjunatha U, Boshoff HI, Barry CE. The mechanism of action of PA-824: Novel insights 
from transcriptional profiling. Commun Integr Biol. 2009;2(3):215-218. 
31. 
Manjunatha UH, Boshoff H, Dowd CS, Zhang L, Albert TJ, Norton JE, et al. Identification 
of a nitroimidazo-oxazine-specific protein involved in PA-824 resistance in Mycobacterium 
tuberculosis. Proc Natl Acad Sci U S A. 2006;103(2):431-436. 
32. 
Nuermberger E, Tyagi S, Williams KN, Rosenthal I, Bishai WR, Grosset JH. Rifapentine, 
moxifloxacin, or DNA vaccine improves treatment of latent tuberculosis in a mouse model. 
Am J Respir Crit Care Med. 2005;172(11):1452-1456. 
33. 
Tasneen R, Betoudji F, Tyagi S, Li SY, Williams K, Converse PJ, et al. Contribution of 
Oxazolidinones to the Efficacy of Novel Regimens Containing Bedaquiline and 
Pretomanid in a Mouse Model of Tuberculosis. Antimicrob Agents Chemother. 
2015;60(1):270-277. 
34. 
Diacon AH, Dawson R, du Bois J, Narunsky K, Venter A, Donald PR, et al. Phase II dose-
ranging trial of the early bactericidal activity of PA-824. Antimicrob Agents Chemother. 
2012;56(6):3027-3031. 
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35. 
Burman WJ, Goldberg S, Johnson JL, Muzanye G, Engle M, Mosher AW, et al. 
Moxifloxacin versus ethambutol in the first 2 months of treatment for pulmonary 
tuberculosis. Am J Respir Crit Care Med. 2006;174(3):331-338. 
36. 
Rustomjee R, Lienhardt C, Kanyok T, Davies GR, Levin J, Mthiyane T, et al. A Phase II 
trial of the sterilising activities of ofloxacin, gatifloxacin and moxifloxacin in pulmonary 
tuberculosis. Int J Tuberc Lung Dis. 2008;12(2):128-138. 
37. 
Conde MB, Efron A, Loredo C, De Souza GR, Graca NP, Cezar MC, et al. Moxifloxacin 
versus ethambutol in the initial treatment of tuberculosis: a double-blind, randomised, 
controlled phase II trial. Lancet. 2009;373(9670):1183-1189. 
38. 
Dorman SE, Johnson JL, Goldberg S, Muzanye G, Padayatchi N, Bozeman L, et al. 
Substitution of moxifloxacin for isoniazid during intensive phase treatment of pulmonary 
tuberculosis. Am J Respir Crit Care Med. 2009;180(3):273-280. 
39. 
Investigator's Brochure: Bayer HealthCare AG, moxifloxacin.  01 October 2011. 
40. 
Package insert: HR Combination Tablets.  MacLeods Pharmaceuticals Ltd., September 
2011. 
41. 
Gillespie SH, Crook AM, McHugh TD, Mendel CM, Meredith SK, Murray SR, et al. Four-
month moxifloxacin-based regimens for drug-sensitive tuberculosis. N Engl J Med. 
2014;371(17):1577-1587. 
42. 
Tiemersma EW, van der Werf MJ, Borgdorff MW, Williams BG, Nagelkerke NJ. Natural 
history of tuberculosis: duration and fatality of untreated pulmonary tuberculosis in HIV 
negative patients: a systematic review. PLoS One. 2011;6(4):e17601. 
43. 
Recommendations for the Conduct, Reporting, Editing, and Publication of Scholarly work 
in Medical Journals.  Available at: http://www.icmje.org/icmje-recommendations.pdf, 
Updated December 2016. 
44.  
Reuben A (2004). “Hy’s Law”. Landmarks in Hepatology 39(2): 574-578. 
45. 
Temple RJ (2006). “Hy’s Law: predicting serious hepatotoxicity”. Pharmacoepidemoiology 
and Drug Safety 15: 241-243. 
46. 
Parmar, M.K., et al., Testing many treatments within a single protocol over 10 years at 
MRC Clinical Trials Unit at UCL: Multi-arm, multi-stage platform, umbrella and basket 
protocols. Clin Trials, 2017. 14(5): p. 451-461. 
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47. 
Bratton, D.J., P.P. Phillips, and M.K. Parmar, A multi-arm multi-stage clinical trial design 
for binary outcomes with application to tuberculosis. BMC Med Res Methodol, 2013. 13: 
p. 139. 
48. 
Royston, P., et al., Designs for clinical trials with time-to-event outcomes based on 
stopping guidelines for lack of benefit. Trials, 2011. 12: p. 81. 
 
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Appendices 
Appendix 1: The IUATLD Scale 
The IUATLD scale proposes five groups for reporting the results of reading smears for acid fast 
bacilli. They should be recorded as follows: 
FINDING 
RECORDING 
No acid-fast bacilli found in at least 100 fields 
negative 
1 to 9 acid-fast bacilli per 100 fields 
scanty positive 
10 to 99 acid-fast bacilli per 100 fields 
+ 
1 to 10 acid-fast bacilli per field in at least 50 
fields 
++ 
More than 10 acid-fast bacilli per field in at least 
20 fields 
+++ 
Reference: The Public Health Service National Tuberculosis Reference Laboratory and the 
National Laboratory Network. Minimum Requirements, Role and Operation in a Low-Income 
Country. International Union Against Tuberculosis and Lung Disease 1998. 
 
 
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Appendix 2: Division of Microbiology and Infectious Disease (DMID) Toxicity 
Table 
Source:  U.S. National Institute of Allergy and Infectious Diseases, DMID, November 2007 (Draft) 
ABBREVIATIONS:  Abbreviations utilized in the Table: 
ULN = Upper Limit of Normal 
LLN = Lower Limit of Normal 
Rx = Therapy 
Req = Required 
Mod = Moderate 
IV = Intravenous 
ADL = Activities of Daily Living 
Dec = Decreased 
 
ESTIMATING SEVERITY GRADE 
For abnormalities NOT found elsewhere in the Toxicity Tables use the scale below to estimate 
grade of severity: 
Grade 
Severity Rating 
Definition 
GRADE 1 
Mild 
Transient or mild discomfort (< 48 hours); no medical 
intervention/therapy required. 
GRADE 2 
Moderate 
Mild to moderate limitation in activity - some assistance may be 
needed; no or minimal medical intervention/therapy required. 
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. 
 
SERIOUS OR LIFE-THREATENING AEs 
ANY clinical event deemed by the clinician to be serious or life-threatening should be considered 
a grade 4 event. Clinical events considered to be serious or life-threatening include, but are not 
limited to: seizures, coma, tetany, diabetic ketoacidosis, disseminated intravascular coagulation, 
diffuse petechiae, paralysis, acute psychosis, severe depression. 
COMMENTS REGARDING THE USE OF THESE TABLES 
• 
Standardized and commonly used toxicity tables (Division of Acquired Immune Deficiency 
Syndrome (AIDS), NCI’s Common Toxicity Criteria (CTC), and World Health Organization 
(WHO)) have been adapted for use by the DMID and modified to better meet the needs of 
participants in DMID trials. 
• 
For parameters not included in the following Toxicity Tables, sites should refer to the “Guide 
For Estimating Severity Grade” located above. 
• 
Criteria are generally grouped by body system. 
• 
Some protocols may have additional protocol specific grading criteria, which will supersede 
the use of these tables for specified criteria. 
 
 
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HEMATOLOGY 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Hemoglobin 
9.5 - 10.5 gm/dL 
8.0  - 9.4gm/dL 
6.5 - 7.9 gm/dL 
< 6.5 gm/dL 
Absolute Neutrophil 
Count 
1000-1500/mm3 
750-999/mm3 
500-749/mm3 
<500/mm3 
Platelets 
75,000- 
99,999/mm3 
50,000- 
74,999/mm3 
20,000- 
49,999/mm3 
<20,000/mm3 
WBCs 
11,000-13,000/ 
mm3 
13,000-15,000 
/mm3 
15,000- 
30,000/mm3 
>30,000 or <1,000 
/mm3 
% Polymorphonuclear 
Leucocytes + Band 
Cells 
> 80% 
90 – 95% 
>95% 
---------- 
Abnormal Fibrinogen 
Low: 
100-200 mg/dL 
High: 
400-600 mg/dL 
Low: 
<100 mg/dL 
High: 
>600 mg/dL 
Low: 
< 50 mg/dL 
---------- 
Fibrinogen 
associated with 
gross bleeding or 
with disseminated 
coagulation 
Fibrin Split Product 
20-40 mcg/ml 
41-50 mcg/ml 
51-60 mcg/ml 
> 60 mcg/ml 
Prothrombin Time (PT) 
1.01 - 1.25 x ULN 
1.26-1.5 x ULN 
1.51 -3.0 x ULN 
>3 x ULN 
Activated 
Partial 
Thromboplastin (APPT) 
1.01 -1.66 x ULN 
1.67 - 2.33 x ULN 
2.34 - 3 x ULN 
> 3 x ULN 
Methemoglobin 
5.0 - 9.9 % 
10.0 - 14.9 % 
15.0 - 19.9% 
> 20.0 % 
 
CHEMISTRIES 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Hyponatremia 
130-135 mEq/L 
123-129 mEq/L 
116-122 mEq/L 
< 116 mEq/L or abnormal 
sodium with mental status 
changes or seizures 
Hypernatremia 
146-150 mEq/L 
151-157 mEq/L 
158-165 mEq/L 
> 165 mEq/L or abnormal 
sodium with mental status 
changes or seizures 
Hypokalemia 
3.0 - 3.4 mEq/L 
2.5 - 2.9 mEq/L 
2.0 - 2.4 mEq/L or 
intensive 
replacement 
therapy or 
hospitalization 
required 
< 2.0 mEq/L or abnormal 
potassium with paresis, ileus 
or life-threatening arrhythmia 
Hyperkalemia 
5.6 - 6.0 mEq/L 
6.1 - 6.5 mEq/L 
6.6 - 7.0 mEq/l 
> 7.0 mEq/L or abnormal 
potassium with life- 
threatening arrhythmia 
Hypoglycemia 
55-64 mg/dL 
40-54 mg/dL 
30-39 mg/dL 
<30 mg/dL or abnormal 
glucose with mental status 
changes or coma 
Hyperglycemia 
(non-fasting and no 
prior diabetes) 
116 - 160 mg/dL 
161- 250 mg/dL 
251 - 500 mg/dL 
> 500 mg/dL or abnormal 
glucose with ketoacidosis or 
seizures 
 
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Hypocalcemia 
(corrected 
for 
albumin) 
8.4 - 7.8 mg/dL 
7.7 - 7.0 mg/dL 
6.9 - 6.1 mg/dL 
< 6.1 mg/dL or abnormal 
calcium with life threatening 
arrhythmia or tetany 
Hypercalcemia 
(correct for albumin) 
10.6 - 11.5 mg/dL 
11.6 - 12.5 
mg/dL 
12.6 - 13.5 mg/dL 
> 13.5 mg/dL or abnormal 
calcium with life threatening 
arrhythmia 
Hypomagnesemia 
1.4 - 1.2 mEq/L 
1.1 - 0.9 mEq/L 
0.8 - 0.6 mEq/L 
< 0.6 mEq/L or abnormal 
magnesium with life- 
threatening arrhythmia 
Hypophosphatemia 
2.0 - 2.4 mg/dL 
1.5 -1.9 mg/dL 
or replacement 
Rx required 
1.0 -1.4 mg/dL 
intensive therapy or 
hospitalization 
required 
< 1.0 mg/dL or abnormal 
phosphate with life- 
threatening arrhythmia 
Hyperbilirubinemia 
(when accompanied 
by any increase in 
other liver function 
test) 
1.1 - <1.25 x ULN 
1.25 - <1.5 x 
ULN 
1.5 – 1.75 x ULN 
 
> 1.75 x ULN 
Hyperbilirubinemia 
(when 
other 
liver 
function are in the 
normal range) 
1.1 - <1.5 x ULN 
1.5 - <2.0 x ULN 
2.0 – 3.0 x ULN 
> 3.0 x ULN 
BUN 
1.25 - 2.5 x ULN 
2.6 - 5 x ULN 
5.1 - 10 x ULN 
> 10 x ULN 
Hyperuricemia (uric 
acid) 
7.5 – 10.0 mg/dL 
10.1 – 12.0 
mg/dL 
12.1 – 15.0 mg/dL 
>15.0 mg/dL 
Creatinine 
1.1 - 1.5 x ULN 
1.6 - 3.0 x ULN 
3.1 - 6 x ULN 
> 6 x ULN or dialysis 
required 
 
ENZYMES 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
AST (SGOT) 
1.1 - <2.0 x ULN 
2.0 – <3.0 x ULN 
3.0 – 8.0 x ULN 
> 8 x ULN 
ALT (SGPT) 
1.1 - <2.0 x ULN 
2.0 – <3.0 x ULN 
3.0 – 8.0 x ULN 
> 8 x ULN 
GGT 
1.1 - <2.0 x ULN 
2.0 – <3.0 x ULN 
3.0 – 8.0 x ULN 
> 8 x ULN 
Alkaline Phosphatase 
1.1 - <2.0 x ULN 
2.0 – <3.0 x ULN 
3.0 – 8.0 x ULN 
> 8 x ULN 
Amylase 
1.1 - 1.5 x ULN 
1.6 - 2.0 x ULN 
2.1 - 5.0 x ULN 
> 5.1 x ULN 
Lipase 
1.1 - 1.5 x ULN 
1.6 - 2.0 x ULN 
2.1 - 5.0 x ULN 
> 5.1 x ULN 
 
URINALYSIS 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Proteinuria 
1+ or 200 mg - 1 
gm loss/day 
2-3+ or 1- 2 gm 
loss/day 
4+ or 2-3.5 gm 
loss/day 
nephrotic 
syndrome or > 3.5 
gm loss/day 
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Hematuria 
microscopic only 
<10 rbc/hpf 
gross, no clots >10 
rbc/hpf 
gross, with or 
without clots, OR 
red blood cell 
casts 
obstructive or 
required 
transfusion 
 
CARDIOVASCULAR 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Cardiac Rhythm 
asymptomatic, 
transient signs, no 
Rx required 
recurrent/persistent 
; symptomatic Rx 
required 
unstable 
dysrythmia; 
hospitalization and 
treatment required 
Hypertension 
transient increase 
> 20 mm/Hg; no 
treatment 
recurrent, chronic 
increase 
> 
20mm/Hg. 
/treatment required 
acute 
treatment 
required; 
outpatienttreatm 
ent 
or 
hospitalization 
possible 
end organ damage 
or 
hospitalization 
required 
Hypotension 
transient 
orthostatic 
hypotension with 
heart 
rate 
increased by <20 
beat/min 
or 
decreased by <10 
mm Hg systolic 
BP, No treatment 
required 
symptoms due to 
orthostatic 
hypotension or BP 
decreased by <20 
mm 
Hg 
systolic; 
correctable with oral 
fluid treatment 
requires IV fluids; 
no hospitalization 
required 
mean 
arterial 
pressure <60mm/ 
Hg or end organ 
damage or shock; 
requires 
hospitalization and 
vasopressor 
treatment 
Pericarditis 
minimal effusion 
mild/moderate 
asymptomatic 
effusion, 
no 
treatment 
symptomatic 
effusion; pain; EKG 
changes 
tamponade; 
pericardiocentesis 
or surgery required 
Hemorrhage, Blood 
Loss 
microscopic/occult 
mild, no transfusion 
gross blood loss; 
1-2 
units 
transfused 
massive blood 
loss; > 3 units 
transfused 
 
RESPIRATORY 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Cough 
Transient - no 
treatment 
persistent 
cough; 
treatment responsive 
Paroxysmal cough; 
uncontrolled with 
treatment 
-------------------- 
Bronchospasm, 
Acute 
transient; no 
treatment; 70% - 
80% FEV1 of peak 
flow 
requires treatment; 
normalizes with 
bronchodilator; FEV1 
50% - 70% (of peak 
flow) 
no normalization with 
bronchodilator;FEV1 
25% - 50% of peak 
flow; or retractions 
present 
cyanosis: FEV1 < 
25% of peak flow 
or intubation 
necessary 
Dyspnea 
dyspnea on exertion 
dyspnea with normal 
activity 
dyspnea at rest 
dyspnea requiring 
Oxygen therapy 
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GASTROINTESTINAL 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Nausea 
mild or transient; 
maintains 
reasonable intake 
moderate 
discomfort; intake 
decreased 
significantly; some 
activity limited 
no 
significant 
intake; requires IV 
fluids 
hospitalization 
required; 
Vomiting 
1 episode in 24 
hours 
2-5 episodes in 24 
hours 
>6 episodes in 24 
hours or needing 
IV fluids 
physiologic 
consequences 
requiring 
hospitalization 
or 
requiring 
parenteral nutrition 
Constipation 
requiring 
stool 
softener or dietary 
modification 
requiring laxatives 
obstipation 
requiring manual 
evacuation 
or 
enema 
obstruction or toxic 
megacolon 
Diarrhea 
mild or transient; 3- 
4 loose stools/day 
or 
mild 
diarrhea 
last < 1 week 
moderate 
or 
persistent; 5-7 loose 
stools/day 
or 
diarrhea lasting >1 
week 
>7 loose stools/day 
or bloody diarrhea; 
or 
orthostatic 
hypotension 
or 
electrolyte 
imbalance or >2L 
IV fluids required 
hypotensive shock 
or 
physiologic 
consequences 
requiring 
hospitalization 
Oral 
Discomfort/Dysphagia 
mild discomfort; no 
difficulty 
swallowing 
some limits on 
eating/drinking 
eating/talking very 
limited; unable to 
swallow solid foods 
unable to drink 
fluids; requires IV 
fluids 
 
NEUROLOGICAL 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Neuro-Cerebellar 
slight 
incoordination 
dysdiadochokinesis 
intention 
tremor, 
dysmetria, slurred 
speech; nystagmus 
locomotor ataxia 
incapacitated 
Psychiatric 
mild anxiety or 
depression 
moderate anxiety or 
depression; therapy 
required; change in 
normal routine 
severe 
mood 
changes requiring 
therapy; or suicidal 
ideation; 
or 
aggressive ideation 
acute 
psychosis 
requiring 
hospitalization;  or 
suicidal 
gesture/attempt or 
hallucinations 
Muscle Strength 
Subjective 
weakness 
no 
objective 
symptoms/ signs 
mild 
objective 
signs/symptoms no 
decrease in function 
objective 
weakness function 
limited 
paralysis 
Paresthesia (burning, 
tingling, etc.) 
mild discomfort; no 
treatment required 
moderate 
discomfort; 
non- 
narcotic analgesia 
required 
severe discomfort; 
or 
narcotic 
analgesia required 
with symptomatic 
improvement 
incapacitating; or 
not responsive to 
narcotic analgesia 
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Neuro-sensory 
mild impairment in 
sensation 
(decreased 
sensation, 
e.g., 
vibratory, pinprick, 
hot/cold in great 
toes) in focal area 
or 
symmetrical 
distribution; 
or 
change in 
taste, 
smell, vision and/or 
hearing 
moderate 
impairment 
(mod 
decreased 
sensation, 
e.g., 
vibratory, pinprick, 
hot/cold to ankles) 
and/or joint position 
or mild impairment 
that 
is 
not 
symmetrical 
severe impairment 
(decreased or loss 
of 
sensation 
to 
knees or wrists) or 
loss of sensation of 
at 
least 
mod 
degree in multiple 
different 
body 
areas (i.e., upper 
and 
lower 
extremities) 
sensory 
loss 
involves limbs and 
trunk; paralysis; or 
seizures 
 
MUSCULOSKELETAL 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Arthralgia (joint pain) 
mild pain not 
interfering with 
function 
moderate 
pain, 
analgesics 
and/or 
pain interfering with 
function but not with 
activities 
of 
daily 
living 
severe pain; pain 
and/or analgesics 
interfering 
with 
activities of daily 
living 
disabling pain 
Arthritis 
mild 
pain 
with 
inflammation, 
erythema or joint 
swelling – but not 
interfering 
with 
function 
moderate pain with 
inflammation, 
erythema 
or 
joint 
swelling – interfering 
with function, but not 
with 
activities 
of 
daily living 
severe pain with 
inflammation, 
erythema or joint 
swelling 
–and 
interfering 
with 
activities of daily 
living 
permanent and/or 
disabling 
joint 
destruction 
Myalgia 
myalgia 
with 
no 
limitation of activity 
muscle tenderness 
(at 
other 
than 
injection site) or with 
moderate 
impairment 
of 
activity 
severe 
muscle 
tenderness 
with 
marked impairment 
of activity 
frank 
myonecrosis 
 
SKIN 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Mucocutaneous 
erythema; pruritus 
diffuse, 
maculo 
papular rash, dry 
desquamation 
vesiculation or moist 
desquamation 
or 
ulceration 
exfoliative 
dermatitis, mucous 
membrane 
involvement 
or 
erythema, 
multiforme 
or 
suspected Stevens- 
Johnson or necrosis 
requiring surgery 
Induration 
< 15mm 
15-30 mm 
>30mm 
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Erythema 
< 15mm 
15-30 mm 
>30mm 
Edema 
< 15mm 
15-30 mm 
>30mm 
Rash at Injection 
Site 
< 15mm 
15-30 mm 
>30mm 
Pruritus 
slight itching at 
injection site 
moderate itching at 
injection extremity 
itching over entire 
body 
 
SYSTEMIC 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Allergic Reaction 
pruritus without rash 
localized urticaria 
generalized 
urticaria; 
angioedema 
anaphylaxis 
Headache 
mild, no treatment 
required 
transient, moderate; 
treatment required 
severe; responds to 
initial 
narcotic 
therapy 
intractable; requires 
repeated 
narcotic 
therapy 
Fever: oral 
37.7 - 38.5 C or 
100.0 - 101.5 F 
38.6 - 39.5 C or 
101.6 - 102.9 F 
39.6 - 40.5 C or 103 
- 105 F 
> 40 C or > 105 F 
Fatigue 
normal 
activity 
reduced < 48 hours 
normal 
activity 
decreased 25- 50% 
> 48 hours 
normal 
activity 
decreased > 50% 
can’t work 
unable to care for 
self 
 
 
 
 
 
 
 
 
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Page 98 of 101 
Appendix 3: Who Clinical Staging of HIV/AIDS for Adults and Adolescents  
Primary HIV Infection 
Asymptomatic 
Acute retroviral syndrome 
Clinical Stage 1 
Asymptomatic 
Persistent generalized lymphadenopathy 
Clinical Stage 2 
Moderate unexplained weight loss (<10% of presumed or measured body weight) 
Recurrent respiratory infections (sinusitis, tonsillitis, otitis media, and pharyngitis) 
Herpes zoster 
Angular cheilitis 
Recurrent oral ulceration 
Papular pruritic eruptions 
Seborrheic dermatitis 
Fungal nail infections 
Clinical Stage 3 
Unexplained severe weight loss (>10% of presumed or measured body weight) 
Unexplained chronic diarrhea for >1 month 
Unexplained persistent fever for >1 month (>37.6ºC, intermittent or constant) 
Persistent oral candidiasis (thrush) 
Oral hairy leukoplakia 
Pulmonary tuberculosis (current) 
Severe presumed bacterial infections (e.g., pneumonia, empyema, pyomyositis, bone 
or joint infection, meningitis, bacteremia) 
Acute necrotizing ulcerative stomatitis, gingivitis, or periodontitis 
Unexplained anemia (hemoglobin <8 g/dL) 
Neutropenia (neutrophils <500 cells/µL) 
Chronic thrombocytopenia (platelets <50,000 cells/µL) 
Clinical Stage 4 
HIV wasting syndrome 
Pneumocystis pneumonia 
Recurrent severe bacterial pneumonia 
Chronic herpes simplex infection (orolabial, genital, or anorectal site for >1 month or 
visceral herpes at any site) 
Esophageal candidiasis (or candidiasis of trachea, bronchi, or lungs) 
Extrapulmonary tuberculosis 
Kaposi sarcoma 
Cytomegalovirus infection (retinitis or infection of other organs) 
Central nervous system toxoplasmosis 
HIV encephalopathy 
Cryptococcosis, extrapulmonary (including meningitis) 
Disseminated nontuberculosis mycobacteria infection 
Progressive multifocal leukoencephalopathy 
Candida of the trachea, bronchi, or lungs 
Chronic cryptosporidiosis (with diarrhea) 
Chronic isosporiasis 
Disseminated mycosis (e.g., histoplasmosis, coccidioidomycosis, penicilliosis) 
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Recurrent nontyphoidal Salmonella bacteremia 
Lymphoma (cerebral or B-cell non-Hodgkin) 
Invasive cervical carcinoma 
Atypical disseminated leishmaniasis 
Symptomatic HIV-associated nephropathy 
Symptomatic HIV-associated cardiomyopathy 
Reactivation of American trypanosomiasis (meningoencephalitis or myocarditis) 
 
REF: World Health Organization. WHO Case Definitions of HIV for Surveillance and Revised Clinical Staging and Immunological 
Classification of HIV-Related Disease in Adults and Children; 2007 
Vital Signs 
The following abnormalities will be defined for vital signs: 
Abnormality Code 
Vital Signs Parameter 
 
Pulse 
DBP 
SBP 
RR 
Abnormalities on actual values 
“Abnormally low” 
≤ 50 bpm 
≤ 50 mmHg 
≤ 90 mm Hg 
<12 
Breaths per minute 
“Grade 1 or mild” 
- 
> 
90 
mmHg-
<100 mmHg 
> 140 mmHg-
<160 mmHg 
17-20 
Breaths per minute 
“Grade 2 or moderate” 
- 
≥ 100 mmHg-
<110 mmHg 
≥ 160 mmHg-
<180 mmHg 
21-25 
Breaths per minute 
“Grade 3 or severe” 
- 
≥ 110 mmHg 
≥ 180 mmHg 
>25 
Breaths per minute 
“Abnormally high or Grade 
4” 
≥ 120 bpm 
- 
- 
Intubation 
 
 
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Appendix 4: Cardiovascular Safety 
CARDIOVASCULAR 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Cardiac 
Rhythm 
 
asymptomatic, 
transient signs, 
no Rx required 
recurrent/persisten
t; symptomatic Rx 
required 
unstable dysrythmia; 
hospitalization and 
treatment required 
Hypertension 
transient increase > 
20 mm/Hg; no 
treatment 
recurrent, chronic 
increase > 
20mm/Hg. 
/treatment 
required 
acute treatment 
required; 
outpatient 
treatment or 
hospitalization 
possible 
end organ damage 
or hospitalization 
required 
Hypotension 
transient orthostatic 
hypotension with 
heart rate increased 
by <20 beat/min or 
decreased by <10 
mm Hg systolic BP, 
no treatment 
required. 
symptoms due to 
orthostatic 
hypotension or 
BP decreased by 
<20 mm Hg 
systolic; 
correctable with 
oral fluid 
treatment 
requires IV fluids; 
no hospitalization 
required 
mean arterial 
pressure <60mm/ 
Hg or end organ 
damage or shock; 
requires 
hospitalization and 
vasopressor 
treatment 
Pericarditis 
minimal effusion 
mild/moderate 
asymptomatic 
effusion, no 
treatment 
symptomatic 
effusion; pain; 
EKG changes 
tamponade; 
pericardiocentesis or 
surgery required 
Hemorrhage, 
Blood Loss 
microscopic/occult 
mild, no 
transfusion 
gross blood loss; 
1-2 units 
transfused 
massive blood loss; 
> 3 units transfused 
All-important abnormalities from the ECG readings will be reported. 
The percentage of participants with increases in QTc of <30, 30-60, or > 60 ms from baseline will 
also be tabulated at each time point. 
Abnormality Code 
ECG parameter 
 
HR 
PR 
QRS 
QTcorrected 
Abnormalities on actual values 
“Abnormally low” 
≤ 50 bpm 
NAP 
≤ 50 ms 
- 
“Abnormally high” 
≥ 120 bpm 
≥ 210 ms 
≥ 120 ms 
- 
“]450 ms, 480 ms] 
- 
- 
- 
450 ms < QTc ≤ 480 ms 
“]480 ms, 500 ms] 
- 
- 
- 
480 ms < QTc ≤ 500 ms 
“More than 500 ms 
- 
- 
- 
QTc > 500 ms 
Abnormalities on changes from baseline 
“[30; 60] ms” 
- 
- 
- 
[30; 60] ms 
“> 60 ms” 
- 
- 
- 
> 60 ms 
 
 
 
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CONFIDENTIAL 
Page 101 of 101 
Appendix 5: Karnofsky Performance Status Scale Definitions Rating (%) Criteria 
Description 
% 
Able to carry on normal activity 
and to work; no special care 
needed. 
Normal no complaints; no evidence of disease. 
100 
Able to carry on normal activity; minor signs or 
symptoms of disease. 
90 
Normal activity with effort; some signs or symptoms 
of disease.  
80 
Unable to work; able to live at 
home 
and 
care 
for 
most 
personal needs; varying amount 
of assistance needed. 
Cares for self; unable to carry on normal activity or 
to do active work. 
70 
Requires occasional assistance, but is able to care 
for most of his personal needs. 
60 
Requires considerable assistance and frequent 
medical care.  
50 
Unable to care for self; requires 
equivalent of institutional or 
hospital care; disease may be 
progressing rapidly. 
Disabled; requires special care and assistance. 
40 
Severely disabled; hospital admission is indicated 
although death not imminent. 
30 
Very sick; hospital admission necessary; active 
supportive treatment necessary. 
20 
Moribund; fatal processes progressing rapidly. 
10 
Dead 
0 
 
Ref: Oxford Textbook of Palliative Medicine, Oxford University Press.  1993; 109. 
 
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Protocol Amendment  
or Administrative Change 
 
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CONFIDENTIAL 
This document is proprietary and shall not be reproduced without prior written permission from TB Alliance. 
Lead Trial Number 
Trial Name
NC-008 
SimpliciTB 
x   Protocol Amendment Number 2, Dated 14/JAN/2019 
 Protocol Administrative Change Number _ _, Dated _ _/_ _ _/_ _ _ _ 
Summary - Protocol section changed 
Does amendment / 
administrative change 
affect any of the 
elements listed? 
YES
NO
A 
Purpose of trial 
 
x 
B 
Design of trial 
 
x 
C 
Informed consent 
x 
 
D 
Recruitment procedure 
 
x 
E 
Measures of efficacy 
 
x 
F 
Schedule of samples 
 
x 
G 
Addition or deletion of tests or measures 
x 
 
H 
Number of participants 
x 
 
I 
Age range of participants 
 
x 
J 
Inclusion criteria 
x 
 
K 
Exclusion criteria 
x 
 
L 
Safety monitoring 
x 
 
M 
Duration of exposure to the investigational medicinal product(s) 
 
x 
N 
Change of posology of the investigational medicinal product(s) 
 
x 
O 
Change of comparator 
 
x 
P 
Statistical analysis 
x 
 
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CONFIDENTIAL 
This document is proprietary and shall not be reproduced without prior written permission from TB Alliance. 
Reasons for Protocol Amendment or Administrative Change: 
1 
Change: All references to The Global Alliance for TB Drug Development have been changed to TB Alliance (TBA).  The correct and current TBA logo has been 
placed into the header of the protocol, on the cover page. 
2 
Delete: Lead Investigator signature filed, as there has not been in the past 
unnecessary RA and EC queries, as experienced with the review and approval cycles of the prior Protocol Versions 1.0 and 2.0. 
3 
Add: Abbreviations and Definition of Terms - DST, Drug Susceptibility Testing 
4 
Add: Abbreviations and Definition of Terms - HR, Hazard Ratio 
5 
Change: Abbreviations and Definition of Terms - LTFU, previously described as Long-Term Follow-up, changed to Lost to Follow-up in the section 
6 
Add: Abbreviations and Definition of Terms - WGS, Whole Genome Sequencing. 
7 
Delete: 1.1 Synopsis Summary, Section Trial Objective(s) - description and treatment duration from the as it is not applicable to this section. 
8 
Add:  1.1 Synopsis Summary, Statistical Methods  description of abbreviated definitions from the SAP to provide further clarity 
9 
Clarify: 1.1 Synopsis Summary and Protocol Section 6.1.2 Instructions for Dosing Control Treatment Regimen (HRZE/HR) - The participants weight at the 
Screening (HRZE) and Week 8 (HR) visits will be used to determine which weight band and HRZE and HR does to administer, to ensure optimal dosing at these
2 time-points when changing from HRZE to HR. 
10
Clarify: 1.1 Synopsis Summary and Protocol Section 6.3 Treatment Modification(s)  If more than 7 to  35 consecutive doses are missed, these must be made 
up with the same treatment combination or dose that was missed, as the Bedaquiline dose (BPaMZ treatment regime) changes from 200mg to 100 mg at Week 
9, and from HRZE to HR at Week 9 (HRZE/HR treatment regime).  
 
11
Change:  1.1 Synopsis, Statistical Methods and Protocol Section 9.0 Statistical Analysis - the Statistical Analysis Plan (SAP) will be written and signed of prior 
to the interim analysis. 
12
Change: 1.1 Synopsis, Statistical Methods and Protocol Section 9.3 Interim Analysis - There is one planned interim efficacy analysis which will occur after 
approximately 60 assessable participants have been randomised to the control arm and have reached the 8-week primary endpoint. Time to culture negative 
status in liquid media up to 8 weeks will be analysed using a Cox regression model, censoring for death and lost to follow up/withdrawal to estimate the hazard 
ratio (HR). Following a review of these interim findings, the following considerations will be given to modify the trial objectives and sample size: 
 
If the observed HR (time to culture negativity, experimental arm vs. HRZE control arm) is >2, the sample size may be increased to adequately power the study 
on the key secondary efficacy endpoint (clinical and microbiological outcome at 52 weeks from randomization), which will then become the primary efficacy 
endpoint. The study efficacy objectives will be updated as follows: 
 
- 
Primary Objective: To determine the incidence of bacteriologic failure or relapse or clinical failure at 52 weeks from the start of treatment / 
randomisation.  
- 
Secondary Objective: To evaluate the time to culture negativity over 8 weeks, from the start of treatment / randomisation. 
 
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TMP-C-SOP01-C V1.0 30-Nov-2018 
CONFIDENTIAL 
This document is proprietary and shall not be reproduced without prior written permission from TB Alliance. 
To achieve 90% power and overall 5% 2-sided significance after adjusting for the interim analysis, this will mean increasing the sample size to 
225 participants per randomised arm, i.e., to a total of 450 DS-TB participants (and up to 225 DR-TB participants). This adaptation is based on the Multi-arm 
Multi-stage (MAMS) framework and full details are provided in the Statistical Analysis Plan. 
13
Delete: Synopsis, Trial Duration  removed reference to 3 database locks as it is not applicable to the trial duration. 
14
Clarify: 1.2 Synopsis Flow Chart and Procedures - Week 1 occurs on Day 8 and not Day 7 (Day 7 deleted), as per Protocol Memo 1 dated 11 May 2018, to 
ensure that 7 days of IMP are administered to the participant between Day 1 / Baseline and Week 1. 
15
Change: 1.2 Synopsis and Flow Chart (foot note) General:  vital signs and blood draws (removed ECGs) are to be performed before dosing, unless otherwise 
specified.  Vital signs and or ECGs should be done before blood draws (safety and PK) on days with those assessments. 
16
Change: Synopsis and Flow Chart (foot note, a)  Screening assessments must occur during the Screening period (Day -9 to -1) before Day 1 (Baseline). This 
has been amended for clarity. 
17
Clarify: 1.2 Synopsis and Flow Chart (foot note, f) that rifampicin resistance testing includes Hain MTBDRPlus and Hain MTBRsl. 
18
Clarify: 1.2 Synopsis and Flow Chart (foot note, f) that unscheduled visits referenced in this section, are for the collection of additional sputum samples. 
19
Change: 1.2 Synopsis and Flow Chart (foot note, f) if sputum samples collected at Week 8 or later (remove reference to Weeks 17, 26, 52 and 104) are 
contaminated the participant return for an unscheduled visit. 
20
Change: 1.2 Synopsis and Flow Chart (foot note, g) Rapid molecular tests will be done for fluoroquinolones, injectables, isoniazid and rifampicin resistance 
(only on MTB positive cultures in the follow-up period) and Drug Susceptibility Testing will be done for streptomycin, rifampicin, isoniazid, ethambutol, 
moxifloxacin and pyrazinamide only, in liquid culture 
21
Add: 1.2 Synopsis and Flow Chart (foot note, n)  Additional single 12-lead ECGs to be performed prior to pre- and post-dose PK sampling to observe the 
cardiac safety profile at defined timepoints after dosing, over time, on these days (weeks 2, 8 and 17). 
22
Add: 1.2 Synopsis and Flow Chart (foot note, s) Blood draws for PK samples collected pre and post-dose must be done after the ECG is performed, as 
-dose. 
23
Add: 1.2 Synopsis and Flow Chart (foot note, s) PK samples at Weeks 39, 65, 78 and 104 are to be obtained at any time on the day of the scheduled visit, and 
only bedaquiline and M2 will be measured. 
24
Add: 1.2 Synopsis and Flow Chart (foot note, s) and Protocol Section 7.4 PK Variables and Procedures - If IMP is not administered during Week 2, 8 and or 17, 
then only a single PK sample is required to be obtained at any time during the visit assessment. 
25
Clarify: 1.2 Synopsis and Flow Chart (foot note, v) the Investigator Assessment, per the Synopsis and Flow Chart, is only performed at Week 52 and 104 or 
anytime the Investigator determines that the participant fulfills the criteria for outcome of treatment failure. 
26
Add: 1.2 Synopsis and Flow Chart (additional foot note, x) and Protocol Section 7.1 Demographic and Background Variables and Procedures - The Karnofsky 
Score is only to be performed on HIV+ participants. 
27
Clarify: Protocol Section 3.1 Primary Endpoint - To evaluate the time to culture negativity over 8 weeks from the start of the following treatment regimens in 
participants with: Drug Sensitive TB (DS-TB) and Drug Resistant TB (DR-TB). DR-TB are defined as participants with: mono-resistance to rifampicin or 
isoniazid, OR resistance to both rifampicin and isoniazid (DR-TB).  The treatment allocation descriptions have been removed as they are irrelevant to this 
section. 
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Protocol Number: NC-008 
Protocol Amendment No.: 2 / 14-JAN-2019 
Protocol Name: SimpliciTB 
 
 
Protocol Amendment  
or Administrative Change 
 
TMP-C-SOP01-C V1.0 30-Nov-2018 
CONFIDENTIAL 
This document is proprietary and shall not be reproduced without prior written permission from TB Alliance. 
28
Clarify: Protocol Section 3.2 Secondary Endpoints, PK and PD - Plasma concentrations from sparse sampling will be used to update existing population PK 
models and derive exposure metrics (e.g., minimum plasma concentration [Cmin], maximum plasma concentration [Cmax], area under curve over a 
dosing interval [AUC]) for bedaquiline and its M2 metabolite, pretomanid, moxifloxacin, and pyrazinamide. 
29
Clarify: Protocol Section 4.1 Summary of Trial Design - Participants, trial Investigators and staff, including laboratory staff, will not be blinded to treatment 
randomisation and allocation (as all DR-TB participants are allocated and not randomised, to only receive 6 months BPaMZ) during the treatment phase of the 
trial. 
30
Clarify: Protocol Section 4.1 has been re-written to state that DS participants will be randomized (either to HRZE/HR or 4 months BPaMZ) and all DR 
participants will be allocated and not randomized to 6 months BPaMZ. 
31
Change: Protocol Section 5.1 Inclusion Criteria #5 has been changed to the following for the DS-TB treatment arm participants: sensitive to rifampicin, isoniazid 
and fluoroquinolones by rapid sputum-based test. 
32
Change: Protocol Section 5.1 Inclusion Criteria #5 has been changed to not (late) exclude DS-TB participants who are randomized to the trial due to being 
sensitive to rifampicin and isoniazid by rapid molecular sputum-based test, however on receipt of the rifampicin and or isoniazid phenotypic resistance testing in 
liquid culture this shows they are rifampicin or isoniazid resistant. 
33
Change: Protocol Section 5.1 Inclusion Criteria #5 has been changed for the DR-TB treatment arm participants, as follows:  
 
- 
Resistant to rifampicin and/or isoniazid; but sensitive to fluoroquinolones by rapid sputum-based test AND  
- 
Should not have had previous treatment for DR-TB/MDR-TB, although may have been on a DR-TB/MDR-TB treatment regimen for no longer than 3 
days (previously, was 7 days) at start of screening. 
- 
Participants with resistance to injectables by rapid sputum-based test are allowed in the trial. 
- 
When Phenotypic DST and whole genome sequencing (WGS) results on baseline samples become available, any results that are discordant with the 
 trial will be reviewed by the Sponsor Medical Monitor in consultation with 
the Investigator to determine whether that participant is unlikely to respond to treatment and should therefore be removed from the trial and given 
alternative treatment.  If a participant is removed from the trial for such a reason, they will be classified as a late exclusion. 
34
Change: Protocol Section 5.1 Inclusion Criteria #7, Contraception  Contraception has been updated to require that both the female trial participants and the 
Barrier method combined with hormone-based contraceptives or an intra-
uterine device.   
 
Both male and female participants must be willing to continue practicing birth control methods and are not planning to conceive throughout treatment and for 6 
months (previously stated in this section as 3 months) after the last dose of trial IMP or discontinuation from trial IMP in case of premature discontinuation, to 
ensure consistency throughout the protocol, as per Section 5.2 Exclusion Criteria #13 that also references a period of 6 months.  
35
Add: Protocol Section 5.2 Exclusion Criteria #3 - Historical and or current use of local traditional medications/herbs which in the opinion of the Investigator 
-specified restrictions, visits and evaluations. 
36
Delete: Protocol Section 5.2 Exclusion Criteria #9 - Resistant to fluoroquinolones (rapid, sputum-based molecular screening tests). If they are randomised into 
the trial due to being sensitive to fluoroquinolones by rapid sputum-based test, however on receipt of the moxifloxacin phenotypic resistance testing in liquid 
culture they are found to be fluoroquinolones resistant, they will be excluded as late exclusions. This criterion is already stipulated in the updated Inclusion 
Criteria #5.  
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Protocol Amendment No.: 2 / 14-JAN-2019 
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Protocol Amendment  
or Administrative Change 
 
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CONFIDENTIAL 
This document is proprietary and shall not be reproduced without prior written permission from TB Alliance. 
37
Change: Protocol Section 5.2 Exclusion Criteria #14, 15, 16 and 17, as these criteria are consolidated and described more specifically in the updated Exclusion 
Criteria #14, including an update to a limit of 3 days previous DR-TB/MDR-TB treatment regimen for the DR-TB participants. 
38
Clarify: Protocol Section 5.2 Exclusion Criteria #17 (previously #20) has been corrected, as follows:  Use of systemic glucocorticoids within one year of the start 
of the Screening visit (topical, inhaled or intranasal glucocorticoids are allowed), as they can lead to visual opacities or cataracts. 
39
Add: Protocol Section 5.2 Exclusion Criteria #18 (previously #21) has been extended to provide additional instructions wrt ART for HIV infected participants. 
40
Delete: Protocol Section 5.2 Exclusion Criteria #19 (previously #22) has been updated to remove the DMID grade for platelets, haemoglobin, AST, ALT, ALP 
and total bilirubin to provide clarity and remove ambiguity.  The actual values of these laboratory results remain unchanged. 
41
Delete: Protocol Section 5.3 Restrictions  1st paragraph, 2nd sentence has 
However, 
or. 
42
Clarify: Protocol Section 5.3 Restrictions  The section that describes medications that should be avoided has been updated to state the following:  The 
following medicinal products should be avoided from Day 1 (Baseline visit) and during the treatment period as much as possible (unless this is required for 
emergency management of the participant). Investigators may also contact the Sponsor Medical Monitor for further guidance. 
43
Delete: Protocol Section 5.3 Restrictions  
 the list of medications to be avoided, since it is a contraceptive requirement 
(Inclusion Criteria #7) to participate in this trial. 
44
Change:  Protocol Section 5.4 Treatment Discontinuation and/or Early Withdrawal, as the criteria for late exclusion based on phenotypic DST and whole 
genome sequencing has been amended. 
45
Delete: Protocol Section 5.4 Treatment Discontinuation and/or Early Withdrawal  the following 2 reasons for withdrawal have been removed, due to the 
updated Inclusion Criteria #5: 
- 
Participants, who have been randomised onto the trial as fluoroquinolone sensitive on the rapid sputum-based test result, who on receipt of the 
fluoroquinolone resistance testing using an indirect susceptibility test in liquid culture; this shows a fluoroquinolone resistant result. 
- 
Early withdrawal due to TB (removed as this is now detailed in the additional criteria listed in item #44 above) 
46
Clarify: Protocol Section 5.4.2 Unscheduled Visits has been updated to provide additional clarity, as follows: 
- 
Addition of the following reason: For any medical reason, as determined by the Investigator or participant. 
- 
End of Treatment Period (Week 17 or 26) has been removed from the timepoint at which sputum cultures are assessed for the primary outcome status, 
as this was incorrectly stated in the previous protocol 
- 
General rewording of this section to provide clarity to the Investigator on when Unscheduled Assessments should occur 
- 
Addition of Table 6: Summary of Scenarios Requiring Unscheduled Visit for 
Unscheduled Assessment requirements. 
- 
should 
 
47
Clarify: Protocol Section 5.4.4 Early Withdrawal due to TB  last paragraph has been updated to ensure that the Investigator provides a referral letter and at a 
minimum should include all treatment received by the participant and information about any suspected/confirmed adverse event/reaction related to any of the 
 A follow-up call should 
by the trial site staff to the clinic to ensure the 
participant attended the NTP clinic. 
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48
Clarify: Protocol Section 7.1 Demographic and Background Variables and Procedures  The following 2 descriptions of testing as documented in Section 7.5 
Mycobacteriology Characterization Variable and Procedures: 
- 
Rapid molecular tests for isoniazid, rifampicin, fluoroquinolones resistance (Hain MTBDRplus and HainMTBRsl) 
- 
Liquid Culture (MGIT) for Mycobacterium tuberculosis (MTB), followed by a speciation test to detect presence or absence of MTB and obtain time to 
positivity (TTP) when positive. 
Delete:  Protocol Section 7.1 Demographic and Background Variables and Procedures - Gene Xpert, as this was incorrectly included in the previous version of 
the protocol. 
49
Clarify: Protocol Section 7.1 Demographic and Background Variables and Procedures  method of birth control: make and female participants and their sexual 
partners 
50
Delete:  Protocol Section 7.4 PK Variables and Procedures  references to linezolid and the NiX-TB trial, as these were incorrectly included in the previous 
version of the protocol. 
51
Clarify:  Protocol Section 7.5 Mycobacteriology Characterization Variable and Procedures  exact wording documented in 1.2 Synopsis and Flowchart 
(footnote, g) to ensure consistency of procedure description. 
 
Delete: Pre-screening culture that was used for the tests that qualified the participant for inclusion into the trial to be sub-cultured and sent to the central 
microbiology laboratory from the applicable local microbiology laboratory, for relevant participants / no positive culture
because only assessments perform from the Screening visit will be used for this trial. 
 
Change: Protocol Section 7.5 Mycobacteriology Characterization Variable and Procedures  all MTB isolates (not just those obtained at Baseline / Day 1, as 
 
52
Clarify: Protocol Section 8.2.1 Follow-up of Adverse Events  reference to the reporting requirements is now referenced as the eCRF Guidelines (incorrectly 
referenced as SAE Completion Guidelines, in the previous version of the protocol). 
53
Clarify: Protocol Section 8.2.6 Pregnancy  reporting required at any time during the trial. 
54
Delete: Protocol Section 8.3 Monitoring for Specific Toxicities  16.3.3 Neurological, has been removed, as it is not a requirement given the safety profiles of the 
BPaMZ and or HRZE/HR trial regimens. 
55
Add: (moved from the Synopsis): Protocol Section 9.0 Statistical Analysis  added the following:  There will be 3 data analyses and trial reports generated for 
this trial:  
- 
When all participants have completed 8 weeks (2 months) of treatment from baseline.  
- 
When all participants have completed 52 weeks (12 months) follow-up from start of therapy. 
- 
When all participants have completed 104 weeks (24 months) follow-up from start of therapy.  
56
Delete: Protocol Section 11.3 Protocol Deviations  reference to the Monitoring Plan has been removed as the Investigator is not provided with this plan, and 
therefore would not deviate from this plan. 
57
Delete: Removal of the following appendixes and references in the protocol, as these appendixes are now included in separate trial documents, and provided to 
the Investigator: 
- 
Appendix 6 TB Symptom Profile is 
 
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- 
Appendix 7 Patient Reported Health Status is 
 
- 
 
58
Clarify:  Protocol Section 5.2 Exclusion Criteria  with the addition of criteria #3, deletion of #9, 14, 15 the numbering of the Exclusion Criteria has had to 
change. 
59
Change:  Tables  with the addition of Table #5, Tables 5 to 7 become Tables 6 to 8  
60
Change:  all references to the 2 treatment periods of Week 17 (4-month treatment arm) and Week 26 (6-month treatment arm) are stated as either Week 17 or 
Week 26, only. 
61
Change:  
 
62
Change:  
 
63
Change: all references to B-Pa-M-Z have been changed to BPaMZ. 
64
Change: all references to therapy  has been changed to treatment  for consistency. 
65
Change: all references to early morning sample or early morning sputum, has been changed to 
 
66
Change:  all references to Drug Resistant TB (DR-TB) and Drug Sensitive TB (DS-TB), are documented as either DS-
 
67
Change:  all references to trial medication and or study medication, has been changed t
 
68
Delete: all references to study time points 
.  All study time points are only referenced in weeks. 
69
Administrative changes, including spelling, grammar, format, 
updated throughout the entire document.   
# 
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1 
Cover Page 
Global Alliance for TB Drug Development 
TB Alliance 
 
1 
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2 
Protocol 
signature page 
2 
3 
Abbreviations 
and Definitions of 
Terms 
No previous text 
DST 
Drug Susceptibility Testing 
 
3 
4 
Abbreviations 
and Definitions of 
Terms 
No previous text 
HR 
Hazard Ratio 
4 
5 
Abbreviations 
and Definitions of 
Terms 
LTFU 
Long term follow-up 
LTFU Lost to Follow-up 
5 
6 
Abbreviations 
and Definitions of 
Terms 
No previous text 
WGS
Whole Genome Sequencing
6 
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7 
1.1 Synopsis 
Summary, Trial 
Objectives 
To evaluate the efficacy, safety and tolerability at 8 weeks 
(2-months), 52 weeks (12-months), and 104 Weeks (24-
months) post the start of the following treatment regimens 
in participants with: 
 
Drug Sensitive TB (DS-TB) 
 
BPaMZ given for 17 Weeks (4 months), or 
 
Standard HRZE/HR treatment given for 26 weeks 
(6  
months) 
 
Drug Resistant TB (DR-TB)  
 
BPaMZ given for 26 Weeks (6 months) 
 
DR-TB Defined as participants with  
1. mono-resistance to rifampicin or isoniazid, OR 
2. resistance to both rifampicin and isoniazid (MDR-TB) 
To evaluate the efficacy, safety and tolerability at 8 weeks 
(2-months), 52 weeks (12-months), and 104 Weeks (24-
months) post the start of the following treatment regimens 
in participants with: 
 
Drug Sensitive TB (DS-TB) 
 
BPaMZ given for 17 Weeks (4 months), or 
 
Standard HRZE/HR treatment given for 26 weeks 
(6  
months) 
 
Drug Resistant TB (DR-TB)  
 
BPaMZ given for 26 Weeks (6 months) 
 
DR-TB Defined as participants with  
1. mono-resistance to rifampicin or isoniazid, OR 
2. resistance to both rifampicin and isoniazid (MDR-TB) 
7 
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8 
1.1 Synopsis 
Summary, 
Statistical 
Methods 
No previous text to describe the abbreviated SAP 
definitions 
Abbreviated Definitions, full definitions will be 
described in the Statistical Analysis Plan (SAP):  
 
 
Bacteriologic failure: During the treatment period, 
failure to attain or maintain culture conversion to 
negative.  
 
Bacteriologic relapse: During the follow-up 
period, failure to maintain culture conversion to 
negative status, with culture conversion to 
positive status with a strain of Mycobacterium 
tuberculosis (MTB) genetically identical to the 
infecting strain at baseline.  
 
Clinical failure: A change from protocol-specified 
TB treatment to a new regimen before end of 
protocol specified treatment due to treatment 
failure, retreatment for TB during follow up, or TB-
related death.  
 
Note:  
 
o 
Culture conversion requires at least 2 
consecutive culture negative/positive samples 
at least 7 days apart.  
o 
Participants who are documented at a visit as 
unable to produce sputum and who are 
clinically considered to be responding well to 
treatment will be considered to be culture 
negative at that visit.  
 
8 
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9 
1.1 Synopsis 
Summary, 
Positive Control 
Product, Dose 
and Mode of 
Administration 
and Protocol 
Section 6.1.2 
No previous text 
Week 8 (HR) visits will be used to determine which 
weight band and HRZE and HR dose to administer. 
 
9 
10
1.1 Synopsis 
Summary, 
Treatment 
Interruptions 
/Pauses and 
Protocol Section 
6.3 
 
Up to 7 consecutive doses of IMP doses: restart 
IMP, no extension of IMP required. 
 
Greater than 
restart IMP and extend the IMP treatment by the 
number of consecutive doses missed. The final 
treatment visit should also be pushed out to the 
date of last dose. It is not necessary to have an 
unscheduled visit at the time when the end of 
treatment visit would have been.   
 
Greater than 35 consecutive doses of IMP, 
discontinue IMP and withdraw participant from the 
trial. 
 
If the participant misses a total (sum) of 56 
cumulative missed doses, discontinue the IMP 
and withdraw participant from the trial. 
 
 
Up to 7 consecutive doses of IMP doses: restart 
IMP, no extension of IMP required. 
 
Greater If more than 
of IMP: restart IMP and extend the IMP treatment 
by the number of consecutive doses missed. The 
final treatment visit should also be pushed out to 
the date of last dose. It is not necessary to have 
an unscheduled visit at the time when the end of 
treatment visit would have been.   
 
Greater If more than 35 consecutive doses of 
IMP, discontinue IMP and withdraw participant 
from the trial. 
 
If the participant misses a total (sum) of 56 
cumulative missed doses, discontinue the IMP 
and withdraw the participant from the trial. 
If more than 7 to  35 consecutive doses are missed, 
these must be made up with the same treatment 
combination or dose that was missed.  
10 
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11
1.1 Synopsis, 
Statistical 
Methods and 
Protocol Section 
9.0 Statistical 
Analysis 
A general description of the statistical methods planned to 
be used to analyse efficacy data is outlined below. 
Specific details will be provided in the statistical analysis 
plan (SAP,) which will be written and signed off prior to 
the first participant enrolled in the trial. 
 
A general description of the statistical methods planned to 
be used to analyse efficacy data is outlined below. 
Specific details will be provided in the Statistical Analysis 
Plan (SAP) which will be written and signed off prior to 
the interim analysis. 
 
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12
1.1 Synopsis, 
Statistical 
Methods and 
Protocol Sections 
2.3.1 Trial Design 
Rationale, and 
9.3 Interim 
Analysis 
No previous text 
Interim Analysis
 
There is one planned interim efficacy analysis which 
will occur after approximately 60 assessable 
participants have been randomised to the control arm 
and have reached the 8-week primary endpoint. Time 
to culture negative status in liquid media up to 8 
weeks will be analysed using a Cox regression 
model, censoring for death and lost to follow 
up/withdrawal to estimate the hazard ratio (HR). 
Following a review of these interim findings, the 
following considerations will be given to modify the 
trial objectives and sample size: 
 
If the observed HR (time to culture negativity, 
experimental arm vs. HRZE control arm) is >2, the 
sample size may be increased to adequately power 
the study on the key secondary efficacy endpoint 
(clinical and microbiological outcome at 52 weeks 
from randomization), which will then become the 
primary efficacy endpoint. The study efficacy 
objectives will be updated as follows: 
 
- 
Primary Objective 
To determine the incidence of bacteriologic failure or 
relapse or clinical failure at 52 weeks from the start of 
treatment / randomisation.  
 
- 
Secondary Objective 
To evaluate the time to culture negativity over 8 
weeks, from the start of treatment / randomisation. 
 
All other study objectives will remain unchanged. 
 
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To achieve 90% power and overall 5% 2-sided 
significance after adjusting for the interim analysis, 
this will mean increasing the sample size to 
225 participants per randomised arm, i.e., to a total of 
450 DS-TB participants (and up to 225 DR-TB 
participants). This adaptation is based on the Multi-
arm Multi-stage (MAMS) framework and full details 
are provided in the Statistical Analysis Plan.  
13
1.1 Synopsis, 
Trial Duration 
Approximately 4 years (18-month enrolment period for 
DS-TB participants, up to 26 week-treatment, and follow-
up until week 104 from start of treatment. Depending on 
the DR-TB recruitment rate, enrolment into this arm may 
continue after enrolment into the DS-TB arms is 
complete.  
 
There will be 3 database locks, data analyses and trial 
reports generated for this trial:  
 
1. When all participants have completed 8 weeks (2 
months) of treatment from baseline.  
2. When all participants have completed 52 weeks 
(12 months) follow-up from start of therapy. 
3. When all participants have completed 104 weeks 
(24 months) follow-up from start of therapy.  
 
Approximately 4 years (18-month enrolment period for 
DS-TB participants, up to 26 week-treatment, and follow-
up until week 104 from start of treatment. Depending on 
the DR-TB recruitment rate, enrolment into this arm may 
continue after enrolment into the DS-TB arms is 
complete.  
 
There will be 3 database locks, data analyses and trial 
reports generated for this trial:  
 
1. When all participants have completed 8 weeks (2 
months) of treatment from baseline.  
2. When all participants have completed 52 weeks 
(12 months) follow-up from start of therapy. 
3. When all participants have completed 104 weeks 
(24 months) follow-up from start of therapy.  
 
13 
14
1.2 Synopsis 
Flow Chart and 
Procedures 
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15
1.2 Synopsis 
Flow Chart and 
Procedures (foot 
notes), General 
GENERAL: Vital signs, ECGs and blood draws are to be 
performed pre-dosing unless otherwise specified. Vital 
signs and/or ECGs should be done prior to blood draws 
(safety and PK) on days with those assessments. 
GENERAL: Vital signs, ECGs and blood draws are to be 
performed before dosing unless otherwise specified. Vital 
signs and/or ECGs should be done before blood draws 
(safety and PK) on days with those assessments. 
15 
16
1.2 Synopsis 
Flow Chart and 
Procedures (foot 
note a) 
Screening: Screening assessments can occur on different 
days, within nine days before Day 1 dosing 
(randomisation).  
 
Screening: Screening assessments can occur on different 
days, within nine days before Day 1 dosing 
(randomisation Baseline).  
 
16 
17
1.2 Synopsis 
Flow Chart and 
Procedures (foot 
notes, f)  
Rapid molecular tests for fluoroquinolones, isoniazid and 
rifampicin resistance 
Rapid molecular tests for fluoroquinolones, isoniazid and 
rifampicin resistance (Hain MTBDRplus and Hain 
MTBRsl);  
 
17 
18
1.2 Synopsis 
Flow Chart and 
Procedures (foot 
notes, f) 
Baseline to Week 104, including any Unscheduled visits:  
 
Day 1 (Baseline) to Week 104 and including any 
Unscheduled visits for additional sputum samples:  
 
 
 
18 
19
1.2 Synopsis 
Flow Chart and 
Procedures (foot 
notes, f) 
If both sputum samples at Weeks 8, 17 (4-month 
treatment arm), 26 (6-month treatment arm), 52 or 104 
are contaminated, the participant should return for an 
unscheduled visit(s) to give additional samples or to 
document that the participant is not able to produce 
sputum. 
If both sputum samples at Weeks 8 or later, 17 (4-month 
treatment arm), 26 (6-month treatment arm), 52 or 104 
are contaminated, the participant should return for an 
unscheduled visit(s) to give additional samples or to 
document that the participant is not able to produce 
sputum. 
19 
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20
1.2 Synopsis 
Flow Chart and 
Procedures (foot 
notes, g) 
Mycobacterial Characterization - MTB isolates will be 
processed for: 
 
- Minimum Inhibitory Concentration (MIC) against 
bedaquiline, pretomanid, and moxifloxacin;  
- Drug Susceptibility Testing for streptomycin, rifampicin, 
isoniazid, ethambutol, moxifloxacin, pyrazinamide and 
second line TB drugs including, but not limited to 
fluoroquinolones, and injectables using an indirect 
susceptibility test in liquid culture;  
- Extraction of organismal (MTB) DNA for whole genome 
sequencing, and comparison of sequences from baseline 
and relapse isolates. 
 
Mycobacterial Characterization - MTB isolates (from the 
first MTB positive culture) will be processed for: 
 
- Rapid molecular tests for fluoroquinolones, 
injectables, isoniazid and rifampicin resistance (only 
on MTB positive cultures in the follow-up period); 
- Minimum Inhibitory Concentration (MIC) against 
bedaquiline, pretomanid, and moxifloxacin;  
- Drug Susceptibility Testing (DST) for streptomycin, 
rifampicin, isoniazid, ethambutol, moxifloxacin, and 
second line TB drugs including, but not limited to 
fluoroquinolones, and injectables using an indirect 
susceptibility test in pyrazinamide in liquid culture;  
- Extraction of organismal (MTB) DNA for whole genome 
sequencing (WGS), and comparison of sequences from 
baseline and relapse isolates. 
 
20 
21
1.2 Synopsis 
Flow Chart and 
Procedures (foot 
notes, n) and 
Protocol Section 
7.3 Safety and 
Tolerability 
Assessments 
Single 12-Lead ECG: To every extent possible, this 
should be performed at approximately the same time of 
day as the trial procedures (+/-1 hour).  
 
Central ECG analysis will be performed. Results from 
central reading of Day -9 to -1 (Screening) ECG must be 
used to determine eligibility.  
 
Single 12-Lead ECG: ECGs to be performed prior to 
pre- and post-dose PK sampling as described below: 
 
Day 1: pre-dose (within 2 hours prior to dosing) 
 
Week 2: pre-dose (within 2 hours prior to dosing), 
1.5 3 hours post-dose and 4-6 hours post-dose 
 
Week 8: pre-dose (within 2 hours prior to dosing), 
1.5 3 hours post-dose and 4-6 hours post-dose 
 
Week 12: pre-dose (within 2 hours prior to dosing) 
 
Week 17 or at early withdrawal if prior to week 17: 
pre-dose (within 2 hours prior to dosing) and 1.5
3 hours post-dose 
Central ECG analysis will be performed. Results from 
central reading of Day -9 to -1 (Screening) Screening 
ECG must be used to determine eligibility.  
 
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22
1.2 Synopsis 
Flow Chart and 
Procedures (foot 
notes, s) 
Pharmacokinetic (PK) Sampling: This process will be 
described in a separate document, the PK Sampling 
Manual. No PK samples will be collected for the HRZE-
HR treatment arm.  Blood draws for PK samples collected 
pre-dose must be done after the ECG is performed.   
Pharmacokinetic (PK) Sampling: This process will be 
described in a separate document, the PK Sampling 
Manual. No PK samples will be collected for the 
HRZE/HR treatment arm.  Blood draws for PK samples 
collected pre- and post-dose must be done after the 
ECG is performed.   
22 
23
1.2 Synopsis 
Flow Chart and 
Procedures (foot 
notes, s) 
Weeks 39, 65, 78 and 104: PK samples are to be 
obtained at any time on the day of the scheduled visit. 
 
Weeks 39, 65, 78 and 104: PK samples are to be 
obtained at any time on the day of the scheduled visit, 
and only bedaquiline and M2 will be measured. 
 
23 
24
1.2 Synopsis 
Flow Chart and 
Procedures (foot 
notes, s) and 
Protocol Section 
7.4 PK Variables 
and Procedures 
No previous text 
If IMP is not administered during Week 2, 8 and or 17, 
then only a single PK sample is required to be 
obtained at any time during the visit assessment. 
 
24 
25
1.2 Synopsis 
Flow Chart and 
Procedures (foot 
notes, v) 
Investigator Assessment: Investigator to review 
participant status and assess whether IMP or TB 
treatment at current 
specify if based on bacteriology and/or clinical 
deterioration and/or radiological deterioration. Investigator 
Assessment to be completed, as shown on the flowchart, 
and at any time Investigator determines that participant 
fulfils criteria for outcome of treatment failure. 
 
Investigator Assessment: Investigator to review the 
participant status and assess whether IMP or TB 
treatment at current visit Week 52 and 104 is considered 
Investigator should specify if the assessment is based on 
bacteriology and/or clinical deterioration and/or 
radiological deterioration. Investigator Assessment to be 
completed, as shown on the flowchart, at Week 52 and 
104, and at any time the Investigator determines that the 
participant fulfils the criteria for outcome of treatment 
failure. 
 
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26
1.2 Synopsis 
Flow Chart and 
Procedures (foot 
notes, x), and 
Protocol section 
7.1 
No previous text 
Karnofsky Score: Only to be performed on HIV+ 
participants. 
26 
27
Protocol Section 
3.1 Primary 
Objective 
Primary Objectives 
 
To evaluate the efficacy, safety and tolerability at 8 weeks 
(2-months), 52 weeks (12-months), and 104 Weeks (24-
months) post the start of the following treatment regimens 
in participants with: 
 
Drug Sensitive TB (DS-TB) 
 
 BPaMZ given for 17 Weeks (4 months) 
 
Standard HRZE/HR treatment given for 26 weeks (6 
months) 
 
Drug Resistant TB (DR-TB)  
 
BPaMZ given for 26 Weeks (6 months) 
 
DR-TB are defined as participants with: 
 
1. 
mono-resistance to rifampicin or isoniazid, OR 
2. resistance to both rifampicin and isoniazid (DR-TB) 
 
Primary Endpoints 
 
To evaluate the time to culture negativity over 8 weeks 
from the start of the following treatment regimens in 
participants with the efficacy, safety and tolerability at 8 
weeks (2-months), 52 weeks (12-months), and 104 
Weeks (24-months) post the start of the following 
treatment regimens in participants with: 
 
- Drug Sensitive TB (DS-TB) 
 
 BPaMZ given for 17 Weeks (4 months) 
 
Standard HRZE/HR treatment given for 26 
weeks (6 months) 
- Drug Resistant TB (DR-TB)  
 
BPaMZ given for 26 Weeks (6 months) 
 
DR-TB are defined as participants with: 
 
2. 
mono-resistance to rifampicin or isoniazid, OR 
2. resistance to both rifampicin and isoniazid (DR-TB) 
 
27 
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TB Alliance 
Protocol Number: NC-008 
Protocol Amendment No.: 2 / 14-JAN-2019 
Protocol Name: SimpliciTB 
 
 
Protocol Amendment  
or Administrative Change 
 
TMP-C-SOP01-C V1.0 30-Nov-2018 
CONFIDENTIAL 
This document is proprietary and shall not be reproduced without prior written permission from TB Alliance. 
# 
Section 
Previous Text 
Version 2.0 dated 21-Feb-18 
 
Amended Text 
Version 3.0 dated 14-Jan-19 
Additional text - bold font. Deleted text  strike-through. 
Reason for 
Change 
Insert reason # 
from table above 
28
Protocol Section 
3.2 Secondary 
Objectives, PK 
and PD 
Secondary Objectives 
 
Plasma concentrations from sparse sampling will be used 
to update existing population PK models and derive 
exposure metrics (e.g., Cmin, Cmax, AUC) for 
bedaquiline and its M2 metabolite, pretomanid, 
moxifloxacin, and pyrazinamide. 
Secondary Endpoints 
 
Plasma concentrations from sparse sampling will be used 
to update existing population PK models and derive 
exposure metrics (e.g., minimum plasma concentration 
[Cmin], maximum plasma concentration [Cmax], area 
under curve over a dosing interval [AUC]) for 
bedaquiline and its M2 metabolite, pretomanid, 
moxifloxacin, and pyrazinamide. 
28 
29
Protocol Section 
4.1 Summary of 
Trial Design 
Participants, trial Investigators and staff, including 
laboratory staff, will not be blinded to treatment allocation 
during the treatment phase of the trial. 
Participants, trial Investigators and staff, including 
laboratory staff, will not be blinded to treatment 
randomisation and allocation during the treatment phase 
of the trial. 
 
29 
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TB Alliance 
Protocol Number: NC-008 
Protocol Amendment No.: 2 / 14-JAN-2019 
Protocol Name: SimpliciTB 
 
 
Protocol Amendment  
or Administrative Change 
 
TMP-C-SOP01-C V1.0 30-Nov-2018 
CONFIDENTIAL 
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# 
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Previous Text 
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Amended Text 
Version 3.0 dated 14-Jan-19 
Additional text - bold font. Deleted text  strike-through. 
Reason for 
Change 
Insert reason # 
from table above 
30
Protocol Section 
4.1 Summary of 
Trial Design, 6th 
paragraph 
Eligible participants who meet all the inclusion criteria and 
none of the exclusion criteria, aged 18 and over, male or 
female will be assigned to one of the 3 treatment groups 
with a target of 50% of the participants being HIV positive. 
An interactive web response system (IWRS) will be used 
which will utilize a dynamic randomization system using 
cavitation with a random element to allocate participants 
evenly across the arms by HIV status and type of TB (DS 
versus DR) after they have given written, informed 
consent during the Screening Visit (Days -9 to -1) and 
met all eligibility criteria. 
 
Eligible participants who meet all the inclusion criteria and 
none of the exclusion criteria, aged 18 and over, male or 
female will be assigned to one of the 3 treatment groups 
with a target of 50% of the participants being HIV positive. 
An interactive web response system (IWRS) will be used 
which will utilize a dynamic randomization system using 
cavitation with a random element to allocate participants 
evenly across the arms by HIV status and type of TB (DS 
versus DR) after they have given written, informed 
consent during the Screening Visit (Days -9 to -1) and 
met all eligibility criteria. 
 
DR participants will be treated with 6 months of 
BPaMZ.  DS participants will be randomised using a 
an interactive web response system (IWRS) 
stratifying for cavitation and HIV status to allocate 
participants evenly across the arms after they have 
given written, informed consent during the Screening 
Visit (Days -9 to -1). 
 
30 
31
Protocol Section 
5.1, Inclusion 
Criteria #5 
DS-TB treatment arm participants should be: sensitive to 
rifampicin and isoniazid by rapid sputum-based test 
DS-TB treatment arm participants should be: sensitive to 
rifampicin, isoniazid and fluoroquinolones by rapid 
sputum-based test. 
31 
32
Protocol Section 
5.1, Inclusion 
Criteria #5 
If they are randomised into the trial due to being sensitive 
to rifampicin and isoniazid by rapid molecular sputum- 
based test, however on receipt of the rifampicin and/or 
isoniazid phenotypic resistance testing in liquid culture 
this shows they are rifampicin or isoniazid resistant, they 
will be: 
 
 - Excluded as late exclusions; 
-  Possibly replaced as determined by the Sponsor.  
If they are randomised into the trial due to being sensitive 
to rifampicin and isoniazid by rapid molecular sputum- 
based test, however on receipt of the rifampicin and/or 
isoniazid phenotypic resistance testing in liquid culture 
this shows they are rifampicin or isoniazid resistant, they 
will be: 
 
 - Excluded as late exclusions; 
-  Possibly replaced as determined by the Sponsor.  
32 
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Protocol Number: NC-008 
Protocol Amendment No.: 2 / 14-JAN-2019 
Protocol Name: SimpliciTB 
 
 
Protocol Amendment  
or Administrative Change 
 
TMP-C-SOP01-C V1.0 30-Nov-2018 
CONFIDENTIAL 
This document is proprietary and shall not be reproduced without prior written permission from TB Alliance. 
# 
Section 
Previous Text 
Version 2.0 dated 21-Feb-18 
 
Amended Text 
Version 3.0 dated 14-Jan-19 
Additional text - bold font. Deleted text  strike-through. 
Reason for 
Change 
Insert reason # 
from table above 
33
Protocol Section 
5.1, Inclusion 
Criteria #5 
DR-TB treatment arm participants should be: 
a. Resistant to rifampicin and/or isoniazid.  
b. Should not have had previous treatment for DR-
TB/MDR-TB, although may have been on a DR-
TB/MDR-TB treatment regimen for no longer than 
7 days at start of screening. 
 
DR-TB treatment arm participants should be: 
a. Resistant to rifampicin and/or isoniazid; but 
sensitive to fluoroquinolones by rapid sputum-
based test AND  
b. Should not have had previous treatment for DR-
TB/MDR-TB, although may have been on a DR-
TB/MDR-TB treatment regimen for no longer than 
7 3 days at start of screening. 
c. Participants with resistance to injectables by 
rapid sputum-based test are allowed in the 
trial. 
When Phenotypic DST and whole genome sequencing 
(WGS) results on baseline samples become available, 
any results that are discordant with the screening 
eligibility for the trial will be reviewed by the Sponsor 
Medical Monitor in consultation with the Investigator 
to determine whether that participant is unlikely to 
respond to treatment and should therefore be removed 
from the trial and given alternative treatment.  If a 
participant is removed from the trial for such a reason, 
they will be classified as a late exclusion. 
33 
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TB Alliance 
Protocol Number: NC-008 
Protocol Amendment No.: 2 / 14-JAN-2019 
Protocol Name: SimpliciTB 
 
 
Protocol Amendment  
or Administrative Change 
 
TMP-C-SOP01-C V1.0 30-Nov-2018 
CONFIDENTIAL 
This document is proprietary and shall not be reproduced without prior written permission from TB Alliance. 
# 
Section 
Previous Text 
Version 2.0 dated 21-Feb-18 
 
Amended Text 
Version 3.0 dated 14-Jan-19 
Additional text - bold font. Deleted text  strike-through. 
Reason for 
Change 
Insert reason # 
from table above 
34
Protocol Section 
5.1 Inclusion 
Criteria #7, 
Contraception 
Effective birth control methods: 
a. Double barrier method which can include a male 
condom, diaphragm, cervical cap, or female condom; 
or  
b. Female participant: Barrier method combined with 
hormone-based contraceptives or an intra-uterine 
device for the female participant.  
c. 
barrier method or hormone-based contraceptives or 
an intra-uterine device for the female partner.  
Both male and female participants must be willing to 
continue practicing birth control methods and are not 
planning to conceive throughout treatment and for 12 
weeks after the last dose of trial medication or 
discontinuation from trial medication in case of premature 
discontinuation.  
Effective birth control methods: 
a. Double barrier method which can include a male 
condom, diaphragm, cervical cap, or female condom; 
or  
b. Female participant: Barrier method combined with 
hormone-based contraceptives or an intra-uterine device 
for the female participant.  
Double 
Barrier method combined with hormone-based 
contraceptives or an intra-uterine device for the female 
partner.  
Both male and female participants must be willing to 
continue practicing birth control methods and are not 
planning to conceive throughout treatment and for 6 
months 12 weeks after the last dose of trial IMP or 
discontinuation from trial IMP in case of premature 
discontinuation.  
34 
35
Protocol Section 
5.2 Exclusion 
Criteria #3 
No previous text 
Historical and or current use of local traditional 
medications/herbs which in the opinion of the 
safety or ability to follow through with all protocol-
specified restrictions, visits and evaluations. 
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TB Alliance 
Protocol Number: NC-008 
Protocol Amendment No.: 2 / 14-JAN-2019 
Protocol Name: SimpliciTB 
 
 
Protocol Amendment  
or Administrative Change 
 
TMP-C-SOP01-C V1.0 30-Nov-2018 
CONFIDENTIAL 
This document is proprietary and shall not be reproduced without prior written permission from TB Alliance. 
# 
Section 
Previous Text 
Version 2.0 dated 21-Feb-18 
 
Amended Text 
Version 3.0 dated 14-Jan-19 
Additional text - bold font. Deleted text  strike-through. 
Reason for 
Change 
Insert reason # 
from table above 
36
Protocol Section 
5.2 Exclusion 
Criteria #9 
(previous 
protocol) 
Resistant to fluoroquinolones (rapid, sputum-based 
molecular screening tests)  
- If they are randomised into the trial due to being 
sensitive to fluoroquinolones by rapid sputum-based test, 
however on receipt of the moxifloxacin phenotypic 
resistance testing in liquid culture they are found to be 
fluoroquinolones resistant, they will be excluded as late 
exclusions. 
Resistant to fluoroquinolones (rapid, sputum-based 
molecular screening tests)  
- If they are randomised into the trial due to being 
sensitive to fluoroquinolones by rapid sputum-based test, 
however on receipt of the moxifloxacin phenotypic 
resistance testing in liquid culture they are found to be 
fluoroquinolones resistant, they will be excluded as late 
exclusions. 
36 
37
Protocol Section 
5.2 Exclusion 
Criteria #14, 15, 
16, 17 (previous 
protocol) 
14. Previous treatment with pretomanid or bedaquiline. 
 
15. Previous treatment for TB which includes, but is not 
limited to, gatifloxacin, amikacin, cycloserine, 
rifabutin, kanamycin, para-aminosalicylic acid, 
rifapentine, thioacetazone, capreomycin, quinolones, 
thioamides, and metronidazole. 
 
16. For DS-TB participants: Previous treatment for 
tuberculosis within 3 years prior to the Screening visit. 
Participants who have previously received isoniazid
prophylactically may be included in the trial if that 
treatment is/was discontinued at least 7 days prior to 
randomization 
 
17. For the DR-TB participants: Previous treatment for DR-
TB/MDR-TB, although may have been on a DR/MDR-
TB treatment regimen for no longer than 7 days at start 
of screening. 
 
 
Previous treatment with pretomanid or bedaquiline. 
 
Previous treatment for TB which includes, but is not 
limited to, gatifloxacin, amikacin, cycloserine, rifabutin, 
kanamycin, para-aminosalicylic acid, rifapentine, 
thioacetazone, capreomycin, quinolones, thioamides, and 
metronidazole. 
 
14. Previous treatment for TB: 
 
For DS-TB participants: Previous treatment for 
tuberculosis within 3 years prior to the Screening visit. 
Participants who have previously received isoniazid 
prophylactically may be included in the trial if that 
treatment is/was discontinued at least 7 days at the 
start of the Screening visit. 
 
For the DR-TB participants: Previous treatment for 
DR-TB/MDR-TB, although may have been on a DR-
TB/MDR-TB treatment regimen for no longer than 3 
days at the start of the Screening visit. 
 
 
37 
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TB Alliance 
Protocol Number: NC-008 
Protocol Amendment No.: 2 / 14-JAN-2019 
Protocol Name: SimpliciTB 
 
 
Protocol Amendment  
or Administrative Change 
 
TMP-C-SOP01-C V1.0 30-Nov-2018 
CONFIDENTIAL 
This document is proprietary and shall not be reproduced without prior written permission from TB Alliance. 
# 
Section 
Previous Text 
Version 2.0 dated 21-Feb-18 
 
Amended Text 
Version 3.0 dated 14-Jan-19 
Additional text - bold font. Deleted text  strike-through. 
Reason for 
Change 
Insert reason # 
from table above 
38
Protocol Section 
5.2 Exclusion 
Criteria # 17  
Use of systemic glucocorticoids within one year of the 
start of the Screening visit (topical, inhaled or intranasal 
glucocorticoids are allowed), due to visual opacities or 
cataracts. 
 
Use of systemic glucocorticoids within one year of the 
start of the Screening visit (topical, inhaled or intranasal 
glucocorticoids are allowed), due to as they can lead to 
visual opacities or cataracts. 
38 
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TB Alliance 
Protocol Number: NC-008 
Protocol Amendment No.: 2 / 14-JAN-2019 
Protocol Name: SimpliciTB 
 
 
Protocol Amendment  
or Administrative Change 
 
TMP-C-SOP01-C V1.0 30-Nov-2018 
CONFIDENTIAL 
This document is proprietary and shall not be reproduced without prior written permission from TB Alliance. 
39
Protocol Section 
5.2 Exclusion 
Criteria # 18 
For HIV infected participants, only the following types of 
ART are permissible:  
 
a. Lopinavir/ritonavir-based regimen consisting 
of lopinavir/ritonavir in combination with any 
two NRTI. TDF/ABC and FTC/3TC. 
b. Integrase inhibitor (e.g., dolutegravir) in 
combination with TDF/ABC and FTC/3TC. 
c. In participants who have viral load suppressed 
on efavirenz at the time of screening, their 
ART can be changed to rilpivirine in 
combination with TDF/ABC and FTC/3TC. If 
possible, the same nucleoside backbone 
should be used. 
d. Nevirapine (NVP) based regimen consisting of 
NVP in combination with any two nucleosidase 
reverse 
transcriptase 
inhibitors 
(NRTIs) 
tenofovir 
(TDF)/abacavir 
(ABC) 
and 
emtricitabine (FTC)/lamivudine (3TC). 
 
In the case where participants are randomized to a 
rifampicin containing regime: 
 
a. EFV can be used with rifampicin.  
b. LPV needs to be double dosed.  
c. Rilpivirine cannot be given with rifampicin  
 
For HIV infected participants only the following types of 
ART are permissible: 
 
a. The following antiretroviral therapy (ART) should 
not be used with either (BPaMZ and HRZE/HR) 
trial regimen: 
 
1. Stavudine  
2. Didanosine  
3. Triple NRTI regimen is not considered optimal 
for HIV treatment (poor efficacy) 
 
b. In the case where participants are randomised to 
HRZE arm, rilpivirine and etravirine cannot be 
given with rifampicin due to drug-drug 
interactions. A standard NRTI backbone may be 
used in combination with one of the following: 
 
1. Efavirenz requires no dose adjustment  
2. Dolutegravir dose adjustment is required 
 double dose when co-prescribed with 
rifampicin. 
3. Raltegravir requires no dose adjustment 
4. Lopinavir/r dose adjustment is required  
double dose when co-prescribed with 
rifampicin 
5. Nevirapine requires no dose adjustment, 
however please note that nevirapine 
based regimens are associated with 
higher ART failure in participants having 
or known to have a previous viral load 
more than or equal to 100,000/ mL 
 
c. In the case where participants are randomized to 
the BPaMZ trial regimen, a standard NRTI 
backbone may be combined with the following:  
39 
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TB Alliance 
Protocol Number: NC-008 
Protocol Amendment No.: 2 / 14-JAN-2019 
Protocol Name: SimpliciTB 
 
 
Protocol Amendment  
or Administrative Change 
 
TMP-C-SOP01-C V1.0 30-Nov-2018 
CONFIDENTIAL 
This document is proprietary and shall not be reproduced without prior written permission from TB Alliance. 
# 
Section 
Previous Text 
Version 2.0 dated 21-Feb-18 
 
Amended Text 
Version 3.0 dated 14-Jan-19 
Additional text - bold font. Deleted text  strike-through. 
Reason for 
Change 
Insert reason # 
from table above 
 
1. Rilpivirine 
2. Dolutegravir  
3. Raltegravir 
4. Nevirapine  
5. Lopinavir/r  
6. Participants who are on efavirenz, 
atazanavir/r or darunavir/r at the time of 
screening and have an undetectable viral 
load, should have their ART switched to 
one of the agents listed above (1-5). It 
would be preferable to switch to another 
permissible ARV within the same class 
accompanied by the same nucleoside 
backbone. 
 
d. ART regimen choice should be discussed with the 
Sponsor Medical Monitors if there are any 
concerns. 
 
Confirmed plans to use Isoniazid prophylaxis for HIV 
positive participants during the treatment and follow 
up period is not permitted. 
 
26 of 48
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TB Alliance 
Protocol Number: NC-008 
Protocol Amendment No.: 2 / 14-JAN-2019 
Protocol Name: SimpliciTB 
 
 
Protocol Amendment  
or Administrative Change 
 
TMP-C-SOP01-C V1.0 30-Nov-2018 
CONFIDENTIAL 
This document is proprietary and shall not be reproduced without prior written permission from TB Alliance. 
40
Protocol Section 
5.2 Exclusion 
Criteria, 
Diagnostic and 
Laboratory 
Abnormalities, 
Item #19 
(Previously #22) 
a. platelets grade 2 or greater (<100,000/mm3) 
b. creatinine grade 2 or greater (>1.5 times upper limit of 
normal [ULN])  
c. 
2 
d. haemoglobin 
 
e. serum potassium less than the lower limit of normal for 
the laboratory. This may be repeated once 
f. 
GGT: greater than 3 x ULN 
g. AST: 
 
excluded; 
 
results between 1.5 x ULN and 3 x ULN must 
be discussed with and approved by the 
Sponsor Medical Monitor 
h. ALT: 
 
 
greater than ULN must be discussed with and 
approved by the Sponsor Medical Monitor 
i. 
 ALP: 
 
 
grade 2 (2.0  <3.0 x ULN) must be discussed 
with and approved by the Sponsor Medical 
Monitor 
j. 
Total bilirubin: 
 
>1.5 x ULN to be excluded; 
 
1  1.5 x ULN must be discussed with and 
approved by the Sponsor Medical Monitor 
k. Direct bilirubin: 
 
greater than 1x ULN to be excluded 
 
a. platelets grade 2 or greater (<100<75,000/mm3) 
b. creatinine grade 2 or greater (>1.5 times upper limit of 
normal ([ULN])  
c. 
/m2 
d. haemoglobin grade 2 or greater 
<8.0 g/dL) 
e. serum potassium less than the lower limit of normal 
for the laboratory. This may be repeated once 
f. 
GGT: greater than 3 x ULN 
g. AST:  
 
grade 3 or greater (
) to be 
excluded; 
 
results between 1.5 x ULN and 3 x ULN must 
be discussed with and approved by the 
Sponsor Medical Monitor 
h. ALT: 
 
grade 3 or greater (
) to be 
excluded 
 
greater than ULN must be discussed with and 
approved by the Sponsor Medical Monitor 
i. 
ALP: 
 
grade 3 or greater (
) to be 
excluded 
 
grade 2 (2.0  <3.0 x ULN) must be 
discussed with and approved by the Sponsor 
Medical Monitor 
j. 
Total bilirubin: 
 
>1.5 x ULN to be excluded; 
 
greater than 1  1.5 x ULN must be 
discussed with and approved by the Sponsor 
Medical Monitor 
k. Direct bilirubin: 
 
greater than 1x ULN to be excluded 
 
40 
41
Protocol Section 
5.3 Restrictions 
Concomitant medications should be kept to a minimum 
during the trial. However, if concomitant medications are 
Concomitant medications should be kept to a minimum 
during the trial. However, if concomitant medications are 
and are unlikely to 
41 
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TB Alliance 
Protocol Number: NC-008 
Protocol Amendment No.: 2 / 14-JAN-2019 
Protocol Name: SimpliciTB 
 
 
Protocol Amendment  
or Administrative Change 
 
TMP-C-SOP01-C V1.0 30-Nov-2018 
CONFIDENTIAL 
This document is proprietary and shall not be reproduced without prior written permission from TB Alliance. 
# 
Section 
Previous Text 
Version 2.0 dated 21-Feb-18 
 
Amended Text 
Version 3.0 dated 14-Jan-19 
Additional text - bold font. Deleted text  strike-through. 
Reason for 
Change 
Insert reason # 
from table above 
interfere with the IMP, they may be given at the discretion 
of the Investigator. 
interfere with the IMP, they may be given at the discretion 
of the Investigator. 
42
Protocol Section 
5.3 Restrictions 
The following medicinal products should be avoided from 
Day 1 (Baseline visit) and during the treatment period as 
much as possible unless discussed with the Sponsor 
Medical Monitor: 
 
The following medicinal products should be avoided from 
Day 1 (Baseline visit) and during the treatment period as 
much as possible (unless this is required for 
emergency management of the participant) unless 
discussed with the Sponsor Medical Monitor. 
Investigators may also contact the Sponsor Medical 
Monitor for further guidance. 
42 
43
Protocol Section 
5.3 Restrictions 
Any drug known to be hepatotoxic (including but not 
limited to acetaminophen/paracetamol, acetazolamide, 
allopurinol, amiodarone, amitriptyline, amoxicillin, 
amprenavir, atorvastatin, augmentin/co-amoxiclav, 
azathioprine, baclofen, bumetanide, captopril, 
carbamazepine, celecoxib, chlorpromazine, 
chlorpromazine, clindamycin, clopidogrel, contraceptive 
 
Any drug known to be hepatotoxic (including but not 
limited to acetaminophen/paracetamol, acetazolamide, 
allopurinol, amiodarone, amitriptyline, amoxicillin, 
amprenavir, atorvastatin, augmentin/co-amoxiclav, 
azathioprine, baclofen, bumetanide, captopril, 
carbamazepine, celecoxib, chlorpromazine, 
chlorpromazine, clindamycin, clopidogrel, contraceptive 
pill
 
43 
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TB Alliance 
Protocol Number: NC-008 
Protocol Amendment No.: 2 / 14-JAN-2019 
Protocol Name: SimpliciTB 
 
 
Protocol Amendment  
or Administrative Change 
 
TMP-C-SOP01-C V1.0 30-Nov-2018 
CONFIDENTIAL 
This document is proprietary and shall not be reproduced without prior written permission from TB Alliance. 
44
Protocol Section 
5.4 Treatment 
Discontinuation 
and/or Early 
Withdrawal 
A participant must be prematurely withdrawn from the trial 
(during the trial treatment or follow-up periods) because of 
the following: 
 
 
Withdrawal of informed consent 
 
Investigator considers that for safety reasons it is in 
the best interest of the participant that he/she be 
withdrawn, including a concern that the participant 
has 
symptomatic 
TB 
and/or 
bacteriological 
failure/relapse and requires a change in TB treatment.
 
Pregnancy 
 
At the specific request of the Sponsor or termination 
of the trial by the Sponsor. 
 
Lost to follow-up 
 
Drug-Sensitive TB treatment arms: participants, who 
have been randomised onto the trial as a rifampicin 
sensitive participant on the rapid sputum based test 
result, who on receipt of the rifampicin resistance 
testing using an indirect susceptibility test in liquid 
culture, shows a rifampicin resistant result. 
 
Participants, who have been randomised onto the trial 
as fluoroquinolone sensitive on the rapid sputum
based 
test 
result, 
who 
on 
receipt 
of 
the 
fluoroquinolone resistance testing using an indirect 
susceptibility test in liquid culture; this shows a 
fluoroquinolone resistant result. 
 
A participant must be prematurely withdrawn from the trial 
(during the trial treatment or follow-up periods) because of 
the following: 
 
 
Withdrawal of informed consent 
 
Investigator considers that for safety reasons it is 
in the best interest of the participant that he/she be 
withdrawn, including a concern that the participant 
has 
symptomatic 
TB 
and/or 
bacteriological 
failure/relapse and requires a change in TB 
treatment 
 
Pregnancy 
 
At the specific request of the Sponsor or 
termination of the trial by the Sponsor 
 
Lost to follow-up 
 
Drug-Sensitive TB treatment arms: participants, 
who have been randomised onto the trial as a 
rifampicin sensitive participant on the rapid sputum 
based test result, who on receipt of the rifampicin 
resistance testing using an indirect susceptibility 
test in liquid culture, shows a rifampicin resistant 
result. 
 
Participants, who have been randomised onto the 
trial as fluoroquinolone sensitive on the rapid 
sputum based test result, who on receipt of the 
fluoroquinolone resistance testing using an indirect 
susceptibility test in liquid culture; this shows a 
fluoroquinolone resistant result. 
 
When Phenotypic DST and whole genome 
sequencing 
(WGS) 
results 
on 
baseline 
samples become available, any results that are 
discordant with the screening molecular test 
for the trial will be reviewed by the Sponsor 
Medical Monitor in consultation with the 
Investigator 
to 
determine 
whether 
that 
44 
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TB Alliance 
Protocol Number: NC-008 
Protocol Amendment No.: 2 / 14-JAN-2019 
Protocol Name: SimpliciTB 
 
 
Protocol Amendment  
or Administrative Change 
 
TMP-C-SOP01-C V1.0 30-Nov-2018 
CONFIDENTIAL 
This document is proprietary and shall not be reproduced without prior written permission from TB Alliance. 
# 
Section 
Previous Text 
Version 2.0 dated 21-Feb-18 
 
Amended Text 
Version 3.0 dated 14-Jan-19 
Additional text - bold font. Deleted text  strike-through. 
Reason for 
Change 
Insert reason # 
from table above 
participant is unlikely to respond to treatment 
and should therefore be removed from the trial 
and given alternative treatment.  If a participant 
is removed from the trial for such a reason, 
they will be classified as a late exclusion. 
45
Protocol Section 
5.4 Treatment 
Discontinuation 
and/or Early 
Withdrawal 
- Participants, who have been randomised onto the trial 
as fluoroquinolone sensitive on the rapid sputum-based 
test result, who on receipt of the fluoroquinolone 
resistance testing using an indirect susceptibility test in 
liquid culture; this shows a fluoroquinolone resistant 
result. 
- Early withdrawal due to TB (see Section 5.4.4) 
 
- Participants, who have been randomised onto the trial 
as fluoroquinolone sensitive on the rapid sputum-based 
test result, who on receipt of the fluoroquinolone 
resistance testing using an indirect susceptibility test in 
liquid culture; this shows a fluoroquinolone resistant 
result. 
- Early withdrawal due to TB (see Section5.4.4) 
 
45 
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TB Alliance 
Protocol Number: NC-008 
Protocol Amendment No.: 2 / 14-JAN-2019 
Protocol Name: SimpliciTB 
 
 
Protocol Amendment  
or Administrative Change 
 
TMP-C-SOP01-C V1.0 30-Nov-2018 
CONFIDENTIAL 
This document is proprietary and shall not be reproduced without prior written permission from TB Alliance. 
46
Protocol Section 
5.4 Treatment 
Discontinuation 
and/or Early 
Withdrawal 
The following situation/s would require an unscheduled 
visit/s: 
 
- If both sputum samples (Early Morning and Spot) at 
Week 8 or later are contaminated, the participant should 
return for an unscheduled visit(s) to give additional 
sputum samples x 2 (one early morning and one spot at 
the research site under the coaching and observation of 
the trial staff) or to document that the participant is not 
able to produce sputum. 
- If there is a MTB confirmed positive culture at or after 
the end of treatment at Week 17 (4-month treatment) or 
Week 26 (6-month treatment), the participant should 
return for an Unscheduled visit(s) to give additional 
sputum samples x 2 (one early morning and one spot at 
the research site under the coaching and observation of 
the trial staff) or to document that the participant is not 
able to produce sputum. If no early morning sputum 
sample was provided by the participant, 2 samples may 
be collected at the site, at least 30 minutes apart. 
 
Table 6 is a new table and did not previously exist in 
Protocol V2.0. 
 
If the Investigator is unsure of the outcome in any of the 
above scenarios the Investigator is to contact the Sponsor 
Medical Monitor and discuss and agree on how the 
participant is to be managed. 
 
The following situation/s would require an unscheduled 
visit/s: 
 
- For any medical reason, as determined by the 
Investigator or participant. 
- If both sputum samples (EMS and spot sputum sample) 
at Week 8 or later are contaminated, the participant 
should return for an unscheduled visit/s to give 2 (EMS 
and spot sputum sample, at each visit under the coaching 
and observation of the trial staff) additional sputum 
samples or to document that the participant is not able to 
produce sputum.  
- If there is a MTB confirmed positive culture If after 
having converted to culture negative, the participant 
has a MTB confirmed positive culture at or after the 
last visit of the treatment period (Week 17 or Week 26) 
Week 17 (4-month treatment) or Week 26 (6-month 
treatment), the participant should return for Unscheduled 
visit/s to provide 2 (EMS and spot sputum sample, at 
each visit) additional sputum samples under the 
coaching and observation of the trial staff), at a minimum 
of 7 days apart, or to document that the participant is not 
able to produce a sputum sample. 
 
Table 6: Summary of Scenarios Requiring 
Unscheduled Visits for Mycobacteriology Testing  
Time-point
Scenario
Unscheduled 
Visit/s 
Required? 
Comment
Week 8 or 
later 
Both sputum cultures 
are contaminated 
Yes
Provide additional 
samples until a positive 
or negative result is 
reported, or it is 
confirmed that the 
participant is unable to 
produce sputum 
At or after the 
last treatment 
visit (Week 17 
or Week 26) 
Previously converted 
to culture negative but 
now has an MTB-
positive culture 
Yes
Provide additional 
samples at least 7 days 
after the previous 
sample until the result 
is confirmed, or it is 
confirmed that the 
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participant is unable to 
produce sputum.  
End of 
Follow-up 
Period (Week 
52 and 104)  
Early 
Withdrawal, if 
applicable 
Participan
outcome status cannot 
be confirmed by: 
Two sequential 
negative sputum 
culture results; or   
two sequential positive 
sputum culture results; 
or has been unable to 
produce sputum after 
documentation of two 
negative sputum 
cultures with no 
intervening positive 
and are clinically 
asymptomatic 
Yes
Provide additional 
samples at least 7 days 
after the previous 
sample until one of the 
criteria is met and the 
primary outcome status 
can be determined.  
 
If the Investigator is unsure of the outcome in any of the 
above scenarios, the Investigator should is to contact the 
Sponsor Medical Monitor to discuss and agree on how 
the participant is to be managed. 
 
47
Protocol Section 
5.4.4 Early 
Withdrawal due 
to TB 
The participants will be provided with a referral letter from 
the Investigator to take with them to the TB clinic.  A 
follow-up call will be made by the trial site staff to the 
clinic to ensure the participant attended the clinic. 
The participant will be provided with a referral letter from 
the Investigator to take with them to the TB clinic their 
National Treatment Program (NTP) clinic and the 
referral letter, at a minimum, should include all 
treatment received by the participant and information 
about any suspected/confirmed adverse 
concomitant medications.  A follow-up call will should 
be made by the trial site staff to the clinic to ensure the 
participant attended the NTP clinic.  
 
47 
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48
Protocol Section 
7.1 Demographic 
and Background 
Variables and 
Procedures 
Screening coached spot sputum samples: 
 
o 
Smear microscopy for acid-fast bacilli 
o 
Gene Xpert, Hain Assay MTBDRplus or 
equivalent to determine MTB complex and 
rifamycin resistance 
 
Screening coached spot sputum samples: 
o 
Smear microscopy for acid-fast bacilli  
o 
Gene Xpert Rapid molecular tests for 
isoniazid, rifampicin, fluoroquinolones 
resistance (Hain MTBDRplus and 
HainMTBRsl) 
o 
Liquid Culture (MGIT) for Mycobacterium 
tuberculosis (MTB), followed by a speciation 
test to detect presence or absence of MTB 
and obtain time to positivity (TTP) when 
positive. 
48 
49
Protocol Section 
7.1 Demographic 
and Background 
Variables and 
Procedures 
Method of birth control: male and female participants and 
their partners 
 
Method of birth control: male and female participants and 
their sexual partners 
 
49 
50
Protocol Section 
7.4 PK Variables 
and Procedures 
Plasma concentrations from sparse sampling (see 
Section 1.2) will be used to update population PK models 
for bedaquiline and its M2 metabolite, pretomanid, and 
linezolid to further evaluate the effects of covariates on 
model parameters in this trial population.   
 
PK data from the current trial may be combined with prior 
data (e.g., from the NiX-TB trial) to enhance this 
population PK analysis. 
Plasma concentrations from sparse sampling (see 
Section 1.2) will be used to update population PK models 
for bedaquiline and its M2 metabolite pretomanid, and 
linezolid to further evaluate the effects of covariates on 
model parameters in this trial population.   
 
PK data from the current trial may be combined with prior 
data (e.g., from the NiX-TB trial) to enhance this 
population PK analysis. 
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51
Protocol Section 
7.5 
Mycobacteriology 
Characterisation 
Variable and 
Procedures 
Mycobacteriology Characterization Variable and 
Procedures 
The following Mycobacterial Characterization variables 
will be collected: 
Positive Culture (for MTB) from: 
 
 
Day 1 or if Day 1 is not available, first positive 
result between screening through Week 4 
 
Pre-screening culture that was used for the tests 
that qualified the participant for inclusion into the 
trial to be sub-cultured and sent to the central 
microbiology laboratory from the applicable local 
microbiology laboratory, for relevant participants / 
no positive cultures from screening through week 
4  
 
When applicable, at last visit of the treatment 
period (Week 17 for the 4-month treatment arm 
and Week 26 for the 6-month treatment arm) or 
visits with positive cultures, during the post-
treatment follow-up period 
 
The MTB isolates will be processed at the central 
microbiology laboratory for: 
 
 
MIC against bedaquiline, pretomanid and 
moxifloxacin  
 
Drug Susceptibility Testing in liquid culture for 
streptomycin, rifampicin, isoniazid, ethambutol, 
moxifloxacin and pyrazinamide, and second line 
TB drugs including but not limited to 
fluoroquinolones, and injectables 
 
Extraction of organismal (MTB) DNA for whole 
genome sequencing, and the comparison of 
sequences from baseline and relapse isolates. 
 
Mycobacteriology Characterization Variable and 
Procedures 
The following Mycobacterial Characterization variables 
will be collected: 
Positive Culture (for MTB) from: 
 
 
Day 1 (Baseline) sputum sample (or any positive 
sample from Screening to Week 4, if the baseline 
cultures are contaminated or negative). 
 
Pre-screening culture that was used for the tests that 
qualified the participant for inclusion into the trial to be 
sub-cultured and sent to the central microbiology 
laboratory from the applicable local microbiology 
laboratory, for relevant participants / no positive 
cultures from screening through week 4  
 
MTB confirmed positive cultures (after the 
participant has previously converted to negative) 
at or after the last visit of the treatment period 
(Week 17 or Week 26) or visits with positive 
cultures, during the post-treatment follow-up 
period. 
 
Refer to the Mycobacteriology Laboratory Manual 
for full details. 
Mycobacterial Characterization - MTB isolates (from 
the first MTB positive culture) will be processed for: 
 
 
Rapid molecular tests for fluoroquinolones, 
injectables, isoniazid and rifampicin resistance 
(only on MTB positive cultures in the follow-up 
period); 
 
Minimum Inhibitory Concentration (MIC) against 
bedaquiline, pretomanid, and moxifloxacin;  
 
DST in liquid culture for streptomycin, rifampicin, 
isoniazid, ethambutol, moxifloxacin, and 
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All Day 1 (Baseline) MTB isolates and isolates from 
positive cultures to be stored at the local and central 
microbiology laboratories, until trial closure.  Extracted 
MTB DNA to be stored at the central microbiology 
laboratory until trial closure. The extracted MTB DNA and 
isolates will then be stored for potential further work to 
advance new assay tools and understanding of MTB as a 
pathogen for a maximum of 5 years after trial closure.  
 
The MTB isolates will be processed at the trial 
microbiology laboratories for positive MTB complex 
at/after the last visit of the treatment period (Week 17 for 
the 4-month treatment arm and Week 26 for the 6-month 
treatment arm) via Hain MTBDRplus and HainMTBRsl. 
 
 
pyrazinamide, and second line TB drugs including but 
not limited to fluoroquinolones, and injectables in 
liquid culture;  
 
Extraction of organismal (MTB) DNA for whole 
genome sequencing (WGS), and comparison of 
sequences from baseline and relapse isolates. 
 
has a MTB positive culture at or after the last visit of 
the treatment period (Week 17 and Week 26), the MTB 
cultures isolates will be processed will be tested at the 
trial mycobacteriology laboratories for positive MTB 
complex using Hain MTBDRplus and HainMTBRsl to 
detect resistance to isoniazid, rifampicin, 
fluoroquinolones and injectables. 
 
All Day 1 (Baseline) MTB isolates and isolates from 
positive cultures to must be stored at the local 
mycobacteriology laboratories, until trial closure.  In 
addition, MTB DNA isolates as well as extracted MTB 
DNA from the applicable baseline and follow-up 
cultures will be stored at the central mycobacteriology 
laboratory for potential further work to advance new assay 
tools and understanding of MTB as a pathogen for a 
maximum of 5 years after trial closure.  
52
Protocol Section 
8.2.1 Follow-up 
of Adverse 
Events 
New or updated information will be recorded in the 
originally completed CRF and submitted to the Sponsor 
within 24 hours of receipt, per SAE reporting guidelines. 
 
New or updated SAE information will be recorded in the 
originally completed CRF and submitted to the Sponsor 
within 24 hours of receipt, per the SAE eCRF 
Completion Guideline. 
 
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53
Protocol Section 
8.2.6 Pregnancy 
All women of childbearing potential will be instructed to 
contact the investigator immediately if they suspect they 
might be pregnant (for example, missed or late menses) 
for the following time-periods: 
 
Any time during the trial 
 
Within 6 months after the last dose of IMP
 
All women of childbearing potential will be instructed to 
contact the investigator immediately if they suspect they 
might be pregnant (for example, missed or late menses) 
at any time during the trial. for the following 
time-periods: 
 
Any time during the trial 
 
Within 6 months after the last dose of IMP
53 
54
Protocol Section 
8.3 Monitoring for 
Specific 
Toxicities 
Neurological 
Participants co-administration with a serotonergic agent, 
including anti-depressants, should be monitored closely 
for signs of serotonin syndrome.  The Investigator should 
determine whether the full regimen or the concomitant 
agent should be discontinued for those who experience 
signs or symptoms of serotonin syndrome such as 
cognitive dysfunction, hyperrexia, hyperreflexia and 
incoordination. 
Neurological 
Participants co-administration with a serotonergic agent, 
including anti-depressants, should be monitored closely 
for signs of serotonin syndrome.  The Investigator should 
determine whether the full regimen or the concomitant 
agent should be discontinued for those who experience 
signs or symptoms of serotonin syndrome such as 
cognitive dysfunction, hyperrexia, hyperreflexia and 
incoordination. 
54 
55
Protocol Section 
9.0 Statistical 
Analysis 
Statistical Analysis 
 
The statistical analysis plan (SAP), which will contain 
details of the analyses specified in this section, will be 
written and signed off prior to first patient randomized. 
 
Statistical Analysis 
 
The statistical analysis plan (SAP), which will contain 
details of the analyses specified in this section, will be 
written and signed off prior to the interim analysis. 
 
There will be 3 data analyses and trial reports 
generated for this trial:  
 
- When all participants have completed 8 weeks (2 
months) of treatment from baseline.  
- When all participants have completed 52 weeks (12 
months) follow-up from start of therapy.
- When all participants have completed 104 weeks (24 
months) follow-up from start of therapy.  
 
55 
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56
Protocol Section 
11.3 Protocol 
Deviations 
A protocol deviation is any noncompliance with the clinical 
trial protocol, GCP, or Monitoring Plan requirements.  
A protocol deviation is any noncompliance with the clinical 
trial protocol and GCP or Monitoring Plan requirements.  
56 
57
Appendix 6 
Appendix 7 
Appendix 8 
TB Symptom Profile  
 
Patient Reported Health Status Questionnaire 
TB Symptom Profile 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patient Reported Health Status Questionnaire 
57 
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Liver Toxicity Management 
Standard anti-TB chemotherapy is known to cause 
derangement of liver function tests in a substantial 
number of patients. In many cases this will be 
asymptomatic and self-limiting. In some cases, severe 
hepatitis and even fulminant liver failure and death can 
occur. 
In pre-marketing clinical trials of new drugs and regimens 
it is especially important to identify and carefully manage 
Liver Toxicity Management 
Standard anti-TB chemotherapy is known to cause 
derangement of liver function tests in a substantial 
number of patients. In many cases this will be 
asymptomatic and self-limiting. In some cases, severe 
hepatitis and even fulminant liver failure and death can 
occur. 
In pre-marketing clinical trials of new drugs and regimens 
it is especially important to identify and carefully manage 
any trial participants who are at risk of progression to 
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any trial participants who are at risk of progression to 
serious liver injury. The observation of altered liver 
function to a degree that has a high risk of progressing to 
liver failure as been referred to informally as 
 
Law;(44, 45); this reflects that pure hepatocellular 
injury sufficient to cause hyperbilirubinemia is an 
ominous indicator of the potential for a drug to cause 
serious liver injury. Briefly, 
 Law cases have the 
following three components: 
1. The drug causes hepatocellular injury, generally 
shown by a higher incidence of 3-fold or greater 
elevations above the ULN of ALT or AST than the 
(non-hepatotoxic) control drug or placebo. 
2. Among 
trial 
participants 
showing 
such 
aminotransferase (AT) elevations, often with ATs 
much greater than 3x ULN, one or more also show 
elevation of serum total bilirubin (TBL) to >2x ULN, 
without initial findings of cholestasis (elevated 
serum alkaline phosphatase (ALP)). 
3. No other reason can be found to explain the 
combination of increased AT and total bilirubin level 
(TBL), such as viral hepatitis A, B, or C; pre-existing 
or acute liver disease; or another drug capable of 
causing the observed injury. 
 
During the trial, liver function will be monitored regularly 
with clinical assessment and blood tests in trial 
participants and this will assist in follow up laboratory 
measurements that can document either resolution of 
abnormalities or signal the potential for drug-induced 
liver injury (DILI). In a clinical trial of new drugs and 
combinations it is especially important for Investigators 
to follow closely any participants who have evidence 
of hepatic inflammation or potential toxicity. The 
serious liver injury. The observation of altered liver 
function to a degree that has a high risk of progressing to 
liver failure as been referred to informally as 
 
Law;(44, 45); this reflects that pure hepatocellular 
injury sufficient to cause hyperbilirubinemia is an 
ominous indicator of the potential for a drug to cause 
serious liver injury. Briefly, 
 Law cases have the 
following three components: 
4. The drug causes hepatocellular injury, generally 
shown by a higher incidence of 3-fold or greater 
elevations above the ULN of ALT or AST than the 
(non-hepatotoxic) control drug or placebo. 
5. Among 
trial 
participants 
showing 
such 
aminotransferase (AT) elevations, often with ATs 
much greater than 3x ULN, one or more also show 
elevation of serum total bilirubin (TBL) to >2x ULN, 
without initial findings of cholestasis (elevated 
serum alkaline phosphatase (ALP)). 
6. No other reason can be found to explain the 
combination of increased AT and total bilirubin level 
(TBL), such as viral hepatitis A, B, or C; pre-existing 
or acute liver disease; or another drug capable of 
causing the observed injury. 
 
During the trial, liver function will be monitored regularly 
with clinical assessment and blood tests in trial 
participants and this will assist in follow up laboratory 
measurements that can document either resolution of 
abnormalities or signal the potential for drug-induced 
liver injury (DILI). In a clinical trial of new drugs and 
combinations it is especially important for Investigators 
to follow closely any participants who have evidence 
of hepatic inflammation or potential toxicity. The 
following procedure describes the management of 
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following procedure describes the management of 
deranged liver function tests in trial participants. 
Procedure 
Blood tests for liver function will be taken routinely at 
screening (Day -9 to -1) and at the specific time points 
designated in the protocol, and at Early Withdrawal. If at 
any other visit the clinician suspects derangement of 
liver function, e.g. the participant describes nausea and 
vomiting, right upper abdominal pain or is jaundiced, 
blood should be taken for liver function tests and the 
participant comprehensively assessed for evidence of 
hepatitis or hepatic impairment and any potentially 
contributing causes. 
Suspected liver toxicity (or elevated liver enzymes 
detected in the absence of symptoms) must be taken 
seriously and detailed guidance will be provided in a 
separate document, Management of Hepatotoxicity 
Guideline. Investigators should refer to this document as 
a guide to management in cases of suspected or 
proven liver toxicity. Importantly, the Sponsor Medical 
Monitor is available to provide further assistance if there is 
any uncertainty or additional questions. 
The laboratory source (print-out of any results) should be 
stored alongside or transcribed into the clinical source 
document. Each abnormal value should be marked as 
clinically significant (CS) or non-clinically significant 
(NCS); the assessment of significance is at the 
discretion of the Investigator. All clinically significant 
abnormal results must be recorded as Adverse Events in 
the eCRF and graded clinically as per the DMID adult 
toxicity table grading, (Appendix 2). Assessments and 
decision making for elevations in aminotransferase values 
deranged liver function tests in trial participants. 
Procedure 
Blood tests for liver function will be taken routinely at 
screening (Day -9 to -1) and at the specific time points 
designated in the protocol, and at Early Withdrawal. If at 
any other visit the clinician suspects derangement of 
liver function, e.g. the participant describes nausea and 
vomiting, right upper abdominal pain or is jaundiced, 
blood should be taken for liver function tests and the 
participant comprehensively assessed for evidence of 
hepatitis or hepatic impairment and any potentially 
contributing causes. 
Suspected liver toxicity (or elevated liver enzymes 
detected in the absence of symptoms) must be taken 
seriously and detailed guidance will be provided in a 
separate document, Management of Hepatotoxicity 
Guideline. Investigators should refer to this document as 
a guide to management in cases of suspected or 
proven liver toxicity. Importantly, the Sponsor Medical 
Monitor is available to provide further assistance if there is 
any uncertainty or additional questions. 
The laboratory source (print-out of any results) should be 
stored alongside or transcribed into the clinical source 
document. Each abnormal value should be marked as 
clinically significant (CS) or non-clinically significant 
(NCS); the assessment of significance is at the 
discretion of the Investigator. All clinically significant 
abnormal results must be recorded as Adverse Events in 
the eCRF and graded clinically as per the DMID adult 
toxicity table grading, (Appendix 2). Assessments and 
decision making for elevations in aminotransferase values 
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or bilirubin of various levels of concern are detailed 
below: 
Elevated liver enzymes considered of clinical 
significance, but not accompanied by other signs and 
symptoms, should be reported as an adverse event 
and should usually be recorded as elevated liver 
enzymes. If the term "hepatitis" is used, the Safety Data 
Manager will question the site for additional evidence 
to support the diagnosis, such as clinical signs and 
serological or biopsy data. While a liver biopsy is not 
required to make a diagnosis of hepatitis, the term 
"hepatitis" should be reserved in most instances for 
cases where there is supportive evidence beyond a 
liver enzyme abnormality. However, if the Investigator 
will confirm the diagnosis of hepatitis just on the basis 
of clinical signs and laboratory values the diagnosis will 
be accepted. Should other symptoms or signs be 
present, these should also be recorded as adverse 
events. 
Temporarily Stopping and Restarting Trial Medication 
Liver function tests that are improving should be repeated 
regularly, such as every 3 days for the first week then 
once a week until they return to near baseline values for 
the participant. Manage the participant symptomatically 
as required using medications that are not potentially 
hepatotoxic and discontinue any concomitant drugs, if 
clinically warranted, that may be hepatotoxic. Infection 
control issues must be carefully managed whilst TB 
medications are being withheld, especially if the 
participant is still culture positive for acid fast bacilli. 
If t r i a l  medication has been temporarily stopped, 
once the liver function values have decreased 
or bilirubin of various levels of concern are detailed 
below: 
Elevated liver enzymes considered of clinical 
significance, but not accompanied by other signs and 
symptoms, should be reported as an adverse event 
and should usually be recorded as elevated liver 
enzymes. If the term "hepatitis" is used, the Safety Data 
Manager will question the site for additional evidence 
to support the diagnosis, such as clinical signs and 
serological or biopsy data. While a liver biopsy is not 
required to make a diagnosis of hepatitis, the term 
"hepatitis" should be reserved in most instances for 
cases where there is supportive evidence beyond a 
liver enzyme abnormality. However, if the Investigator 
will confirm the diagnosis of hepatitis just on the basis 
of clinical signs and laboratory values the diagnosis will 
be accepted. Should other symptoms or signs be 
present, these should also be recorded as adverse 
events. 
Temporarily Stopping and Restarting Trial Medication 
Liver function tests that are improving should be repeated 
regularly, such as every 3 days for the first week then 
once a week until they return to near baseline values for 
the participant. Manage the participant symptomatically 
as required using medications that are not potentially 
hepatotoxic and discontinue any concomitant drugs, if 
clinically warranted, that may be hepatotoxic. Infection 
control issues must be carefully managed whilst TB 
medications are being withheld, especially if the 
participant is still culture positive for acid fast bacilli. 
If t r i a l  medication has been temporarily stopped, 
once the liver function values have decreased 
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# 
Section 
Previous Text 
Version 2.0 dated 21-Feb-18 
 
Amended Text 
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Additional text - bold font. Deleted text  strike-through. 
Reason for 
Change 
Insert reason # 
from table above 
substantially a decision must be made about further TB 
management. This will be dependent on the clinical 
context and a decision must be made in discussion with 
the Sponsor Medical Monitor. Investigational treatment 
can only be restarted if the Sponsor Medical Monitor is 
in agreement with the plan. In all cases treatment 
should be recommenced under close supervision for any 
evidence of recurrent liver function abnormalities. 
If there is a further significant elevation of hepatic 
enzymes or bilirubin or symptoms of clinical concern 
after resumption of trial medication, the trial medication 
should be withdrawn permanently. Participants who 
permanently discontinue trial medication should be 
managed as clinically indicated according to local 
National TB Programme guidelines. The Sponsor 
Medical Monitor can be contacted for further advice when 
referring to the National Treatment Program. 
The Sponsor Medical Monitor is available to assist the 
Investigators in both the management of liver toxicity 
and decisions regarding the holding or re-introduction 
of trial medication. Investigators must involve the 
Sponsor Medical Monitor in any decisions regarding 
medication hold or re-start, and there should always be 
a low threshold for contacting the Sponsor Medical 
Monitor in cases of elevated liver enzymes.  
 
substantially a decision must be made about further TB 
management. This will be dependent on the clinical 
context and a decision must be made in discussion with 
the Sponsor Medical Monitor. Investigational treatment 
can only be restarted if the Sponsor Medical Monitor is 
in agreement with the plan. In all cases treatment 
should be recommenced under close supervision for any 
evidence of recurrent liver function abnormalities. 
If there is a further significant elevation of hepatic 
enzymes or bilirubin or symptoms of clinical concern 
after resumption of trial medication, the trial medication 
should be withdrawn permanently. Participants who 
permanently discontinue trial medication should be 
managed as clinically indicated according to local 
National TB Programme guidelines. The Sponsor 
Medical Monitor can be contacted for further advice when 
referring to the National Treatment Program. 
The Sponsor Medical Monitor is available to assist the 
Investigators in both the management of liver toxicity 
and decisions regarding the holding or re-introduction 
of trial medication. Investigators must involve the 
Sponsor Medical Monitor in any decisions regarding 
medication hold or re-start, and there should always be 
a low threshold for contacting the Sponsor Medical 
Monitor in cases of elevated liver enzymes.  
 
 
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TB Alliance 
Protocol Number: NC-008 
Protocol Amendment No.: 2 / 14-JAN-2019 
Protocol Name: SimpliciTB 
 
 
Protocol Amendment  
or Administrative Change 
 
TMP-C-SOP01-C V1.0 30-Nov-2018 
CONFIDENTIAL 
This document is proprietary and shall not be reproduced without prior written permission from TB Alliance. 
Sponsor 
I agree to the terms of this Protocol Amendment #2. 
Signature of Study Physician 
 
Printed name 
 
Date 
Principal Investigator 
I hereby confirm I have read the above Protocol Amendment or Protocol Administrative Change and agree to conduct this clinical trial as outlined in the 
above. I will provide copies of the Protocol Amendment or Protocol Administrative Change and access to all of the information required to conduct the 
clinical trial according to the above Protocol Amendment or Protocol Administrative Change to the site personnel under my supervision. I will discuss 
this material with them and ensure they are fully informed on all trial requirements.  
Signature of Principal Investigator 
 
Printed name 
 
Date 
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Certificate Of Completion
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Leandra Lombard
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Time Zone: (UTC-08:00) Pacific Time (US & Canada)
40 Wall St FL 24
New York, NY  10005
Leandra.Lombard@tballiance.org
IP Address: 105.184.115.28 
Record Tracking
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Morounfolu Olugbosi
morounfolu.olugbosi@tballiance.org
Senior Director, Clinical Development
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CONFIDENTIAL  
 
 
 
Protocol Number: 
NC-008 (BPaMZ) 
Title: 
An Open-Label, Partially Randomized Trial to Evaluate the 
Efficacy, Safety and Tolerability of a 4-month Treatment of 
Bedaquiline plus Pretomanid plus Moxifloxacin plus Pyrazinamide 
(BPaMZ) Compared to a 6-month Treatment of HRZE/HR (Control) 
in Adult Participants with Drug-Sensitive Smear-Positive 
Pulmonary Tuberculosis (DS-TB) and a 6-month Treatment of 
BPaMZ in Adult Participants with Drug Resistant, Smear-Positive 
Pulmonary Tuberculosis (DR-TB). 
Drug(s)/Combination(s): 
Bedaquiline tablets (B), pretomanid tablets (Pa), moxifloxacin 
tablets (M), pyrazinamide tablets (Z), HRZE tablets [isoniazid (H), 
rifampicin (R), pyrazinamide (Z) and ethambutol (E)] and HR 
tablets [isoniazid (H) plus rifampicin (R) combination tablets] 
Protocol Version/Date: 
V4.0 / 30 September 2019, Incorporating Amendments 1, 2 and 3 
Protocol Name: 
SimpliciTB 
 
 
 
 
 
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TB Alliance
Protocol Number: NC-008 (B-Pa-M-Z)
Protocol Version:
V4.0 / 30 SEP 2019
Protocol Name:
SimpliciTB
CONFIDENTIAL
Page 2 of 106
PROTOCOL SIGNATURE PAGE
Protocol Title:  An Open-Label, Partially Randomized Trial to Evaluate the Efficacy, 
Safety and Tolerability of a 4-month Treatment of Bedaquiline plus Pretomanid plus 
Moxifloxacin plus Pyrazinamide (BPaMZ) Compared to a 6-month Treatment of 
HRZE/HR (Control) in Adult Participants with Drug-Sensitive Smear-Positive Pulmonary 
Tuberculosis (DS-TB) and a 6-month Treatment of BPaMZ in Adult Participants with 
Drug Resistant, Smear-Positive Pulmonary Tuberculosis (DR-TB).
Protocol Number: 
NC-008 (BPaMZ)
Protocol Date:
V4.0 / 30 September 2019, Incorporating Amendments 1, 2 and 3
Protocol Name:
SimpliciTB
Sponsor:
TB Alliance
I agree to the terms of this trial protocol.
Morounfolu Olugbosi
Signature of Study Physician
Printed Name
40 Wall Street, 24th Floor
New York, NY 10005
Phone +27 87 700 3900 / +27 79 045 4917
E-mail: morounfolu.olugbosi@tballiance.org
Date
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TB Alliance 
Protocol Number: NC-008 (B-Pa-M-Z) 
Protocol Version: V4.0 / 30 SEP 2019 
Protocol Name: 
SimpliciTB 
CONFIDENTIAL 
Page 3 of 106 
 
PRINCIPAL INVESTIGATOR PROTOCOL SIGNATURE PAGE 
 
An Open-Label, Partially Randomized Trial to Evaluate the Efficacy, Safety and 
Tolerability of a 4-month Treatment of Bedaquiline plus Pretomanid plus Moxifloxacin 
plus Pyrazinamide (BPaMZ) Compared to a 6-month Treatment of HRZE/HR (Control) in 
Adult Participants with Drug-Sensitive Smear-Positive Pulmonary Tuberculosis (DS-TB) 
and a 6-month Treatment of BPaMZ in Adult Participants with Drug Resistant, Smear-
Positive Pulmonary Tuberculosis (DR-TB). 
Protocol Number:  
NC-008 (BPaMZ) 
Protocol Date:  
V4.0 / 30 September 2019, Incorporating Amendments 1, 2 and 3 
Protocol Name:  
SimpliciTB 
 
I hereby confirm that I have read the above protocol and agree to conduct this clinical trial as 
outlined in the above protocol. I will provide copies of the protocol and access to all the information 
required to conduct the clinical trial according to the above protocol to the site personnel under 
my supervision. I will discuss this material with them and ensure they are fully informed on all trial 
requirements. 
 
 
 
 
 
Signature 
 
Printed Name 
 
 
 
Date 
 
 
 
 
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TB Alliance 
Protocol Number: NC-008 (B-Pa-M-Z) 
Protocol Version: V4.0 / 30 SEP 2019 
Protocol Name: 
SimpliciTB 
CONFIDENTIAL 
Page 4 of 106 
 
Table of Contents 
Page 
List of Tables ............................................................................................................................. 8 
List of Figures ............................................................................................................................ 8 
List of Appendices ...................................................................................................................... 8 
1.0 
Synopsis ........................................................................................................................11 
1.1 
Synopsis Summary ................................................................................................11 
1.2 
Synopsis Flow Chart and Procedures .....................................................................18 
2.0 
Introduction and Rationale .............................................................................................23 
2.1 
Tuberculosis Disease .............................................................................................23 
2.2 
Tuberculosis Clinical Research ..............................................................................23 
2.3 
Trial Rationale ........................................................................................................25 
2.3.1 
Trial Design Rationale ...............................................................................25 
2.3.2 
Trial Drug Regimen Rationale ...................................................................26 
2.4 
Agents used within SimpliciTB................................................................................27 
2.5 
Background of Agents to be Studied in SimpliciTB .................................................29 
2.5.1 
Bedaquiline (B) .........................................................................................29 
2.5.2 
Pretomanid (P) ..........................................................................................36 
2.5.3 
Moxifloxacin (M) ........................................................................................42 
2.5.4 
Pyrazinamide (Z) .......................................................................................44 
2.6 
Overall Benefit/Risk Assessment ............................................................................45 
2.6.1 
Bedaquiline (B) .........................................................................................45 
2.6.2 
Pretomanid (P) ..........................................................................................46 
2.6.3 
Moxifloxacin (M) ........................................................................................47 
2.6.4 
Pyrazinamide (Z) .......................................................................................47 
2.6.5 
HRZE/HR Control ......................................................................................47 
3.0 
Trial Objectives ..............................................................................................................48 
3.1 
Primary Endpoint ....................................................................................................48 
3.2 
Secondary Endpoints .............................................................................................48 
3.3 
Exploratory Objectives ...........................................................................................49 
4.0 
Trial Design ...................................................................................................................50 
4.1 
Summary of Trial Design ........................................................................................50 
4.2 
Treatment Plan: Schedule of Assessments ............................................................50 
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TB Alliance 
Protocol Number: NC-008 (B-Pa-M-Z) 
Protocol Version: V4.0 / 30 SEP 2019 
Protocol Name:  
SimpliciTB 
 
Table of Contents (continued) 
Page 
CONFIDENTIAL 
Page 5 of 106 
5.0 
Trial Population .............................................................................................................52 
5.1 
Inclusion Criteria ....................................................................................................52 
5.2 
Exclusion Criteria ...................................................................................................53 
5.3 
Restrictions ............................................................................................................57 
5.4 
Treatment Discontinuation and/or Early Withdrawal ...............................................58 
5.4.1 
Early Withdrawal .......................................................................................59 
5.4.2 
Unscheduled Visits ....................................................................................60 
5.4.3 
Lost-to-Follow-up ......................................................................................61 
5.4.4 
Early Withdrawal due to TB .......................................................................62 
5.5 
Participant Progress Definitions ..............................................................................62 
5.6 
Trial Stopping Rules ...............................................................................................63 
6.0 
Treatment ......................................................................................................................64 
6.1 
IMP Administration .................................................................................................64 
6.1.1 
Instructions for Dosing of Test Regimen (BPaMZ) .....................................64 
6.1.2 
Instructions for Dosing Control Treatment Regimen (HRZE/HR) ...............64 
6.2 
Participant Compliance ..........................................................................................64 
6.3 
Treatment Modification(s) .......................................................................................64 
6.4 
IMP Packaging and Labelling .................................................................................65 
6.5 
Blinding and Procedures for Breaking the Blind ......................................................66 
6.6 
Handling, Storage and Accountability .....................................................................66 
7.0 
Trial Variables and Procedures......................................................................................67 
7.1 
Demographic and Background Variables and Procedures ......................................67 
7.2 
Efficacy Variables and Procedures .........................................................................68 
7.3 
Safety and Tolerability Assessments ......................................................................68 
7.4 
PK Variables and Procedures.................................................................................70 
7.5 
Mycobacteriology Characterization Variable and Procedures .................................70 
8.0 
Adverse Events .............................................................................................................72 
8.1 
Definitions ..............................................................................................................72 
8.1.1 
Adverse Event (AE) ...................................................................................72 
8.1.2 
Serious Adverse Event (SAE) ...................................................................72 
8.1.3 
Attribution/Causality ..................................................................................73 
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TB Alliance 
Protocol Number: NC-008 (B-Pa-M-Z) 
Protocol Version: V4.0 / 30 SEP 2019 
Protocol Name:  
SimpliciTB 
 
Table of Contents (continued) 
Page 
CONFIDENTIAL 
Page 6 of 106 
8.1.4 
Severity .....................................................................................................74 
8.2 
Reporting ...............................................................................................................74 
8.2.1 
Follow up of Adverse Events .....................................................................75 
8.2.2 
Clinical Laboratory Adverse Events ...........................................................75 
8.2.3 
Disease Symptoms During Trial ................................................................75 
8.2.4 
Overdose ..................................................................................................76 
8.2.5 
Drug Interaction.........................................................................................76 
8.2.6 
Pregnancy .................................................................................................76 
8.3 
Monitoring for Specific Toxicities ............................................................................76 
8.3.1 
ALT, AST and Bilirubin Elevations .............................................................77 
8.3.2 
Lipase .......................................................................................................77 
8.3.3 
Musculoskeletal System and Cardiac Muscle Myalgia ..............................77 
8.3.4 
Cardiac Rhythm Disturbances ...................................................................77 
8.4 
Safety Monitoring by Data Monitoring Committee ...................................................78 
9.0 
Statistical Analysis .........................................................................................................79 
9.1 
Analysis Populations ..............................................................................................79 
9.2 
Sample Size ...........................................................................................................79 
9.3 
Interim Analyses .....................................................................................................79 
9.4 
Primary and Secondary Efficacy Endpoint Analysis ................................................80 
9.4.1 
Primary Efficacy Endpoint, Time to Culture Conversion at 8 Weeks ..........80 
9.4.2 
Key Secondary Efficacy Endpoint, Clinical Outcome at 52 Weeks 
from Randomization ..................................................................................80 
9.4.3 
Other Secondary Efficacy Endpoints .........................................................81 
9.5 
Safety and Tolerability Assessments ......................................................................81 
9.6 
Pharmacokinetics ...................................................................................................81 
9.7 
Pharmacokinetics/Pharmacodynamics ...................................................................82 
10.0 
Records Management ...................................................................................................83 
10.1 
Data Collection .......................................................................................................83 
10.2 
Source Documents .................................................................................................83 
10.3 
File Management at the Trial Centre ......................................................................83 
10.4 
Records Retention at the Trial Centre ....................................................................83 
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TB Alliance 
Protocol Number: NC-008 (B-Pa-M-Z) 
Protocol Version: V4.0 / 30 SEP 2019 
Protocol Name:  
SimpliciTB 
 
Table of Contents (continued) 
Page 
CONFIDENTIAL 
Page 7 of 106 
11.0 
Quality Control and Assurance ......................................................................................84 
11.1 
Site Procedures ......................................................................................................84 
11.2 
Monitoring ..............................................................................................................84 
11.3 
Protocol Deviations ................................................................................................85 
11.4 
Auditing ..................................................................................................................85 
12.0 
Ethics and Regulatory ...................................................................................................86 
12.1 
Basic Principles ......................................................................................................86 
12.2 
Independent Ethics Committee/Institutional Review Board (EC/IRB) Review .........86 
12.3 
Regulatory Authorities ............................................................................................86 
12.4 
Informed Consent ...................................................................................................86 
12.5 
Confidentiality .........................................................................................................87 
13.0 
Publication Policy ..........................................................................................................88 
14.0 
Protocol Amendment Policy ...........................................................................................88 
15.0 
Sponsor, Financial Aspects, Insurance and Indemnity ...................................................88 
16.0 
References ....................................................................................................................90 
Appendices ...............................................................................................................................95 
 
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TB Alliance 
Protocol Number:  NC-008 (B-Pa-M-Z) 
Protocol Version: V4.0 / 30 SEP 2019 
Protocol Name:  
SimpliciTB 
 
CONFIDENTIAL 
Page 8 of 106 
List of Tables 
Table 1.  Bedaquiline Adverse Drug Reactions .........................................................................34 
Table 2.  Key findings of Pretomanid in Safety and Toxicity Trials.............................................37 
Table 3.  Summary of Phase 2b trials in which moxifloxacin were administered as part of a four-
drug regimen during the intensive phase of treatment (total treatment duration: 2 months) .......43 
Table 4: Treatment Groups .......................................................................................................51 
Table 5: Follow-up Visits Required for Early Withdrawal Participants ........................................59 
Table 6: Summary of Scenarios Requiring Unscheduled Visits for Mycobacteriology Testing ...61 
Table 7: Participant Progress Definitions...................................................................................62 
 
List of Figures 
Figure 1.  Unified Drug Sensitive/Drug Resistant Regimen Development Path .........................24 
Figure 2.  Log10 CFU Counts in Lungs .....................................................................................37 
Figure 3.  Mean log Colony Forming Unit Values over Time Trial CL-010 .................................40 
 
List of Appendices 
Appendix 1: The IUATLD Scale ................................................................................................95 
Appendix 2: Division of Microbiology and Infectious Disease (DMID) Toxicity Table .................96 
Appendix 3: Who Clinical Staging of HIV/AIDS for Adults and Adolescents ............................ 103 
Appendix 4: Cardiovascular Safety ......................................................................................... 105 
Appendix 5: Karnofsky Performance Status Scale Definitions Rating (%) Criteria ................... 106 
 
 
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Protocol Number:  NC-008 (B-Pa-M-Z) 
Protocol Version: V4.0 / 30 SEP 2019 
Protocol Name:  
SimpliciTB 
 
CONFIDENTIAL 
Page 9 of 106 
Abbreviations and Definition of Terms 
 
3TC 
Lamivudine 
ABC 
Abacavir 
AE  
Adverse Event  
AFB 
Acid-fast bacilli 
AIDS 
Acquired Immune Deficiency Syndrome 
ALP 
Alkaline Phosphatase 
ALT 
Alanine aminotransferase 
AREDS2 
Age Related Eye Disease Scale 2 
ART 
Anti-Retroviral Therapy 
AST 
Aspartate aminotransferase 
AUCτ 
Area Under Curve over a dosing interval 
B 
Bedaquiline 
BA 
Bacterial activity 
BMI 
Body Mass Index 
BPaMZ 
Combination of bedaquiline plus pretomanid plus moxifloxacin plus 
pyrazinamide 
C 
Clofazimine 
CFU 
Colony Forming Units 
C(max), (min) 
plasma Concentration (maximum), (minimum) 
CO2 
Carbon dioxide 
CPK 
Creatine Phosphokinase 
CYP3A4 
Cytochrome P450 3A4 
DMID 
Division of Microbiology and Infection Disease 
DNA 
Deoxyribonucleic Acid 
DR-TB 
Drug-resistant tuberculosis 
For this particular protocol defined as TB participants with  
1. mono-resistance to rifampicin or isoniazid, OR 
2. resistance to both rifampicin and isoniazid (MDR-TB) 
(participants with fluoroquinolone resistance are excluded) 
DS-TB 
Drug-sensitive tuberculosis 
DSMC 
Data Safety and Monitoring Committee 
DST 
Drug Susceptibility Testing  
E 
Ethambutol 
EBA 
Early Bactericidal Activity 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
EFV 
Efavirenz 
(e)CRF 
(electronic) Case Report Form 
EMS 
Early Morning Sputum 
EWD 
Early Withdrawal 
FTC 
Emtricitabine 
FSH 
Follicle-stimulating hormone 
GCP  
Good Clinical Practice 
GMR 
Geometric Mean Ratio 
H 
Isoniazid 
HR 
Hazard Ratio 
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Protocol Number:  NC-008 (B-Pa-M-Z) 
Protocol Version: V4.0 / 30 SEP 2019 
Protocol Name:  
SimpliciTB 
 
CONFIDENTIAL 
Page 10 of 106 
 
 
hERG 
Human Ether-à-go-go Related Gene 
HIV  
Human Immunodeficiency Virus 
HRZE 
Isoniazid, Rifampicin, Pyrazinamide, Ethambutol 
HR 
Isoniazid plus rifampicin combination tablet 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IMP 
Investigational Medicinal Product 
IRB 
Institutional Review Board 
ITT 
Intent to Treat 
IUATLD 
International Union Against Tuberculosis and Lung Disease 
IWRS 
Interactive Web Randomization System 
kg 
Kilogram 
L 
Linezolid 
LH 
Luteinizing hormone 
LLN 
Lower Limit of Normal 
LPV 
Lopinavir 
LTFU 
Lost to follow-up  
M 
Moxifloxacin 
MBD 
Minimum Bactericidal Dose 
MIC 
Minimum Inhibitory Concentration 
MTB 
Mycobacterium tuberculosis 
MDR-TB 
Multi Drug Resistant Tuberculosis 
MGIT 
Mycobacterial Growth Inhibiting Tube 
mITT 
Modified Intent to Treat 
ms 
Millisecond 
NVP 
Nevirapine 
NO 
Nitric Oxide 
NOAEL 
No Observed Adverse Effect Level 
NRTI 
(Triple) Nucleosidase Reverse Transcriptase Inhibitor 
Pa 
Pretomanid 
PD 
Pharmacodynamic 
PP 
Per Protocol 
PK 
Pharmacokinetic 
PR 
PR interval 
R 
Rifampicin 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SSCC 
Serial sputum colony counting 
TB 
Tuberculosis 
TDF 
Tenofovir 
TEAE 
Treatment Emergent Adverse Events 
TTP 
Time to Positivity  
ULN 
Upper Limit of Normal 
WGS 
Whole Genome Sequencing 
WHO 
World Health Organization 
XDR-TB 
Extensively Drug Resistant Tuberculosis 
μg(/ml) 
micrograms (per millilitre) 
Z 
Pyrazinamide (tablets) 
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Protocol Number:  NC-008 (B-Pa-M-Z) 
Protocol Version: V4.0 / 30 SEP 2019 
Protocol Name:  
SimpliciTB 
 
CONFIDENTIAL 
Page 11 of 106 
1.0 
Synopsis 
1.1 
Synopsis Summary 
Synopsis 
Description  
Name of 
Sponsor/Company 
TB Alliance 
Name of Finished 
Products 
Bedaquiline tablets (B), pretomanid tablets (Pa), moxifloxacin tablets 
(M), pyrazinamide tablets (Z), HRZE tablets [isoniazid (H), rifampicin 
(R), pyrazinamide (Z) and ethambutol (E)] and HR tablets [isoniazid 
(H) plus rifampicin (R) combination tablets] 
 
Protocol 
Number/Title 
NC-008 (BPaMZ) An Open-Label, Partially Randomized Trial to 
Evaluate the Efficacy, Safety and Tolerability of a 4-month 
Treatment of Bedaquiline plus Pretomanid plus Moxifloxacin plus 
Pyrazinamide (BPaMZ) Compared to a 6-month Treatment of 
HRZE/HR (Control) in Adult Participants with Drug-Sensitive Smear-
Positive Pulmonary Tuberculosis (DS-TB) and a 6-month Treatment 
of BPaMZ in Adult Participants with Drug Resistant, Smear-Positive 
Pulmonary Tuberculosis (DR-TB) 
 
Treatment Indication 
Pulmonary Tuberculosis (TB) 
 
Trial Objective(s) 
To evaluate the efficacy, safety and tolerability at 8 weeks (2-
months), 52 weeks (12-months), and 104 Weeks (24-months) post 
the start of the treatment regimens in participants with Drug 
Sensitive TB (DS-TB) and Drug Resistant TB (DR-TB).  
 
DR-TB is defined as participants with:  
 
1. mono-resistance to rifampicin or isoniazid, OR 
2. resistance to both rifampicin and isoniazid (MDR-TB) 
 
Trial Design 
Phase 2c multi-centre, open-label, partially randomized clinical trial 
in Drug Sensitive-TB (DS-TB) and Drug Resistant-TB (DR-TB) 
participants.  
 
All participants will enter post-treatment follow-up which continues 
until Week 104 from start of treatment / randomisation. 
 
Participants with DS-TB: 
 
Participants with DS-TB will be randomized to one of two treatment 
arms. These participants will receive either BPaMZ daily for 17 
weeks (4 months), or HRZE/HR tablets daily for 26 weeks (6 
months). Participants will be stratified for co-infection with human 
immunodeficiency virus (HIV) and cavitation. 
 
Participants with DR-TB: 
 
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Protocol Number:  NC-008 (B-Pa-M-Z) 
Protocol Version: V4.0 / 30 SEP 2019 
Protocol Name:  
SimpliciTB 
 
CONFIDENTIAL 
Page 12 of 106 
Synopsis 
Description  
Participants with DR-TB will be assigned to receive BPaMZ daily for 
26 weeks (6 months). 
Participant 
Population 
Up to 450 male and female participants, diagnosed with DS-TB or 
DR-TB, aged 18 years and over with a target of up to 50% being HIV 
positive. 
300 DS-TB participants (150 per treatment arm) will be randomized 
and stratified for co-infection with HIV and cavitation. 
Up to 150 DR-TB participants will be enrolled. 
Test Product, Dose 
and Mode of 
Administration 
The Test Product (BPaMZ) consists of a combination of the following 
products and will be supplied as: 
 
Product 
Tablet Strength 
Abbreviation 
Bedaquiline 
100 mg 
(B) 
Pretomanid 
200 mg 
(Pa) 
Moxifloxacin 
400 mg 
(M) 
Pyrazinamide 
500 mg 
(Z) 
 
Instructions for Dosing of BPaMZ 
 
Investigational Medicinal Product (IMP) will be administered orally 
once daily, to be taken during breakfast, with a full glass of water 
(approximately 240 ml), for 17 weeks (4 months) or 26 weeks (6 
months) in the following dosing schemes: 
 
Participants with DS-TB:  
Bedaquiline 200 mg daily for 8 weeks then 100 mg daily for 9 
weeks, together with pretomanid 200 mg + moxifloxacin 400 
mg + pyrazinamide 1500 mg daily for 17 weeks (total 
treatment duration 4 months)  
 
OR 
 
Participants with DR-TB: 
Bedaquiline 200 mg daily for 8 weeks then 100 mg daily for 
18 weeks, together with pretomanid 200 mg + moxifloxacin 
400 mg + pyrazinamide 1500 mg daily for 26 weeks (Total 
treatment duration 6 months). 
 
Positive Control 
Product, Dose and 
Mode of 
Administration 
The Control Treatment Regimen (HRZE/HR) will be supplied as:  
 
HRZE Tablets: isoniazid 75 mg plus rifampicin 150 mg plus 
pyrazinamide 400 mg plus ethambutol 275 mg combination tablets. 
This combination will be given for the first 8 weeks. 
 
AND 
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Protocol Number:  NC-008 (B-Pa-M-Z) 
Protocol Version: V4.0 / 30 SEP 2019 
Protocol Name:  
SimpliciTB 
 
CONFIDENTIAL 
Page 13 of 106 
Synopsis 
Description  
 
HR Tablets: isoniazid 75 mg plus rifampicin 150 mg combination 
tablets. This combination will be given from Weeks 9 to 26. 
 
Instructions for Dosing Control Treatment Regimen 
 
To be taken with a glass of water (approximately 240 ml).  HRZE or 
HR should not be taken with a meal (generally, no closer to meals 
than 1 hour before or 2 hours after a meal) in the following dosing 
schemes: 
 
Treatment will be administered orally once daily to the HRZE/HR 
randomized DS-TB participants as follows: 
 
 
Weeks 1-26: HRZE/HR tablets daily dose per the 
 
participant’s weight as follows:  
 
 
Weight Band 
Weight Range 
Number of 
tablets 
1 
30-39 kg 
2 
2 
40-54 kg 
3 
3 
55-70 kg 
4 
4 
≥ 71 kg 
5 
 
The participant’s weight at the Screening (HRZE) and Week 8 (HR) 
visits will be used to determine which weight band and HRZE and 
HR dose to administer. 
 
Vitamin B6 daily supplement to be taken with the HRZE/HR 
treatment, as per each country’s TB Treatment Guidelines.  
 
Treatment 
Interruptions/Pauses 
For All Trial Regimens 
The trial treatment regimens may require interruptions/pauses due to 
toxicities. All dose interruptions/pauses should be discussed with the 
Sponsor’s Medical Monitor prior to implementation, unless an 
interruption/pause is required urgently for a safety concern.   
Action required for participants missing the following number of 
doses within the trial treatment regimens:  
• 
Up to 7 consecutive doses: restart treatment, no extension of 
treatment required. 
• 
If more than 7 and to ≤ 35 consecutive doses missed, before 
the end of the treatment period (Week 17/26): restart 
treatment, extend the treatment by the number of 
consecutive doses missed. In this case, the last visit of the 
treatment period should also be pushed out to the date of the 
last dose. 
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Protocol Number:  NC-008 (B-Pa-M-Z) 
Protocol Version: V4.0 / 30 SEP 2019 
Protocol Name:  
SimpliciTB 
 
CONFIDENTIAL 
Page 14 of 106 
Synopsis 
Description  
• 
If more than 35 consecutive doses: discontinue treatment 
and withdraw participant from the trial. 
• 
If the participant misses a total of 56 cumulative missed 
doses, discontinue the IMP and withdraw the participant from 
the trial. 
• 
If more than 7 to ≤ 35 consecutive doses are missed, these 
must be made up with the same treatment combination or 
dose, that was missed.  
Any participant for whom the trial IMP is discontinued (including for 
non-adherence) should be discussed with the Sponsor Medical 
Monitor and, if applicable, the participant will be restarted on trial 
IMP as soon as possible. 
Statistical Methods 
 
A general description of the statistical methods planned to be used 
to analyse efficacy data is outlined below. Specific details will be 
provided in the Statistical Analysis Plan (SAP) which will be written 
and signed off prior to the interim analysis. 
 
Criteria for Evaluation 
 
Primary Endpoint 
 
The primary efficacy endpoint will be time to culture negativity over 8 
weeks. The primary hypothesis to be evaluated is:  
 
• 
In the participants with DS-TB in the experimental BPaMZ 
treatment regimen, the time to culture negativity by 8 weeks will 
be superior, compared to the participants who are treated with 
the standard HRZE/HR regimen. 
 
Secondary Endpoints 
 
• 
A key secondary efficacy endpoint will be the proportion of 
participants experiencing bacteriologic failure or relapse or 
clinical failure (unfavourable outcome) at 52 weeks. 
 
The hypothesis to be evaluated for this endpoint is: 
 
• 
In the participants with DS-TB in the experimental BPaMZ 
treatment regimen, the proportion experiencing an unfavourable 
outcome will be non-inferior compared to the participants who 
are treated with the standard HRZE regimen. 
 
Abbreviated Definitions, full definitions will be described in the 
Statistical Analysis Plan (SAP):  
 
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Synopsis 
Description  
• 
Bacteriologic failure: During the treatment period, failure to attain 
or maintain culture conversion to negative.  
• 
Bacteriologic relapse: During the follow-up period, failure to 
maintain culture conversion to negative status, with culture 
conversion to positive status with a strain of Mycobacterium 
tuberculosis (MTB) genetically identical to the infecting strain at 
baseline.  
• 
Clinical failure: A change from protocol-specified TB treatment to 
a new regimen before end of protocol specified treatment due to 
treatment failure, retreatment for TB during follow up, or TB-
related death.  
 
Note:  
 
o Culture conversion requires at least 2 consecutive culture 
negative/positive samples at least 7 days apart.  
o Participants who are documented at a visit as unable to 
produce sputum and who are clinically considered to be 
responding well to treatment will be considered to be culture 
negative at that visit.  
 
Other Secondary Endpoints 
 
Efficacy: 
 
• 
Incidence of bacteriologic failure or relapse or clinical failure at 
104 weeks from the start of treatment.  
• 
Proportion of participants with sputum culture conversion to 
negative status in liquid culture (MGIT) at 4, 6, 12 and 17 weeks 
to be explored as a potential biomarker of outcome at 52 weeks 
from start of treatment. 
• 
Change from baseline in weight. 
• 
Change from baseline in TB symptoms. 
• 
Change from baseline in Participant Reported Health Status. 
 
Safety and Tolerability: 
 
• 
Incidence of Treatment Emergent Adverse Events (TEAEs) 
presented by incidence, severity, drug relatedness, seriousness, 
leading to early withdrawal, and leading to death.  
• 
Quantitative and qualitative clinical safety laboratory 
measurements, including observed and change from baseline. 
• 
Quantitative and qualitative electrocardiogram (ECG) results 
(heart rate, RR interval, PR interval, QRS interval, QT interval 
and QTc interval), including observed. QT/QTc intervals, change 
from baseline, will be categorized as these will be centrally read. 
• 
Changes in male reproductive hormones. 
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Synopsis 
Description  
• 
Changes in lens opacities. 
 
These data will be presented as descriptive analyses, and no 
inferential tests will be carried out. 
 
Pharmacokinetics (PK) and Pharmacokinetics/Pharmacodynamics 
(PK/PD): 
 
Plasma concentrations from sparse sampling will be used to update 
existing population PK models and derive exposure metrics (e.g., 
minimum plasma concentration [Cmin], maximum plasma 
concentration [Cmax], area under curve over a dosing interval [AUC]) 
for bedaquiline and its M2 metabolite, pretomanid, moxifloxacin, and 
pyrazinamide.  
 
Effects of baseline covariates on exposure will be assessed; so too, 
will the effects of concomitant medications, including antiretroviral 
therapy (ART), where feasible. Data from other trials may be 
included to enhance the model-based analysis. Relationships will be 
explored between drug exposure and efficacy and safety endpoints. 
These exploratory PK/PD analyses may include HIV status as a 
covariate. 
 
Exploratory Objectives: 
 
Evaluate whether any of the secondary endpoints predict relapse 
free cure. Subgroup analysis of populations by HIV status will be 
performed. 
 
No formal statistical comparisons will be made for the participants 
enrolled with DR-TB. 
 
Sample Size 
 
Primary endpoint: 150 participants per arm (DS-TB patients) will 
provide at least 90% power (5% 2-sided significance) to detect a 
hazard ratio (HR) of at least 2 assuming 50% of control participants 
are culture negative by 8 weeks.  
 
Additional efficacy parameters will be evaluated including the 
incidence of bacteriologic failure or relapse or clinical failure 
(unfavourable outcome) at 52 weeks and 104 weeks from the start of 
treatment. Time to unfavourable outcome from assignment of trial 
treatment through follow-up as a function of time will be analysed 
using Kaplan-Meier analysis. 
 
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Synopsis 
Description  
Interim Analysis 
 
There is one planned interim efficacy analysis which will occur after 
approximately 60 assessable participants have been randomised to 
the control arm and have reached the 8-week primary endpoint. 
Time to culture negative status in liquid media up to 8 weeks will be 
analysed using a Cox regression model, censoring for death and lost 
to follow up/withdrawal to estimate the hazard ratio (HR). Following a 
review of these interim findings, the following considerations will be 
given to modify the trial objectives and sample size: 
If the observed HR (time to culture negativity, experimental arm vs. 
HRZE control arm) is >2, the sample size may be increased to 
adequately power the trial on the key secondary efficacy endpoint 
(clinical and microbiological outcome at 52 weeks from 
randomization), which will then become the primary efficacy 
endpoint. The trial efficacy objectives will be updated as follows: 
• 
Primary Objective 
 
To determine the incidence of bacteriologic failure or 
 
relapse or clinical failure at 52 weeks from the start of 
 
treatment / randomisation.  
• 
Secondary Objective 
 
To evaluate the time to culture negativity over 8 weeks, 
 
from the start of treatment / randomisation. 
All other trial objectives will remain unchanged. 
To achieve 90% power and overall 5% 2-sided significance after 
adjusting for the interim analysis, this will mean increasing the 
sample size to 225 participants per randomised arm, i.e., to a total of 
450 DS-TB participants (and up to 225 DR-TB participants). This 
adaptation is based on the Multi-arm Multi-stage (MAMS) framework 
[46, 47, 48] and full details are provided in the Statistical Analysis Plan. 
 
Trial Duration 
Approximately 4 years (18-month enrolment period for DS-TB 
participants, up to 26 week-treatment, and follow-up until 104 weeks 
from start of treatment). Depending on the DR-TB recruitment rate, 
enrolment into this arm may continue after enrolment into the DS-TB 
arms are complete.  
 
 
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1.2 
Synopsis Flow Chart and Procedures 
Period 
Screen-
inga 
Treatment 
Follow-Upc 
Visitb 
Day -9 to -1 
Day 1 
(Baseline)d 
Week 1  
Week 2 
Week 3 
Week 4 
Week 5 
Week 6 
Week 7 
Week 8  
Week 12 
Week 17 
4-mth treatmente 
Week 17  
6-mth treatmente 
Week 22  
Week 26  
4-mth treatmente 
Week 26  
6-mth treatmente 
Week 39 
Week 52 
Week 65 
Week 78 
Week 104 
Early 
Withdrawalc 
Visit Windowv 
N/A 
+/- 3 Days 
+/- 5 Days 
+/- 14 Days 
Written Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/Treatment/ Smoking History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sputum Samplingf,g 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HIV Statush and CD4 Counti 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Karnofsky Scorex 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Drug Screenj 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Pregnancy Testk 
X 
X 
 
 
 
 
 
 
 
X 
 
X 
X 
 
X 
X 
 
 
 
 
 
X 
Laboratory Safety Testl 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
 
 
 
 
X 
Male Reproductive Hormone Testsm 
X 
X 
 
 
 
 
 
 
 
 
 
X  
 
 
 
X  
X 
 
 
 
 
X  
12-lead ECGn 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X  
X 
X 
 
X 
X 
X 
 
 
 
 
X 
Chest X-Rayo 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TB Symptoms Profile 
X 
X 
 
X 
 
X 
 
 
 
X 
 
X 
X 
 
X 
X 
 
X 
 
 
X 
X 
Patient Reported Health Status  
X 
X 
 
X 
 
X 
 
 
 
X 
 
X 
X 
 
X 
X 
 
X 
 
 
X 
X 
Vital Signs and weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Ophthalmic Examinationp 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
X 
X 
 
 
 
 
X 
Physical Examination – fullq 
X 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
Physical Examination – limitedr 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
Pharmacokinetic Samplings 
 
X 
 
X 
 
 
 
 
 
X 
X 
X 
X 
 
 
 
X 
 
X 
X 
X 
 
IMP Randomization/ Assignmentt 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IMP Compliance Checku 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 Xe 
 
X 
 
 
 
 
 
Xt 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Investigator Assessmentv 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
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GENERAL: Vital signs and blood draws are to be performed before dosing, unless otherwise specified. Vital signs and/or 
ECGs should be done before blood draws (safety and PK) on days with those assessments. 
 
a. Screening: Screening assessments can occur on different days, within nine days before Day 1 (Baseline).  
b. Visit Schedule (due to unforeseen circumstances): If the duration of treatment is extended due to dose interruptions / pauses (7 to ≤ 35 
consecutive doses), the last visit of the corresponding treatment period should also be pushed out to the date of the last dose. It is not 
necessary to have an unscheduled visit at the time that the last visit of the treatment period would have been scheduled on.   
c. Follow-up Visits for Early Withdrawal Participants: Once a participant has been permanently withdrawn from the trial, they will be 
required to attend an Early Withdrawal visit (Week 52, if not already performed) and Week 104 follow-up visits. The Week 52 and Week 
104 visits will be performed to collect Serious Adverse Event (SAE) information (including verification of survival) and the participant 
reported TB outcome information only, and may be performed telephonically, at home or a site visit. Visits will occur at Week 52 and/or 
Week 104 after the participant’s start of treatment date.  Refer to Table 5 for additional guidance. 
d. Day 1 (Baseline): All procedures are to be completed before dosing.  
e. Last Visit of the Treatment Period: Investigational Medicinal Product (IMP) Compliance Check is not performed at the Week 22 visit for 
participants who have completed treatment at Week 17. 
f. 
Sputum Sampling: The sputum sampling methodology, requirements and tests will be described in a separate document, the 
Mycobacteriology Laboratory Manual. 
 
• 
Screening (Days -9 to -1). Two spot sputum samples taken 30 minutes apart will be collected at the research site under the coaching 
and observation of the trial staff. The following analyses will be performed on the first of these samples: 
o 
Smear microscopy for acid-fast bacilli (AFB); 
o 
Rapid molecular tests for fluoroquinolones, isoniazid and rifampicin resistance (Hain MTBDRplus and Hain MTBRsl);  
o 
Liquid Culture (MGIT) for Mycobacterium tuberculosis (MTB), followed by a speciation test to detect the presence or absence 
of MTB and obtain the time to positivity (TTP) when positive. 
o 
The second sample is collected as a back-up sample to the first sample in case it is technically not possible to obtain a 
result/s from the first sample. If the Screening spot sputum smear shows an indeterminate result or is AFB negative, the test 
may be repeated on the back-up sample or on a freshly collected spot sputum, and then that result will be used.  
• 
Day 1 (Baseline) to Week 104 and Unscheduled visits for additional sputum samples:  
o 
Two sputum samples are collected, ideally one Early Morning Sputum (EMS) brought from home and one spot sputum 
sample at the research site, under the coaching and observation of the trial staff. If the participant forgets to bring in the EMS, 
then two spot sputum samples are to be collected at the site, at least 30 min apart, and this altered sample collection is 
captured within case report form (CRF).   
o 
If both sputum cultures at Week 8 or later are contaminated, the participant should return for an unscheduled visit(s) to give 
additional sputum samples or to document that the participant is not able to produce a sputum sample.  
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• 
If after having converted to culture negative, and the participant has a MTB confirmed positive culture at or after the last visit of the 
treatment period (Week 17 or Week 26), the participant should return for unscheduled visit/s to provide additional sputum samples, at 
a minimum of 7 days apart, or to document that the participant is not able to produce a sputum sample. 
• 
Additional samples may be required to define a participants’ primary outcome status as described in Sections 5.4.2 and 7.2.  
• 
Liquid Culture (MGIT) for MTB, followed by a speciation test to detect the presence or absence of MTB and obtain TTP when positive, 
will be performed on all samples. 
g. Mycobacteriology Characterisation Tests Performed: 
• 
Day 1 (Baseline) sputum sample (or any positive sample from Screening to Week 4, if the baseline cultures are contaminated or 
negative); 
• 
MTB confirmed positive cultures (after the participant has previously converted to culture negative) at or after the last visit of the 
treatment period (Week 17 or Week 26) or visits with positive cultures, during the post-treatment follow-up period. 
• 
Refer to the Mycobacteriology Laboratory Manual for full details. 
Mycobacterial Characterization - MTB isolates (from the first MTB positive culture) will be processed for: 
• 
Rapid molecular tests for fluoroquinolones, injectables, isoniazid and rifampicin resistance (only on MTB positive cultures in the follow-
up period); 
• 
Minimum Inhibitory Concentration (MIC) against bedaquiline, pretomanid, and moxifloxacin;  
• 
Drug Susceptibility Testing (DST) for streptomycin, rifampicin, isoniazid, ethambutol, moxifloxacin, and pyrazinamide in liquid culture;  
• 
Extraction of organismal (MTB) DNA for whole genome sequencing (WGS), and comparison of sequences from baseline and relapse 
isolates. 
 
h. HIV Testing: If HIV status is a confirmed known positive, a repeated HIV test is not needed provided that a documented HIV test result 
(ELISA, Western Blot or Electro-Chemiluminescence) is available. If the HIV status is unknown or suspected negative, a HIV test will be 
requested. If an ELISA and/or Western Blot and/or Electro-Chemiluminescence based HIV test was performed within 4 weeks prior to 
screening, it should not be repeated if documentation of testing method and negative HIV results can be provided. Repeated HIV testing, 
during the Screening period is permitted for indeterminate HIV results. 
i. 
CD4 Count: Required for all HIV-positive participants.  
j. 
Urine Drug Screen: Cannabinoids, cocaine, amphetamines, opiates, benzodiazepines, barbiturates, at Screening only. Investigator to 
utilize this result to determine whether participant meets Exclusion Criteria 2. Positive results will not automatically exclude a participant 
from the trial. 
k. Urine Pregnancy Test: Women of childbearing potential only, whether they are sexually active or not.  
l. 
Safety Laboratory Assessments: The safety laboratory sampling methodology and requirements will be described in a separate 
document, the Safety Laboratory Manual, which will be provided prior to the trial start. The following analyses will be performed: 
• 
Full Blood Count (haemoglobin, haematocrit, red blood cell count, white blood cell count with differential, platelet count).  
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• 
Clinical Chemistry (albumin, serum urea, creatinine, direct, indirect and total bilirubin, uric acid, total protein, alkaline phosphatase 
[ALP], aspartate aminotransferase [AST], alanine aminotransferase [ALT], lipase, phosphate, sodium, potassium, calcium (corrected 
for albumin), chloride, magnesium, glucose, bicarbonate/carbon dioxide [CO2], creatine phosphokinase [CPK]). GGT is only routinely 
included at the Screening visit (Day -9 to -1).  
• 
Urinalysis (pH, specific gravity, protein, glucose, micro-albumin, ketones, bilirubin, creatinine, nitrite, sodium, urobilinogen, blood, 
leukocytes). Microscopy will be completed as follow-up to abnormal urinalysis per discretion of Investigator.  
• 
When managing participants with elevated liver enzymes at an Unscheduled visit, the investigator should request additional tests, in 
addition to the repeat LFT [e.g. Gamma Glutamyl Transferase (GGT), screening for Hepatitis A, B, C; to assist in ruling out other 
causes of a dysfunctional liver test (e.g. alcohol induced hepatic cell injury, hepatobiliary disease, hepatic viral infection)]. 
• 
Hepatitis A, B and C serology test to be performed at Day 1 (baseline) or where available, the backup PK sample at Day 1 (pre-dose) 
will be used to obtain a hepatitis A, B and C serology result for all participants already enrolled prior to Protocol V4.0. 
m. Male Reproductive Hormone Tests: Testosterone, follicle-stimulating hormone (FSH), luteinizing hormone (LH) and Inhibin B to be done 
on male participants in ALL treatment groups. 
 
n. Single 12-Lead ECG: ECGs to be performed prior to pre- and post-dose PK sampling as described below: 
• 
Day 1: pre-dose (within 2 hours prior to dosing) 
• 
Week 2: pre-dose (within 2 hours prior to dosing), 1.5–3 hours post-dose and 4-6 hours post-dose 
• 
Week 8: pre-dose (within 2 hours prior to dosing), 1.5–3 hours post-dose and 4-6 hours post-dose 
• 
Week 12: pre-dose (within 2 hours prior to dosing)  
• 
Week 17 or at early withdrawal if prior to week 17: pre-dose (within 2 hours prior to dosing) and 1.5–3 hours post-dose 
Central ECG analysis will be performed. Results from central reading of Screening ECG must be used to determine eligibility.  
o. Chest X-Ray: A chest x-ray (digital image only) within 6 months prior to or at the Screening visit, will be obtained and read locally by the 
Investigator or designee. Digital images will be provided to the Sponsor and this process will be described in a separate document, the 
Radiology Manual. 
p. Slit Lamp Ophthalmic Examination: Slit lamp examination will be done at the Screening visit, the last visit of the treatment period (Week 
17 or 26) and at Week 39 for both treatment groups.  An additional slit lamp at Week 26 will be done for the 4-month treatment group. Slit 
lamp ophthalmology examination will be performed by an Ophthalmologist with AREDS2 training. Ophthalmology examinations may occur 
at any time within the window period for the applicable visit i.e. they do not have to be performed on the same day as the trial procedures. 
q. Physical Examination, Full: Height (m) will only be collected at Screening.  
r. 
Physical Exam, Limited: Limited physical exams will include weight and gross neurological, pulmonary, cardiovascular and abdominal 
exam(s). 
s. Pharmacokinetic (PK) Sampling: This process will be described in a separate document, the PK Sampling Manual. No PK samples will 
be collected for the HRZE/HR treatment arm.  Blood draws for PK samples collected pre- and post-dose must be done after the ECG is 
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performed.  The dates and times of IMP taken prior to all pre-dose PK samples will be collected.  Specific PK blood draws will be obtained 
as follows: 
 
• 
*Day 1: pre-dose (within 2 hours prior to dosing) 
• 
Week 2: pre-dose (within 2 hours prior to dosing), 1.5–3 hours post-dose and 4-6 hours post-dose 
• 
Week 8: pre-dose (within 2 hours prior to dosing), 1.5–3 hours post-dose and 4-6 hours post-dose 
• 
Week 12: pre-dose (within 2 hours prior to dosing)  
• 
Week 17 or at early withdrawal if prior to week 17: pre-dose (within 2 hours prior to dosing) and 1.5–3 hours post-dose 
• 
Weeks 39, 65, 78 and 104: PK samples are to be obtained at any time on the day of the scheduled visit. 
Only bedaquiline and M2 will be measured. 
If IMP is not administered during Week 2, 8 and or 17, then only a single PK sample is required to be obtained at any time during the visit 
assessment. 
* Where available, the backup PK sample at Day 1 (pre-dose) will be used to obtain a hepatitis A, B and C serology result for all 
participants already enrolled prior to Protocol V4.0. 
t. 
Investigational Medicinal Product (IMP) Randomization/Assignment: Randomization/Assignment may occur once all the Screening 
results are available and the Investigator has determined that the participant is eligible for the trial. 
u. IMP/Compliance Check: IMP administration will be supervised per local site practice to assure compliance to the regimen. Performed at 
all visits and Early Withdrawal (EWD), if during the treatment period.  
v. Investigator Assessment: Investigator to review the participant status and assess whether IMP or TB treatment at Week 52 and 104 is 
considered a “success” or “failure”.  If considered a failure, the Investigator should specify if the assessment is based on bacteriology 
and/or clinical deterioration and/or radiological deterioration. Investigator Assessment to be completed, at Week 52 and 104, and at any 
time the Investigator determines that the participant fulfils the criteria for outcome of treatment failure. 
w. Visit Windows: The windows noted on the flowchart for timing of visit also apply to the timing within a visit.  Procedures should be 
performed within +/- 3 days of scheduled visit from Day 1 to Week 8 or +/- 5 Days of scheduled visit from Week 12 to Week 26 or +/- 14 
days of scheduled visit at or after Week 39.  Sites should make every effort to ensure all procedures are done on the same day, when 
possible. 
x. Karnofsky Score: Only to be performed on HIV+ participants.  
 
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2.0 
Introduction and Rationale 
2.1 
Tuberculosis Disease 
Although some progress has been made in recent years in controlling tuberculosis (TB) globally, 
TB has remained a persistent problem in the developing countries of Africa, Asia and South 
America.  TB is currently one of the top three killer infectious diseases, and there is more TB in 
the world today than at any other time in history.  The current first-line anti-tuberculosis agents 
have been in use for over 40 years and are relatively ineffective in controlling TB as a public health 
problem.  Although the current regimens and drugs have been very successful in controlled 
clinical trials resulting in the permanent cure of more than 95% of trial participants, treatment takes 
6 months or more to complete. This, long duration treatment plus side effects, result in poor 
adherence which particularly occurs after the second month of treatment.  
The current TB treatment regimens and treatments for drug-sensitive TB are decades old. The 
available treatments have a lengthy duration of treatment, involve multi-drug therapy, and require 
large commitments of resources and infrastructure. High rates of noncompliance are common, 
which often results in increased mortality and chronic, infectious, drug-resistant cases. The 
present TB epidemic and the challenge of current treatment options demonstrate the clear need 
for effective novel TB drugs and drug regimens that are safe for drug sensitive and drug resistant 
TB disease and that are well-tolerated and will shorten the current treatment duration for patients. 
The full application of the Directly Observed Treatment, Short-Course strategy is becoming more 
and more difficult in the developing countries of the world that are also battling to control the HIV-
epidemic.  Because of poor treatment adherence, drug resistance is becoming more common 
and fears of an epidemic with virtually untreatable strains of TB are growing.  Since the discovery 
of the rifamycins,[1] and their introduction into standard antituberculosis regimens, very few new 
classes of drugs have been evaluated with a view to their registration as antituberculosis agents.  
On December 28, 2012 the U.S. Food and Drug Administration approved bedaquiline (B) as part 
of combination therapy to treat adults with multi-drug resistant (MDR) pulmonary tuberculosis (TB) 
when other alternatives are not available. Following the declaration of TB as a global emergency 
by the World Health Organization (WHO) in 1993, there has been a resurgence of efforts to 
develop improved TB therapies and several promising new agents are presently in or approaching 
clinical evaluation.   
New combination regimens are desperately needed for two reasons: to shorten treatment to a 
duration more easily manageable by patients and public health services, and to provide more 
efficacious, safer and better tolerated, affordable treatments for the growing number of patients 
suffering from multidrug-resistant and extensively drug-resistant tuberculosis. 
2.2 
Tuberculosis Clinical Research 
TB currently must be treated with multiple drugs to achieve maximal efficacy and prevent 
resistance. To transform treatment, novel TB regimens are needed. To telescope the time, it takes 
to develop novel, tolerable multi-drug treatments, it is necessary to use the regimen development 
paradigm. This approach tests promising combinations of drugs together to find the most 
impactful treatment once the individual drug candidates have been tested in a robust pre-clinical 
program and the establishment of the individual drug candidates’ safety and efficacy have been 
evaluated.  It evaluates novel combinations of TB drugs — instead of single drugs — as part of a 
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single development program, enabling the development of novel TB drug regimens that have 
potential to transform treatment for drug-sensitive and drug-resistant tuberculosis. This approach 
offers the potential to reduce the time previously needed to develop a novel treatment regimen 
by up to 75%, shortening the clinical development from decades to years. The steps followed in 
this development model are shown in Figure 1 Between each step on the unified development 
pathway a decision is made as to whether to proceed. 
Figure 1.  Unified Drug Sensitive/Drug Resistant Regimen Development Path 
 
Early Bactericidal Activity (EBA) Trials 
EBA trials are the backbone clinical trials to quantify the bactericidal action of anti-tuberculosis 
agents alone or in combination by either trialling the fall in the number of colony forming units 
(CFU) or measuring the TTP in liquid culture of M. tuberculosis (MTB) present in the sputum of 
participants with microscopy smear-positive pulmonary TB. EBA trials have been conducted over 
2, 5, 7 and 14 days.[2]. A review of EBA trials conducted on the key anti-TB drugs has shown the 
value these trials offer to demonstrate the early anti-TB effect that a new therapeutic agent may 
have and to explore the relationships between dose, pharmacokinetics and bactericidal activity in 
participants.[3] 
8-week Bactericidal Activity (BA) Trials 
EBA methodology of quantitative colony counting on solid medium has been adapted to Phase 2, 
8-week TB treatment trials based on serial sputum colony counting (SSCC) or measurement of 
TTP liquid culture to provide a more sensitive efficacy endpoint than the previously used binary 
endpoint of rate of sputum conversion measured after 8 weeks of treatment.[4-6] Such trials are 
conducted to provide data on which to base the selection of treatment-shortening regimens.  
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2.3 
Trial Rationale 
The SimpliciTB NC-008 (BPaMZ) trial will evaluate and support that, in addition to previous 
studies evaluated with BPaMZ, this drug regimen will be safe and effective, is well-tolerated and 
could potentially shorten the current treatment duration compared to the standard HRZE/HR 
treatment for patients with drug sensitive TB disease. This trial will also evaluate if the BPaMZ 
drug regimen given for 6 months will be safe and effective in drug resistant TB disease. 
Therefore, the trial design addresses the need to find and evaluate a potentially effective and 
shorter regimen compared to regimens (standard HRZE/HR) that are currently being used. 
2.3.1 
Trial Design Rationale 
The SimpliciTB NC-008 (BPaMZ) trial is a Phase 2c multi-centre, open-label, partially randomized 
clinical trial in DS-TB and DR-TB participants. This trial is to evaluate the combination regimen of 
Bedaquiline (B) plus Pretomanid (Pa) plus Moxifloxacin (M) plus Pyrazinamide (Z) (BPaMZ), 
in participants with pulmonary TB. 
All participants will enter post-treatment follow-up which continues until Week 104 after start of 
treatment / randomisation. 
Participants with DS-TB: 
Participants with DS-TB will be randomized to one of two treatment arms. These participants will 
receive either: 
• 
BPaMZ daily for 17 weeks (4 months),  
OR  
• 
HRZE/HR combination tablets daily for 26 weeks (6 months).  
Participants will be stratified for co-infection with HIV and cavitation. 
Participants with DR-TB are defined as: 
1. mono-resistance to rifampicin or isoniazid, OR 
2. resistance to both rifampicin and isoniazid (multi-drug resistant tuberculosis [MDR-TB]) 
Up to 150 participants with DR-TB will be assigned to receive BPaMZ daily for 26 weeks (6 
months).  Approximately 300 DS-TB participants (150 per treatment arm) will be randomized and 
stratified for co-infection with HIV and cavitation to either BPaMZ for 4 months or HRZE/HR for 6 
months.  
 
The trial is sufficiently statistically powered to not only show superiority of 8 Weeks culture 
conversion but should also demonstrate non-inferiority for cure at 52 Weeks (this is in the 
participants with DS-TB in the experimental BPaMZ treatment regimen, the proportion 
experiencing an unfavourable outcome will be non-inferior compared to the participants who are 
treated with the standard HRZE regimen). 
 
There is one planned interim efficacy analysis which will occur after approximately 60 assessable 
participants have been randomised to the control arm and have reached the 8-week primary 
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endpoint. Time to culture negative status in liquid media up to 8 weeks will be analysed using a 
Cox regression model, censoring for death and lost to follow up/withdrawal to estimate the hazard 
ratio (HR). Following a review of these interim findings, the following considerations will be given 
to modify the trial objectives and sample size: 
If the observed HR (time to culture negativity, experimental arm vs. HRZE control arm) is >2, the 
sample size may be increased to adequately power the trial on the key secondary efficacy 
endpoint (clinical and microbiological outcome at 52 weeks from randomization), which will then 
become the primary efficacy endpoint. The trial efficacy objectives will be updated as follows: 
- 
Primary Objective 
To determine the incidence of bacteriologic failure or relapse or clinical failure at 
52 weeks from the start of treatment / randomisation.  
- 
Secondary Objectives 
To evaluate the time to culture negativity over 8 weeks, from the start of treatment 
/ randomisation. 
All other trial objectives will remain unchanged. 
To achieve 90% power and overall 5% 2-sided significance after adjusting for the interim analysis, 
this will mean increasing the sample size to 225 participants per randomised arm, i.e., to a total 
of 450 DS-TB participants (and up to 225 DR-TB participants). This adaptation is based on the 
Multi-arm Multi-stage (MAMS) framework [46, 47, 48] and full details are provided in the Statistical 
Analysis Plan.  
As previously described in the background information, in order to telescope the time it takes to 
develop novel, tolerable multi-drug treatments, it is necessary to use the regimen development 
paradigm and utilize data generated in non-clinical and clinical studies regarding combining of 
anti-tuberculosis agents which could contribute significantly to the sterilization of lesions and thus 
treatment shortening. Therefore, the trial design and proposed trial regimen (BPaMZ) which is 
supported with previous non-clinical and clinical studies outlined below should address the need 
and manner of evaluating an effective shorter regimen compared to regimes that are currently 
being used. 
2.3.2 
Trial Drug Regimen Rationale 
The BPaMZ regimen has been studied singularly and in different combinations as outlined above. 
Moxifloxacin has been added to the B-Pa-Z regimen because of the high rate of pyrazinamide 
resistance seen in MDR-TB participants in the NC-002 trial. It essentially provides protection 
against the development of new resistance to the B-Pa-Z drugs. Based on the exciting and 
promising results seen in NC-005, this regimen can be initiated in drug sensitive and drug resistant 
TB participants whom are sensitive to the individual drugs in the regimen (excluding extensively 
drug-resistant tuberculosis [XDR-TB] and Pre-XDR tuberculosis) and has the potential to shorten 
TB treatment to less than 4 months in drug sensitive TB. These are also oral regimens, removing 
the need for injectables as part of MDR-TB treatment, and also project to be markedly less 
expensive than current MDR-TB therapy. Additionally, these regimens can be administered in a 
fixed dose for all patients and will therefore be simpler for health systems to deliver and patients 
to use. 
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2.4 
Agents used within SimpliciTB 
Bedaquiline (TMC207; SirturoTM package insert)[7]  is a novel agent approved for TB treatment. 
As detailed in the Investigator’s Brochure,[8] bedaquiline is a diarylquinoline that offers a novel 
mechanism of anti-tuberculosis action by specifically inhibiting mycobacterial adenosine 
triphosphate synthase.[9, 10]) In vitro, bedaquiline potently inhibits both drug-sensitive and drug-
resistant M. Tb isolates,[10, 11], and is also bactericidal against non-replicating M. Tb.[12] In the 
murine model of TB, bedaquiline was as active as the triple combination of isoniazid (H), rifampin 
(R), and pyrazinamide (Z). Addition of bedaquiline to HRZ results in accelerated clearance of M. 
Tb.[3, 4] There appears to be a synergistic interaction with pyrazinamide: 100% of mice were 
culture negative after 8 weeks of treatment with bedaquiline and pyrazinamide compared to 0% 
of mice treated with the standard regimen of rifampicin, isoniazid and pyrazinamide.[13] 
Collectively, these findings in the mouse model have led to the suggestion that regimens 
containing bedaquiline and pyrazinamide could be effective in the treatment of both DS- and 
MDR-TB and shorten treatment duration in patients. While the combination of bedaquiline and 
pretomanid in the murine model of TB appeared somewhat antagonistic relative to bedaquiline 
alone, it was as active as the triple combination of HRZ[13] and in a subsequent trial it was more 
active in the mouse model than HRZ.[14] Thus, a novel regimen with a bedaquiline plus pretomanid 
core could be effective in the treatment of MDR-TB by providing two novel drugs for which there 
is no known pre-existing resistance.  
Pretomanid, (Pa)[15]  is a new chemical entity being developed by TB Alliance for the treatment 
of TB.  It is a member of a class of compounds known as nitroimidazo-oxazines, which possess 
significant anti-tuberculosis activity and a unique mechanism of action.[16] PRETOMANID has 
been under development for several years and entered clinical trials in 2005. Several trials of 
pretomanid have also been conducted previously in healthy volunteers.  Collectively, these trials 
in participants with active TB and healthy participants have defined the efficacy, safety and 
pharmacokinetic features of the drug.  Overall, pretomanid has mycobactericidal activity in 
participants and is well tolerated and bioavailable after oral dosing.  Pretomanid demonstrated in 
vitro activity against both drug-sensitive (DS) and MDR-TB,[17] and in vivo activity in a mouse 
model of TB[17, 18] with a significant promise for shortening treatment of active TB. 
Moxifloxacin (M)[19]  is a microbial compound, approved in most countries around the world for 
the treatment of acute bacterial sinusitis, acute bacterial exacerbation of chronic bronchitis, 
community-acquired pneumonia, skin and soft tissue infections.  Clinical studies have been 
carried out for many additional indications (urinary tract infections, pelvic infections, 
pharyngitis/tonsillitis, and tuberculosis). Moxifloxacin is an 8-methoxyquinolone whose oral 
formulation (which will be used in this trial) has enhanced activity against Gram-positive 
pathogens, and anaerobes while retaining useful activity against Gram-negative organisms. 
Moxifloxacin is not metabolized by or induces the cytochrome P450 system, thus the risk of 
clinically relevant drug interactions is reduced. It has a positive safety profile within the 
fluoroquinolone class at the approved daily dose of 400 mg. Moxifloxacin while not approved for 
TB by most regulatory authorities, it is regularly used in second line MDR-TB treatment. The WHO 
TB Treatment Guidelines place moxifloxacin in the category of Group 3 drugs and notes that “all 
patients [with MDR-TB] should receive a Group 3 medication if the MTB strain is susceptible or if 
the agent is thought to have efficacy. One of the higher generation fluoroquinolones, such as 
levofloxacin or moxifloxacin, is the fluoroquinolone of choice.[5]” It is currently in late stage clinical 
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development for first-line TB treatment in combination with other TB drugs, including 
pyrazinamide in two different four-month long regimens.  
Pyrazinamide (Z)[20] is a pyrazine analogue of nicotinamide and an approved anti-tuberculosis 
agent which is indicated for the initial treatment of active tuberculosis in adults and children when 
combined with other anti-tuberculosis agents and contributes significantly to the sterilization of 
lesions and thus treatment shortening.[21]   
Control Group: HRZE/HR 
The HRZE/HR combination [HRZE tablets [isoniazid (H), rifampicin (R), pyrazinamide (Z) and 
ethambutol (E)] and HR tablets [isoniazid (H) plus rifampicin (R) combination tablets] is approved 
indicated and commonly used as a 6-month treatment for drug-sensitive TB patients.  Participants 
with DS-TB that are randomized to the HRZE/HR control arm in this trial will be given standard 
weight-adjusted doses of HRZE.  Please see the HRZE package insert for more information.[22]   
Additional background data supporting the combined use of new novel agents in this 
BPaMZ regimen for the treatment of TB: 
Data from preclinical studies suggest that a regimen consisting of moxifloxacin plus pretomanid 
plus pyrazinamide may not only be appropriate for treating both DS and MDR-TB but may also 
shorten duration of therapy.  Results from an 8-week Phase 2b SSCC trial, NC-002-(M-Pa-Z), 
showed that this combination regimen was effective as measured by time dependent decline of 
viable bacteria in participants with DS pulmonary TB.  The combination was also shown to be 
safe and well tolerated supporting the evaluation of this combination in a Phase 3 trial. In this 
NC-002 trial 71.4% of participants with DS-TB treated with PaMZ at the 100-mg daily dose of 
pretomanid converted sputum to negative for MTB growth in liquid culture in comparison with only 
37.8 % of participants treated with the HRZE control (p<0.05).  
Studies in mice infected with MTB demonstrated reductions in cultured colony counts from lungs 
over an 8-week period when treated with the PaMZ regimen that were substantially, and 
statistically significantly greater, than the reductions in mice treated with an HRZ control.  
Experiments in mice found that mice did not relapse with MTB infection when treated with PaMZ 
for 4 months and followed for 3 months off treatment, in comparison to mice that required 6 
months of treatment with HRZ to prevent relapse.[14]   
Drug Resistant TB Background: 
Although some progress has been made in recent years in controlling tuberculosis (TB) globally, 
TB has remained a persistent problem in many countries. TB is the world’s leading cause for 
mortality from infectious disease and is responsible for more deaths than HIV.[23] It is the leading 
cause of death among HIV-infected individuals, and there is more TB in the world today than at 
any other time in history. Because of poor treatment adherence, in addition to primary 
transmission, drug resistance is becoming more common and fears of an epidemic with strains 
of extensively drug-resistant TB (XDR-TB) that is very difficult to treat are growing.  Novel drugs 
and regimens for TB are needed for the growing number of patients with drug resistant-TB.  
The regulatory approvals of bedaquiline and delamanid have given hope that outcomes for 
patients with drug resistant TB might be improved when added to background regimens. 
Experience recently published from the C209 uncontrolled trial of bedaquiline given on a 
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background of multiple drugs notes that the subset of 38 participants with XDR-TB had rates of 
sputum culture conversion to negative of 62.2%.[24] However, in this trial only one participant with 
XDR-TB was co-infected with HIV. All participants were required to have Mycobacterium 
tuberculosis (MTB) isolates susceptible to at least 3 drugs at enrolment and participants had a 
median of only 5.4 months of treatment-free follow-up. This trial added bedaquiline for 6 months 
to a background regimen of many drugs given for 18 months or longer. While treatment success 
for MDR-TB is better than for XDR-TB, overall success in treating MDR-TB is still 
approximately 50% according to the World Health Organization 2015 Global TB Report.[23]  This 
report presented that overall, the proportion of MDR-TB patients in the 2012 cohort who 
successfully completed treatment (i.e. cured or treatment completed) was 50%; 16% died, 16% 
were lost to follow-up, 10% failed treatment, and for 8% there was no outcome information.   
With such poor historical outcomes for patients with drug resistant-TB and with the complexity, 
expense and toxicity of treatments for all forms of drug resistant TB, novel drug combinations 
are desperately needed to improve treatment outcomes. Linezolid was identified in a small 
trial as a potentially efficacious drug in patients with XDR-TB when added to a failing regimen[25] 
and this drug has increasingly been added to complex regimens to treat patients with MDR-TB. 
With the current availability of the following three drugs for which there is little, if any, pre-existing 
resistance among strains of MTB (pretomanid [Pa], bedaquiline [B], and linezolid [L]). Mice 
infected with MTB had relapse-free cures with 3 months of treatment with a B-Pa-L regimen. 
While it is not known whether that treatment duration will translate to humans, the ongoing Nix-
TB clinical trial hypothesizes patients with pulmonary XDR-TB or MDR-TB not responsive to or 
intolerant to therapy may have relapse-free cure after as little as 6 months’ treatment with the 
B-Pa-L regimen.[26]  Moxifloxacin has been added to the B-Pa-Z regimen because of the high rate 
of pyrazinamide resistance seen in MDR-TB participants in the NC-002 trial. The proposed trial 
[SimpliciTB] allows the opportunity to assess the efficacy, safety and tolerability of BPaMZ, a new 
6 months regimen that may be administered orally once daily to treat patients with drug resistant 
-TB (excluding participants with XDR-TB). 
Therefore, the overall purpose of the present proposed trial [SimpliciTB] is to assess the 
efficacy, safety and tolerability of the BPaMZ regime after 4 months of treatment in adult 
participants with drug sensitive TB and after 6 months of treatment in participants with multi drug-
resistant TB. The trial will also generate data of the potential for a shorted treatment duration with 
the BPaMZ regime after 4 months compared to a 6-month HRZE/HR (control) treatment regime 
in adult participants with drug sensitive TB. 
This trial will be conducted in accordance with the Protocol, ICH Guidelines for Good Clinical 
Practice (GCP), the ethical principles that have their origin in the Declaration of Helsinki and the 
applicable regulatory requirement(s). 
2.5 
Background of Agents to be Studied in SimpliciTB 
2.5.1 
Bedaquiline (B) 
Bedaquiline (formerly known as TMC-207; SirturoTM package insert[7]) is approved agent for TB 
treatment. As detailed in the Investigator’s Brochure,[8] bedaquiline is a diarylquinoline that offers 
a novel mechanism of anti-tuberculosis action by specifically inhibiting mycobacterial adenosine 
triphosphate synthase.[11] In vitro, bedaquiline potently inhibits both drug-sensitive and 
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drug-resistant MTB isolates,[11, 12] and is also bactericidal against non-replicating MTB[12] In the 
murine model of TB, bedaquiline was as active as the triple combination of isoniazid (H), 
rifampicin (R), and pyrazinamide (Z). Addition of bedaquiline to HRZ results in accelerated 
clearance of MTB.[1, 2]. There appears to be a synergistic interaction with pyrazinamide: 100% of 
mice were culture negative after 8 weeks of treatment with bedaquiline and pyrazinamide 
compared to 0% of mice treated with the standard regimen of rifampicin, isoniazid and 
pyrazinamide.[27].Collectively, these findings in the mouse model have led to the suggestion that 
regimens containing bedaquiline and pyrazinamide could be effective in the treatment of both 
drug sensitive and drug resistant TB and shorten treatment duration in patients. While the 
combination of bedaquiline and pretomanid in the murine model of TB appeared somewhat 
antagonistic relative to bedaquiline alone, it was as active as the triple combination of HRZ[27] and 
in a subsequent trial it was more active in the mouse model than HRZ.[28]. Thus, a novel regimen 
with a bedaquiline plus pretomanid core could be effective in the treatment of MDR-TB/XDR-TB 
by providing two novel drugs for which there is no known pre-existing resistance. 
Bedaquiline is currently registered in many countries to be administered to patients with 
pulmonary tuberculosis by the following scheme: 400mg once daily for Days 1-14 followed by 
200mg three times per week for the remainder of treatment. In this trial bedaquiline will be 
administered as 200 mg daily for 8 weeks, followed by 100 mg daily for the remaining 17 weeks 
or 30 weeks if treatment is extended.  This daily dosing scheme will allow more convenient dosing 
that should ultimately enhance patient adherence and may allow the formulation of fixed dose 
combinations with other drugs.  This daily dosing regimen is supported by safety and efficacy 
demonstrated in the NC-005 trial that administered bedaquiline 200 mg daily over 8 weeks, and 
by pharmacokinetic modelling and simulation of the daily dosing scheme.  This supportive 
information is detailed below. 
2.5.1.1 
Bedaquiline Non-Clinical Studies 
Full details of the preclinical studies are provided in the current bedaquiline Investigator’s 
Brochure,[8] and Sirturo 
TM label.[7] In vitro studies have demonstrated that the range of minimum 
inhibitory concentrations (MICs) for MTB H37Rv, the international reference strain, and 6 fully 
drug-susceptible clinical isolates, was 0.030 to 0.120 μg/ml. The activity of bedaquiline appears 
to be specific for mycobacteria, as the MICs for non- mycobacteria were at least 500-fold higher. 
The activity of the main metabolite of bedaquiline, M2, was determined against MTB.  H37Rv in 
both solid and liquid media and its MIC was found to be 0.1 μg/ml. This MIC shows that M2 is 
active against MTB but 3-6 times less active than the parent compound bedaquiline. Bedaquiline 
demonstrated similar in vitro efficacy against MTB clinical isolates resistant to the known anti-TB 
drugs (isoniazid, rifampicin, pyrazinamide, streptomycin, ethambutol, or fluoroquinolones). As 
expected, from the lack of cross-resistance with currently used anti-tuberculosis agents, 
bedaquiline retained activity against MDR-TB isolates. 
The non-clinical safety evaluation of bedaquiline includes pharmacology, pharmacokinetics, 
toxicology and metabolism studies that were conducted in accordance with current International 
Council for Harmonisation (ICH) guidelines. Repeated dose toxicity studies were performed with 
dosing durations up to 3 months in mice and up to 6 months in rats and in dogs. Recovery was 
studied in rats and dogs. In repeated dose toxicity studies, up to 3 months in mice, up to 6 months 
in the rat and up to 9 months in dogs, bedaquiline was associated with target organ changes in 
the mononuclear phagocytic system (indicative of phospholipidosis), stomach, liver, pancreas, 
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and muscle. Toxicity was often associated with an increased presence of neutrophils in some 
tissues such as the female genital tract and this was preceded by a peripheral neutrophilia. For 
more detailed information please refer to the bedaquiline IB.[8] 
Respiratory parameters in rats were unaffected by treatment. There were no effects suggestive 
of neurological impairment or delayed neurotoxicity in rats. In single dose toxicity studies, there 
were no mortalities following oral doses of up to 200 mg/kg in mice and rats. No mutagenicity or 
clastogenic effects were seen in a series of in vitro and in vivo genotoxicity tests. Bedaquiline 
was evaluated for possible developmental toxicity effects in the rat and the rabbit. No teratogenic 
effects were found. In vitro, bedaquiline slightly to moderately inhibited the delayed rectifier 
potassium current (IKr) in the human ether-à-go-go-related gene (hERG) model. Bedaquiline and 
M2 had no notable effects on IKr at 0.01 μM (0.006 and 0.005 μg/mL, respectively). However, at 
higher concentrations (0.03 to 3 μM), both compounds had a slight to strong 
concentration-dependent effect with a 50% inhibitory concentration (IC50) of 0.37 μM (0.2 μg/mL) 
for bedaquiline and up to 0.45 μM (0.24 μg/mL) for M2. However, this effect did not manifest as a 
prolongation of repolarization in subsequent in vivo studies. 
There were no relevant effects on the isolated right atrium of guinea pigs in vitro, or in the isolated 
Langendorff-perfused rabbit heart. In vivo, positive chronotropic effects were seen in the 
anesthetized guinea pig after IV administration, but not in the conscious dog. In conscious, 
telemetered dogs, oral bedaquiline had no relevant effects on cardio-hemodynamic and ECG 
parameters. 
Prior to the use of pretomanid in combination with bedaquiline in clinical trial NC-001, a preclinical 
cardiovascular safety pharmacology trial was conducted in unrestrained beagle dogs with both 
drugs to explore the potential for additive effects on QT prolongation induced by the combination. 
Results indicate that administration of 100 mg/kg bedaquiline daily, for 7 days, causes a small 
increase in QTc interval by Day 6 in some animals that is not influenced by the addition of 
100 mg/kg pretomanid on Day 7.[28] 
 The effect of pretomanid dosing alone on QT interval 
appeared to be due to discomfort related to the SC route of administration and not related to the 
plasma exposure (please see the pretomanid) Investigators Brochure for more detail. 
2.5.1.2 
Bedaquiline Clinical Studies 
In the clinical studies conducted to date, a total of approximately 645 participants (including 
265 healthy volunteers) have been exposed to bedaquiline in the Phase 1 and 2 clinical trials 
conducted as a part of the development program for the treatment of MDR-TB. An additional 45 
participants received bedaquiline, either as monotherapy (B) or in combination with other agents 
(B-Pa or B-Z) in trial NC-001, and 45 more in trial NC-003 (B-Pa-Z, B-Pa-C, B-Pa-Z-C). Four 
short-term Phase 2a trials enrolled treatment-naïve participants (C202, TMC207-CL001, NC-001 
and NC-003). One long-term, open-label, Phase 2 trial, in MDR-TB participants (bedaquiline- 
TiDP13-C209) and one long-term, Phase 2b trial, consisting of 2 different stages in participants 
infected 
with 
newly 
diagnosed 
sputum 
smear-positive 
pulmonary 
MDR-TB 
(bedaquiline-TiDP13-C208), have been completed. The principal findings of these trials are 
summarized below. Full details of the completed clinical studies are provided in the current 
bedaquiline IB,[8] and Sirturo
TM label.[7]. 
The Phase 1 trials have provided a basic understanding of bedaquiline’s pharmacokinetic 
characteristics, drug- drug interaction potential, and short-term safety/tolerability profile in healthy 
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participants. Bedaquiline was well absorbed with time to reach the maximum plasma 
concentration at approximately 5 hours post-dose. The maximum plasma concentration and AUC 
increased proportionally up to the highest doses studied (up to 700 mg in a single dose-ranging 
trial, 800 mg single dose in trial bedaquiline-TBC1003 and 400 mg q.d. multiple doses). 
Accumulation from Days 1 to 14 was approximately 2-fold expressed as increase in AUC, while 
trough concentrations increased up to 3.5-fold. The pharmacokinetics of bedaquiline were 
comparable between healthy participants and participants with pulmonary TB. The apparently 
close to steady-state concentrations in plasma after 14 days of daily treatment is ascribed to the 
important amount of the drug that is eliminated from the circulation during the ἀ and β phases of 
the plasma concentration-time curve. The average terminal elimination half-life of bedaquiline and 
metabolite M2 noted on extended follow-up after repeat dosing of participants with TB infection is 
about 5.5 months. 
Administration of bedaquiline as the tablet formulation with food, increased the relative 
bioavailability (by 95%) compared to administration without food, and drug-drug interaction trials 
confirmed the role of cytochrome P450 3A4 (CYP3A4) in the metabolism of bedaquiline to M2. A 
recently completed trial (DMID 10-0043) demonstrated that when given in combination, rifampicin, 
and to a lesser degree rifabutin, decreased exposure to bedaquiline presumptively due to 
induction of P450 enzymes. The clinical significance of these findings is unknown, however the 
current trial (NC-005) will not permit the concomitant use of bedaquiline with any rifamycin. 
The efficacy of bedaquiline was initially demonstrated in two monotherapy EBA studies C202 and 
TMC207- CL001. Trial C202 was a 7-day trial of three daily doses of bedaquiline (25, 100 and 
400mg) in treatment-naïve participants with MDR-TB. In this trial, the 400mg dose group 
demonstrated positive EBA and was numerically superior to the 25 and 100mg doses. In trial 
TMC207-CL001, doses of 100, 200, 300 and 400mg daily (following a 2-day loading dose) were 
studied in participants with newly-diagnosed pulmonary TB for 14 days. There were no statistically 
significant differences between the treatment groups, although there was a numerical trend 
suggesting a positive dose-response relationship. Taken together, these studies establish that 
bedaquiline monotherapy has EBA in participants with TB and that higher doses appear to have 
greater efficacy. 
A 14-day EBA regimen trial (TB Alliance Trial NC-001-(B-M-Pa-Z)) evaluated bedaquiline 
administered as monotherapy at 400 mg/d or in combination at that dose with either pretomanid 
administered at 200 mg/d or weight-adjusted pyrazinamide, to participants with pulmonary TB at 
2 clinical sites in South Africa. The results indicate that over 14 days, the mean logCFU decreased 
by 1.3 from baseline in the 15 participants given bedaquiline 400 mg/d after a 2-day loading dose. 
In the cohort of 15 participants given bedaquiline 400 mg/d after a loading dose plus weight-
adjusted daily doses of pyrazinamide (Z), the mean logCFU decreased by 2.0 logs from baseline, 
indicating that Z potentiates the early bactericidal effect of bedaquiline. In the cohort with 15 
participants given bedaquiline 400 mg/d after a loading dose plus 200 mg/d pretomanid, the mean 
logCFU decreased by 1.9. While it appeared that the addition of pretomanid potentiated the anti-
tuberculosis activity of bedaquiline, the mean logCFU decrease of the combination was similar to 
that of two previous EBA studies using pretomanid monotherapy at 200 mg/day. 
The second 14-day EBA combination trial (NC-003) included a number of bedaquiline-containing 
arms: bedaquiline, pyrazinamide and clofazimine (B-Z-C), bedaquiline, pretomanid and 
clofazimine (B-Pa-C), bedaquiline, pretomanid, and pyrazinamide (B-Pa-Z) and bedaquiline, 
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pretomanid, pyrazinamide and clofazimine (B-Pa-Z-C). Among these, B-Pa-Z had the best activity 
which was at least as good as the HRZE control (Daily Log CFU – 0.167 vs 0.151, respectively). 
The long-term efficacy of bedaquiline in participants with MDR-TB has been studied in a placebo-
controlled, randomized Phase 2b trial (C208) and an open-label, uncontrolled, Phase 2b trial 
(C209). In the Phase 2b placebo-controlled trial, C208, the addition of bedaquiline to a 5-drug 
MDR-TB regimen resulted in significantly faster time to culture conversion compared to placebo. 
During the 8-week treatment in Stage 1, 47.6% of participants in the bedaquiline group became 
MGIT culture negative compared to 8.7% of participants in the placebo group. At Week 24 in Stage 
1, after 8 weeks of investigational treatment and 24 weeks of background treatment, 81.0% of 
participants in the bedaquiline group and 65.2% of participants in the placebo group showed 
treatment success, (i.e., completed week 24 and were liquid culture negative, at this time point). 
For C208 Stage 2, in the interim analysis as well as in the primary efficacy analysis, a statistically 
significant difference in time to culture conversion between the treatment groups (p < 0.0001) in 
favour of bedaquiline was shown. In both analyses, an identical number of participants with culture 
conversion at week 24 (i.e., 24-week responders [missing = failure]) was observed: 78.8% in the 
bedaquiline group and 57.6% in the placebo group, which was statistically significantly different 
(p =   0.008) based on a logistic regression model with only treatment as covariate. Microbiological 
response at Week 24 was durable in C208 Stage 2: the percentage of responders 
(missing = failure) at week 72 was 71.2% in the bedaquiline group and 56.1% in the placebo group. 
In the Phase 2b uncontrolled trial, C209, treatment with bedaquiline in combination with an 
individualized MDR- TB treatment regimen was effective against pulmonary MDR-TB both in 
newly diagnosed and in non-newly diagnosed participants. Culture conversion rates after 2 weeks 
of treatment with bedaquiline as part of an individualized anti-tuberculosis regimen were higher in 
participants with lower extent of resistance of the M. Tb strain and in participants with no lung 
cavitation compared to participants with cavitations (in one or both lungs). 
2.5.1.3 
Bedaquiline Clinical Safety 
In the clinical trials conducted to date, a total of approximately 645 participants (including 
265 healthy volunteers) have been exposed to bedaquiline in the Phase 1 and 2 clinical trials 
conducted as a part of the development program for the treatment of MDR-TB. An additional 60 
participants received bedaquiline in a monotherapy EBA trial of 14 days (trial TMC207-CL001) 45 
participants received bedaquiline, either as monotherapy (B) or in combination with other agents 
(B-Pa or B-Z) in trial NC-001 and 45 more in trial NC- 003 (B-Pa-Z, B-Pa-C, B-Pa-Z-C). In these 
trials, bedaquiline has been shown to be an effective treatment for participants with both DS and 
MDR-TB. Specifically, the regimen B-Pa-Z was demonstrated to have efficacy at least as good 
as the HRZE control in trial NC-003. Furthermore, bedaquiline is a novel agent with no pre-existing 
resistance and, based on mouse model data, may result in shortened treatment durations when 
included in novel regimens to treat both DS- and MDR-TB. Based on the combined experience in 
these clinical trials, the following known and potential risks have been identified. 
Adverse Drug Reactions for bedaquiline 
During the Investigational Treatment phase in the controlled trials, the most frequently reported 
Adverse Drug Reactions in the any bedaquiline group (> 10.0% of participants) were nausea, 
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arthralgia, headache, vomiting, and dizziness. Details of Adverse Events, none of which were 
Serious, that were considered Adverse Drug Reactions are in the table below: 
Table 1.  Bedaquiline Adverse Drug Reactions 
 
Mortality 
Overall, there was an imbalance in the number of deaths in the pooled Stage 1 and Stage 2 C208 
trial. In the pooled analysis (Stage 1 and Stage 2), 12 participants in the Any bedaquiline group 
and 5 participants in the Any Placebo group experienced a SAE leading to death; causes of death 
were varied with only death due to TB reported more than once, and none of these participants 
had a treatment-emergent QTcF ≥ 500 ms. The imbalance in deaths is primarily driven by the 
C208 Stage 2 results in which the imbalance was 10 bedaquiline participants (12.7%) compared 
to 3 placebo participants (3.7%). Based on the pooled results (Stage 1 and 2) while being followed 
in the placebo- controlled trial, 7 participants in the Any bedaquiline group and 1 Participant in the 
Any Placebo group died. Of these deaths, 1 occurred during the Investigational Treatment phase 
with bedaquiline/placebo, the remaining deaths occurred afterwards. In the Any bedaquiline 
group, causes of death were myocardial infarction, TB (2 cases), alcohol poisoning, hepatitis and 
hepatic cirrhosis (1 case), septic shock and peritonitis (1 case), and cerebrovascular accident. In 
the Any Placebo group, cause of death was haemoptysis. The Investigator considered the SAEs 
leading to death not related to bedaquiline intake in the Any bedaquiline group and doubtfully 
related to investigational medication in the Any Placebo group. The analysis of long-term follow-up 
for survival outcomes in participants who prematurely discontinued in trial C208 (Stage 1 and 2), 
based on data collection every 24 weeks (6 months) after withdrawal (up to LSLV in the rollover 
arm [16 Oct 2012] in Stage 2), included 9 deaths. One Participant in the bedaquiline group 
(pulmonary TB) and 2 participants in the Placebo group (TB-related illness and pulmonary TB) in 
Stage 1 died, and 4 participants in the bedaquiline group (3 participants with TB-related illness, 1 
Participant motor vehicle accident) and 2 participants in the Placebo group (both TB-related 
illness) died after they discontinued Stage 2 of the trial. None of these participants had a 
treatment-emergent QTcF ≥ 500 ms. The imbalance in deaths is unexplained.  In addition, no 
discernible pattern between death and sputum culture conversion, relapse, sensitivity to other 
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drugs used to treat TB, human immunodeficiency virus (HIV) status, or severity of disease was 
observed. 
In the uncontrolled Phase 2b trial, C209, the most frequently reported AEs during the 
investigational phase were hyperuricemia, arthralgia, nausea, vomiting, headache, diarrhoea, 
blood uric acid increased, hypokalaemia, pruritus, injection site pain, insomnia, and tinnitus. From 
start of the trial up to the final analysis, 12 participants died during the C209 trial due to SAEs that 
included TB (5 cases), congestive cardiac failure, renal impairment, lung infection, cardiac arrest 
(underlying cause pneumonia), haemoptysis, hypertension, and pyopneumothorax/respiratory 
failure. These SAEs leading to death were considered not related to bedaquiline by the 
Investigator, except for renal impairment that was judged doubtfully related to bedaquiline. 
The analysis of long-term follow-up for survival outcomes for participants who prematurely 
discontinued in trial C209, based on data collection every 24 weeks (6 months) after withdrawal, 
included 4 deaths (all described as TB-related). In total, since the start of the C209 trial, 16 
participants (6.9%) have died (12 participants during the trial and 4 participants during the survival 
follow-up phase after premature discontinuation). None of the fatal SAEs were considered related 
to bedaquiline by the Investigator and none of these participants has a treatment- emergent 
adverse event. 
Cardiovascular safety 
During clinical trials with bedaquiline a prolongation of QTc interval was observed. The US 
Product Label for bedaquiline[7] notes that treatment initiation is not recommended in patients with: 
• 
Heart failure; 
• 
QTcF interval > 500 ms (confirmed by repeat electrocardiogram); 
• 
A personal or family history of congenital QT prolongation; 
• 
Concomitant administration of fluoroquinolone antibiotics that have a greater potential 
for significant QT prolongation (i.e., gatifloxacin, moxifloxacin and sparfloxacin). 
• 
Hypokalaemia 
The US Product Label recommends that bedaquiline treatment must be discontinued if the patient 
develops clinically significant ventricular arrhythmia. An additive or synergistic effect on QT 
prolongation of bedaquiline when co-administered with other medicinal products that prolong the 
QT interval cannot be excluded. Caution is recommended when using bedaquiline concomitantly 
with medicinal products with a known risk of QT prolongation. If co-administration of such 
medicinal products with bedaquiline is necessary, clinical monitoring including frequent ECG 
assessment is recommended. 
Hepatic safety 
The US product label notes increases in transaminases were seen in clinical trials during 
administration of bedaquiline with the background regimen. participants should be monitored 
during treatment. Other hepatotoxic medicinal products and alcohol should be avoided while 
taking bedaquiline, especially in those participants with diminished hepatic reserve.[7]  
Additional safety information from a recently completed trial 
In a recently completed phase I trial not yet included in the bedaquiline Investigators Brochure 
that evaluated drug-drug interactions between bedaquiline and either rifampin or rifabutin, 7 
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participants experienced SAEs. Of those participants, 5 experienced SAEs of lymphocytopenia 
(all received rifabutin), which did not appear to be related to the AUC or Cmax of TMC207 or 
rifabutin. One participant experienced an SAE of elevated Creatine Kinase (rifampicin arm) and 
one experienced a grade 4 Total Bilirubin SAE (rifampicin arm). Lymphopenia was previously 
noted to be an infrequent toxicity associated with rifabutin, but not previously seen with 
bedaquiline. 
The bedaquiline/rifabutin regimen demonstrated significant reversible lymphopenia, which did not 
appear to be related to the AUC or Cmax of TMC-207 or rifabutin. 
2.5.2 
Pretomanid (P) 
As detailed in the Investigator’s Brochure,[15] pretomanid is a new chemical entity and a member 
of a class of compounds known as nitroimidazo-oxazines, which possess significant 
anti-tuberculosis activity and a unique mechanism of action.[16] Pretomanid demonstrated in vitro 
activity against both DS- and MDR-TB,[17] and in vivo activity in a mouse model of tuberculosis.[16, 
17]  
2.5.2.1 
Pharmacology 
Key in Vitro Evaluation of Pretomanid Bactericidal Activity 
Non-clinical in vitro trials demonstrated that pretomanid was active against actively growing 
drug- sensitive and drug-resistant MTB strains as well as against non-replicating MTB. The 
minimum inhibitory concentration (MIC) of pretomanid against a variety of drug-sensitive MTB 
isolates in vitro was shown to be like the MIC of isoniazid (MIC of pretomanid, ≤0.015 to 0.25 
µg/mL; MIC of isoniazid, 0.03 to 0.06 µg/mL). Pretomanid was efficacious in vitro against drug-
resistant clinical isolates of MTB with MIC values ranging from 0.03 to 0.53 µg/mL. The 
Investigator’s Brochure contains further information on in vitro bactericidal activity.[16] 
Although not thoroughly elucidated at this time, pretomanid has a novel mechanism of action that 
appears to involve inhibition of the synthesis of cell wall lipids under aerobic conditions and 
generation of reactive nitrogen species under anaerobic conditions. Reduction of pretomanid by 
a deazaflavin (F420)-dependent nitroreductase has been shown to be associated with generation 
of reactive nitrogen species, including nitric oxide (NO),[29] although the exact target(s) of the 
reactive nitrogen species are not known. Transcriptional profiling trials also suggest that 
pretomanid affects both cell wall biosynthesis and the respiratory complex of MTB.[30, 31] 
2.5.2.2 
Key Non-Clinical Trials of Pretomanid 
The activity of pretomanid as a single agent or as part of a multi-drug combination regimen has 
been examined in a number of mouse trials.[13, 14, 18, 32, 33] In a mouse model of established TB, the 
activity of various doses of pretomanid (given once daily, 5 days/week, for 1 month), initiated 22 
days after inhalation infection with H37Rv MTB is shown in Figure 2. In this model, the minimum 
effective dose (MED) for pretomanid, defined as the lowest dose able to prevent the development 
of gross lung lesions and splenomegaly, was 12.5 mg/kg/day, while the minimum bactericidal 
dose (MBD), defined as the lowest dose able to reduce lung colony forming units (CFU) by 99%, 
was 100 mg/kg/day. Moreover, in these experiments, the activity of pretomanid at 100 mg/kg was 
comparable to the activity of isoniazid at 25 mg/kg. 
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Figure 2.  Log10 CFU Counts in Lungs  
After One Month of Daily Treatment with the Indicated Dose (in mg/kg) of Pretomanid 
 
Arrows denote the minimum effective dose (MED) and minimum bactericidal dose (MBD). 
2.5.2.3 
Non-Clinical Toxicology and Safety 
Pretomanid has been evaluated in an ICH recommended battery of safety pharmacology trials, in 
repeat-dose toxicity trials in rats (2 to 26 weeks) and cynomolgus monkeys (7 days to 9 months), 
in 8 genotoxicity trials, and in fertility and teratology trials in rats and rabbits.  
In the repeat-dose toxicity trials, the lowest no-observed adverse effect level (NOAELs) was 
10 mg/kg/day in a 26-week trial in rats, 50 mg/kg/day in a 13-week trial in monkeys and 
<25 mg/kg/day (based on findings of thickening of the gastrointestinal tract at all doses) in a 
9-month trial in monkeys. The major findings in safety and toxicity trials are listed below in Table 
2 and are detailed in the Investigator’s Brochure.[15] 
Table 2.  Key findings of Pretomanid in Safety and Toxicity Trials 
Nervous system-related effects.  
Rats given single oral pretomanid doses had decreased body tone, touch responses and 
decreased grooming behaviour at ≥150 mg/kg, which resolved within 24 hours. Rats given 
repeated daily doses of pretomanid had convulsions, ataxia, hypoactivity, recumbency, 
hyperactivity and sensitivity to touch, and squinting at ≥100 mg/kg/day, and early deaths 
occurred at doses ≥500 mg/kg/day. Monkeys given repeated daily doses of pretomanid had 
hypoactivity, ataxia, tremors, and convulsions at ≥450/300 mg/kg/day. These effects were 
reversible when dosing stopped and were absent at ≤30 mg/kg/day in rats and ≤150 mg/kg/day 
in monkeys. 
 
Testicular toxicity 
Although rat and rabbit embryonic development trials indicate no effects of pretomanid on foetal 
development, testicular atrophy in rats was observed in 3-month and 6-month repeat-dose 
toxicology trials and a Segment I fertility trial. In this fertility trial, testicular atrophy was 
associated with infertility; an approximate 30% reduction in fertility was also observed at a lower 
dose not associated with testicular atrophy. A detailed trial in sexually mature male monkeys 
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demonstrated no effects on testicular histology or function in adult cynomolgus monkeys after 
3 months’ dosing.  
 
Cataracts 
Cataracts developed in rats with prolonged daily administration of pretomanid at doses 
≥100 mg/kg/day. In one 13-week trial in monkeys, cataracts did develop at 450/300 mg/kg/day, 
but only by the end of a 13-week recovery period. In a second 13-week trial in monkeys that 
included extensive ophthalmic examinations, cataracts did not develop at the high-dose level 
of 300 mg/kg/day. 
 
hERG inhibition and QT prolongation 
Altered ventricular repolarisation due to inhibition of hERG-mediated potassium current and 
manifested on the ECG as a prolonged QT interval corrected for heart rate (QTc). Pretomanid 
inhibited hERG current with IC50 values of approximately 6.2 µg/mL. Following a single 
pretomanid dose of 450 mg/kg in monkeys, QTc interval prolongation ranged from 21 to 
36 msec using Fridericia’s formula (QTcF) to correct for heart rate. Co-administration of 
pretomanid with moxifloxacin in the monkey or with bedaquiline in the dog did not result in any 
greater effect on the QT interval than with either agent alone. After repeated daily doses, the 
QTc interval in the monkey was prolonged at pretomanid doses of ≥150 mg/kg/day. 
 
 
2.5.2.4 
Clinical Background Information 
Pretomanid has been evaluated in 8 single- and multi-dose Phase 1 trials with healthy adult male 
and female participants, with 163 participants receiving single oral doses ranging from 50 to 
1500 mg and multiple oral doses ranging from 50 to 1000 mg/day given for up to 7 days. These 
Phase 1 trials have evaluated the safety, tolerability, and pharmacokinetics (PK) of pretomanid. 
Two additional Phase 1 trials Sponsored by the NIH included a Thorough QT trial and a trial of 
drug interactions among pretomanid, efavirenz and ritonavir/lopinavir.  Further details of the trials 
are in the Investigator’s Brochure.[15] 
2.5.2.5 
Pharmacokinetics 
Several Phase 1 trials have evaluated the safety, tolerability, and pharmacokinetics (PK) of 
pretomanid and have demonstrated that pretomanid has a half-life of approximately 18 hours, 
which supports daily dosing, and an effect of food with the 200-mg dose that increases total 
exposure by 88%. Interaction trials with midazolam, efavirenz and ritonavir/lopinavir demonstrate 
effects that are not likely to be clinically significant. 
Drug interaction with midazolam: Trial CL-006 was an open-label, fixed-sequence drug-drug 
interaction trial to evaluate the effects of multiple-dose administration of pretomanid on the PK of 
midazolam, a sensitive probe substrate and representative compound for drugs metabolised by 
CYP3A enzymes. Dosing with pretomanid at 400 mg/day for 14 days (to steady state) had minimal 
effect on the PK of midazolam and its 1-hydroxy metabolite as assessed by measurement of the 
Day 17: Day 1 ratios of maximum concentration (Cmax, AUC0-t, and AUC0-inf. The Cmax and AUC 
values for midazolam after co-administration with pretomanid were approximately 85% of those 
observed after treatment with midazolam alone. Furthermore, midazolam and 1-hydroxy 
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midazolam time to maximum concentration (Tmax) and half-life (t1/2) values were not different in 
the presence or absence of pretomanid. Therefore, 14 days’ dosing with 400 mg/day pretomanid 
does not appear to significantly inhibit CYP3A4 in humans. 
Drug interaction with efavirenz, ritonavir/lopinavir, and rifampicin: The US NIH Sponsored this 
drug interaction trial with rifampicin, a known hepatic enzyme inducer, and with the antiretroviral 
drugs efavirenz and ritonavir/lopinavir (LPV/r) in healthy participants. Participants in Arm 1 were 
randomised to Sequence 1 (pretomanid 200 mg once daily for 7 days, two-week washout period, 
efavirenz (EFV) 600 mg once daily for 14 days, then both drugs for 7 days) or Sequence 2 
(Treatment 1B: EFV, then EFV + pretomanid, washout, and pretomanid). Results indicate that 
comparing pretomanid given with EFV versus pretomanid alone in 16 participants, the geometric 
mean ratio (GMR) for Cmax was 0.71, the GMR for AUC0-24h was 0.65, and the GMR for Cmin was 
0.54. Concentrations of EFV when given with pretomanid versus given alone were similar. 
Participants in Arm 2 were randomised to Sequence 1 (pretomanid 200 mg once daily for 7 days, 
then a 2-week washout period, then LPV/r 400/100 mg twice daily for 14 days, then LPV/r + 
pretomanid together for 7 days) or Sequence 2 (LPV/r, then LPV/r + pretomanid, washout, then 
pretomanid alone). Comparing pretomanid + LPV/r versus pretomanid- alone from 16 PK-
evaluable participants, the GMR for Cmax was 0.87, for AUC0-24h was 0.83, and for Cmin was 0.78. 
In Arm 3, participants received pretomanid for 7 days, then rifampicin 600 mg for 7 days, then 
pretomanid + rifampicin together for 7 days. Comparing pretomanid + rifampicin versus 
pretomanid alone from 16 PK-evaluable participants, the GMR for Cmax, AUC0-24h, and Cmin were 
0.47, 0.34, and 0.15, respectively.  
In conclusion, compared to pretomanid alone, plasma pretomanid values (based on geometric 
mean ratios) for Cmax, AUC0-24h, and Cmin were reduced 28%, 35%, and 46% with efavirenz; 13%, 
17%, and 21% with LPV/r; and 53%, 66%, and 85% with rifampicin, respectively. 
2.5.2.6 
Pretomanid Clinical Efficacy 
The first two Phase 2 trials to evaluate the early bactericidal effect (EBA) of pretomanid oral 
monotherapy (50 to 1200 mg/day for 14 days) examined the dose-response for pretomanid in 
participants with newly diagnosed pulmonary TB infection. The first trial (CL-007) demonstrated 
good EBA, but all doses in this trial (200 to 1200 mg/day) had the same activity. The second trial 
(CL-010) evaluated a lower dose range (50 to 200 mg/day) and the maximum effect on EBA was 
seen at a dose of 100 mg/day over 14 days (Figure 3).[34] 
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Figure 3.  Mean log Colony Forming Unit Values over Time Trial CL-010 
 
CFU = colony-forming unit; PRETOMANID = pretomanid 
* Day 0 = (Day -2 + Day -1)/2 = baseline measurement 
Pretomanid has been evaluated in patients with TB as monotherapy for a maximum duration of 
14 days, the longest considered acceptable for a TB patient to be treated in a clinical trial with a 
single drug.  Trials of pretomanid for both 14 days and for up to 6 months, in combination with 
either bedaquiline and/or linezolid, are described below.  
2.5.2.7 
Pretomanid Clinical Safety 
The pretomanid Investigator’s Brochure[15] provides detailed safety information. 
Across the 16 clinical trials with pretomanid completed to date, a total of 649 participants have 
been exposed to pretomanid, including 289 healthy participants across the 10 Phase 1 trials and 
360 participants with newly diagnosed smear positive pulmonary TB across 5 Phase 2 
trials.  Among the 289 healthy participants, 174 received exposure to a single dose of pretomanid 
ranging from 50 to 1500 mg and 115 received exposures to repeated daily doses of pretomanid 
(50 to 1000 mg) for up to 14 days. The 360 participants with newly diagnosed smear positive 
pulmonary TB were exposed to pretomanid either as a single agent at daily doses of 50 to 
1200 mg for 14 days or in combination with other anti-TB agents (bedaquiline, moxifloxacin, 
pyrazinamide, linezolid and/or clofazimine) at a dose of 100 mg or 200 mg for up to 26 weeks.  The 
overall safety profile determined from the clinical trials completed to date indicates pretomanid is 
well tolerated in healthy adults and in TB patients when administered alone and in combination 
with moxifloxacin, pyrazinamide, bedaquiline and clofazimine.   
4
4.5
5
5.5
6
logCFU
0
2
4
6
8
10
12
14
Day
 PA-824 50mg
 PA-824 100mg
 PA-824 150mg
 PA-824 200mg
 Rifafour e275 
Bi-linear regression of logCFU vs day over treatment
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Pretomanid is an investigational drug and there is limited experience in humans; the safety 
database is being developed and Investigators should be vigilant to any adverse events noted in 
clinical trials.  Across these trials, the most common side effects or AEs associated with 
pretomanid exposure include: 
• 
Headache 
• 
Stomach discomfort (nausea, vomiting, flatulence, and/or diarrhoea) 
• 
Skin and subcutaneous tissue disorders 
The only adverse drug reaction identified in clinical trials completed to date as likely caused by 
pretomanid is blood creatinine increased.  A trial of the effects of repeat doses of pretomanid in 
healthy volunteers determined that the drug does not adversely affect glomerular filtration rate, 
effective renal plasma flow or filtration fraction and the elevations in serum creatinine reverse.  
The following parameters will be followed with particular care in the Phase 3 development 
program: 
• 
Hepatic Safety – Specific guidelines are included in the protocol to assure close 
surveillance and careful management of participants who have elevations in 
aminotransferases and/or bilirubin. Serious liver injury, including death in 3 participants 
taking a combination of pretomanid, pyrazinamide and moxifloxacin, has occurred during 
clinical trials and the risk of liver injury may be higher for participants taking a combination 
of pretomanid and pyrazinamide than it is for the standard HRZE treatment. Therefore, 
close monitoring of liver function is required for participants who are administered 
pretomanid, especially when combined with pyrazinamide.  Administration of the regimen 
of PaMZ has been associated with death in 3 participants associated with hepatic injury. 
Furthermore, the HRZE control regimen, and both pyrazinamide and moxifloxacin, has 
been associated with drug induced liver injury and in rare cases hepatic necrosis.  
Consequently, hepatic safety will be under close surveillance in all clinical trials. 
• 
Ophthalmologic Evaluations – while the detailed examinations in Phase 2 have not raised 
concern for humans, ophthalmologic examinations, with slit lamp exam and grading of 
lens opacities, will continue in all human trials that involve exposure to pretomanid longer 
than 14 days.  These examinations will be conducted at baseline, near the end of the 
dosing period and 3 months after the end of trial drug exposure.  These examinations are 
to follow up on the finding of cataracts in rats exposed to pretomanid in clinical trials. 
• 
Cardiovascular Safety – All participants will have ECGs taken at baseline and at multiple 
time points during the trial.  Although the Thorough QT Trial in healthy participants found 
that pretomanid did not increase corrected QT intervals in a clinically meaningful way and 
did not add to the known effect of moxifloxacin, the ECGs will be carefully monitored during 
Phase 3.  All ECGs will be interpreted, and conduction intervals will be confirmed by a 
central cardiology service. 
• 
Central Nervous System Safety –While pretomanid alone or combined in various regimens 
has been well tolerated overall, one participant in Trial NC-002 of the Pa-M-Z regimen had 
a seizure without any prior seizure history, and some animals in toxicology trials have had 
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seizures at high drug exposures.  Consequently, close surveillance will be made of 
participants in the Phase 3 trial for seizures or any central nervous system adverse events 
of potential concern. 
Of note, preclinical toxicology trials found that rats, but not primates, had testicular toxicity when 
treated with pretomanid. Clinical evaluations of potential testicular toxicity in Phase 2 trials have 
evaluated over 300 participants exposed to pretomanid over 2-6 months with evaluations of 
testosterone, LH, or Inhibin B (2 trials) or FSH values (3 trials) at baseline and after daily dosing 
of regimens containing pretomanid in various combinations with moxifloxacin, pyrazinamide and 
bedaquiline.  A review of data from the 3 trials by an independent reproductive endocrine expert 
concluded that, based on the hormone evaluations to date, there is no evidence that pretomanid 
is a testicular toxicant in men at the doses and exposure times evaluated. 
2.5.3 
Moxifloxacin (M) 
Moxifloxacin (M)[19]  is an 8-methoxyquinolone whose oral formulation (which will be used in 
this trial) has enhanced activity against Gram-positive pathogens, and anaerobes while retaining 
useful activity against Gram-negative organisms. Moxifloxacin is not metabolized by nor induces 
the cytochrome P450 system, thus the risk of clinically relevant drug interactions is reduced. It 
has a positive safety profile within the fluoroquinolone class at the approved daily dose of 400 mg. 
Moxifloxacin while not approved for TB by most regulatory authorities, it is regularly used in 
second line MDR-TB treatment. The WHO TB Treatment Guidelines place moxifloxacin in the 
category of Group 3 drugs and notes that “all patients [with MDR-TB] should receive a Group 3 
medication if the strain of MTB is susceptible or if the agent is thought to have efficacy. One of 
the higher generation fluoroquinolones, such as levofloxacin or moxifloxacin, is the fluoroquinolo-
ne of choice.[5]” It is currently in late stage clinical development for first-line TB treatment in 
combination with other TB drugs, including pyrazinamide in two different four-month long 
regimens.  
2.5.3.1 
Moxifloxacin Clinical Trials 
Moxifloxacin is commonly used as second line therapy for TB (e.g. MDR- TB) and has also been 
evaluated in several clinical studies of participants with TB, including four 8-week treatment period 
Phase 2b studies (see Table 3 below).  
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Table 3.  Summary of Phase 2b trials in which moxifloxacin were administered as 
part of a four-drug regimen during the intensive phase of treatment (total 
treatment duration: 2 months) 
Trial 
Design 
Objective 
Participants 
(N) 
Status 
Trial 27 
Randomized, 
double-blind, 
controlled 
To compare the sputum culture-
conversion rate at the end of the 4-drug 
(intensive) phase of therapy using the 
standard 4-drug regimen HRZE with a 
standard regimen with M replacing E.  
336 
Completed 
OFLOTUB 
Trial 
Randomized, 
Open label, 
Controlled 
To compare the bactericidal activities of 
regimens where gatifloxacin, M, and 
ofloxacin were substituted for E in the 2-
month initial phase of standard TB 
treatment with HRZE.  
 
217 
Completed 
Johns 
Hopkins 
(FDA 
orphan 
drug) Trial 
Randomized, 
double-blind, 
Controlled 
To compare the sputum culture 
conversion rate at the end of the 4-drug 
(intensive) phase of therapy using a 
standard 4-drug regimen (HRZE) with a 
regimen with M replacing E (HRZM). 
170 
Completed 
Trial 28 
Randomized, 
double-blind, 
Controlled 
To compare the culture-conversion rate 
at the end of the 4-drug (intensive) 
phase of therapy using a standard 4-
drug regimen (HRZE 5 days per week) 
with a regimen with M replacing H 
(MRZE 5 days per week). 
 
433 
Completed 
 
2.5.3.2 
Moxifloxacin Clinical Safety 
In Trial 27,[35] the moxifloxacin-containing TB regimens (HRZM) were shown to be safe and well 
tolerated. There was no difference in SAEs between the HRZM and HRZE treatment arms, and 
most SAEs were hospitalizations thought to be unrelated to the trial treatment.  Participants 
treated with the moxifloxacin-containing regimen were more likely to report nausea (22% vs. 9%, 
p = 0.002), but this was generally mild and did not lead to treatment discontinuation as similar 
proportions of participants in both groups completed trial drug treatment (88% HRZM-treated vs. 
89% HRZE-treated).  The one death during the first 2 months of treatment was thought to be 
caused by a pulmonary embolism unrelated to tuberculosis therapy.   
In the OFLOTUB trial,[36] AEs and SAEs occurred with equal frequency in the four treatment arms.  
The most frequent AEs were raised amylase (in 41% of participants due to HIV infection), raised 
transaminase (10%), arthralgia (9%), anaemia (7%), hypokalaemia (6%) and vomiting (5%).  No 
Participant was withdrawn from the trial due to an adverse event.  There were 4 deaths in the 
trial: 2 in the control group, 1 each in the moxifloxacin and ofloxacin arms.  Importantly, 
participants in this trial who received moxifloxacin and pyrazinamide in addition to isoniazid and 
rifampin had more rapid sputum clearance than participants on the four standard first line drugs 
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(isoniazid, rifampin, pyrazinamide and ethambutol). This difference was evident 14 days after 
initiation of treatment. 
In the JHU trial,[37] AEs did not differ by treatment group. There were 16 SAEs (8 in each group) 
in 12 participants. Only 1 event was judged related to trial drug (grade 3 cutaneous reaction in 
the ethambutol group). Eight participants died during the trial, including 1 in each group still 
receiving trial phase treatment. No death was attributed to trial treatment. Only 5 participants 
discontinued treatment because of toxic effects; 2 participants in the moxifloxacin group stopped 
because of grade 2 nausea and vomiting and 1 because of grade 2 paraesthesia’s and ataxia. 
Two participants in the E group stopped because of grade 2 rash and pruritus and 1 because of 
grade 3 peripheral neuropathy.  There was no change in the QTc interval on serial 
electrocardiograms taken during the trial. 
In Trial 28,[38] the proportions of participants with SAEs during the intensive phase treatment were 
similar between arms (isoniazid 3.9% vs. moxifloxacin 4.2%; P = 0.88). Three SAEs attributed to 
trial treatment during the first 2 months occurred among the moxifloxacin group and two in the 
isoniazid group.  Seven participants died during the trial including 3 participants receiving the 
moxifloxacin treatment regimen and 4 participants receiving the isoniazid treatment regimen. The 
3 moxifloxacin participants died during the intensive phase of TB treatment. Two participants died 
from advanced pulmonary TB judged not related to trial treatment and 1 Participant (who 
developed diabetic ketoacidosis considered possibly related to trial treatment) died from possible 
acute pulmonary embolus unrelated to trial treatment. The 4 isoniazid deaths occurred during the 
continuation phase, and all 4 were considered unrelated to trial treatment.  Nausea was more 
common among participants in the moxifloxacin arm than in the isoniazid arm (19.6% vs. 11.7%, 
respectively; P = 0.03) although similar proportions reported vomiting.  However, the proportions 
of participants with hepatitis, defined as serum AST 3 times or greater than the upper limit of 
normal, were similar between treatment arms during intensive phase (isoniazid 3.4% vs. 
moxifloxacin 3.3%; P = 0.93).  Moxifloxacin has also been evaluated in combination with 
pretomanid for two weeks in participants with TB (Trial NC-001) and for 8 weeks in NC-002 (as 
reviewed above). 
For additional information on moxifloxacin, refer to the IB[39] and the manufacturer’s package 
insert.[19] 
2.5.4 
Pyrazinamide (Z) 
Pyrazinamide (Z) is a standard drug used as part of the four drug HRZE regimen used for the first 
two months of intensive therapy for drug-sensitive TB as recommended by the WHO and many 
National TB programs.  Please see the Package Insert[20] for more detail.  Z is active against TB 
in vitro and it potentiates the bactericidal and sterilizing activity of both bedaquiline and  
pretomanid in mouse models of TB infection.[8, 15]  Pyrazinamide enhanced the bactericidal activity 
of both bedaquiline and  pretomanid in Trial NC-001-(J-M-Pa-Z) as noted by decreases over 14 
days in the CFU counts in sputum among participants. 
The pyrazinamide product label notes that pyrazinamide is contraindicated in persons with severe 
hepatic damage, who have shown hypersensitivity to it, and with acute gout.  The most serious 
side effect is hepatotoxicity. Its frequency appears to be dose-related and thus liver function 
should be assessed before and regularly during treatment with pyrazinamide.  Hyperuricemia 
commonly occurs and is occasionally accompanied by arthralgia and may lead to attacks of gout. 
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Photosensitivity and skin rash have been reported less frequently. Other side effects that have 
been reported are anorexia, nausea and vomiting, malaise, fever, sideroblastic anaemia and 
dysuria.  
Pyrazinamide may decrease the efficacy of gout therapy (e.g. allopurinol, colchicine, probenecid 
or sulphinpyrazone) and dosage adjustments of these medications may be necessary.  For 
additional information on pyrazinamide, refer to the manufacturer’s package insert. [20] 
2.6 
Overall Benefit/Risk Assessment 
Some participants with pulmonary TB in this trial will be given a regimen of BPaMZ. These drugs 
individually and in combination are known to have anti-tuberculosis activity and is not expected 
to have an adverse impact on the ultimate cure of TB in these participants. Based on NC-005 and 
other regimens using each of the regimen drugs in different combinations there is good evidence 
that this may be a highly effective therapy for both DS-TB and DR-TB.  
For DS-TB the potential for a shorter regimen than 6 months is expected to be successful based 
on preclinical and clinical information as listed before.  Participants in this trial will have their TB 
infection carefully characterized, with drug sensitivity profiles established, and they will receive 
treatment with trial drugs that have demonstrated activity against MTB.   
Participants will receive individualized medical attention; this will allow a continuous monitoring of 
the health conditions of each participant, any of whom can be withdrawn at any stage of the trial 
and removed from trial treatment should his/her condition suggest to the Investigator that this 
would be in his/her best interest.  Multiple blood samples will be taken for safety laboratory 
studies, and ECGs will be taken at multiple time points.  
One concern, the combination of two agents with known QT-prolonging effects (bedaquiline and 
moxifloxacin), has been addressed specifically by carefully identifying and excluding participants 
with risk factors that might predispose them to cardiac arrhythmias, screening all participants for 
evidence of existing cardiac disease and monitoring all participants with ECGs throughout the 
trial.  
The trial drugs in the proposed regimens to be tested in this trial have all demonstrated safety 
and efficacy in the treatment of pulmonary tuberculosis in non-clinical and clinical studies. 
Specifically, the regimen B-Pa-Z was generally well-tolerated and demonstrated bactericidal 
activity in a 14-day EBA trial. The potential risks associated with the trial drugs and regimens has 
been identified as outlined below and will be monitored carefully throughout the conduct of the 
trial. 
The BPaMZ regimen is a novel regimen treatment expected to be effective, safe and well-
tolerated and might even shorten the current treatment duration for patients with TB. Based on 
data from previous trial evaluations of key monitoring and safety information as outlined before 
suggests a favourable benefit-to-risk ratio trials.  
Key Monitoring and Safety Information Regarding Regimen Agents 
2.6.1 
Bedaquiline (B) 
2.6.1.1 
Adverse Drug Reactions for bedaquiline  
Participants in the Any bedaquiline group compared to the Any Placebo group (difference > 5.0%) 
had headache (23.5% versus 11.4%, respectively), nausea (35.3% versus 25.7%, respectively), 
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arthralgia (29.4% versus 20.0%, respectively), and transaminases increased (6.9% versus 1.0%, 
respectively).and diarrhoea (11.4% versus 5.9%, respectively). 
2.6.1.2 
Cardiovascular safety 
During clinical studies with bedaquiline a prolongation of QTc interval was observed. An ECG 
should be obtained prior to and after initiation of therapy with bedaquiline to monitor the QTc 
interval. 
Bedaquiline treatment initiation is not recommended in patients with: 
• 
Heart failure 
• 
QTcF interval > 450 ms (confirmed by repeat electrocardiogram) 
• 
A personal or family history of congenital QT prolongation 
• 
Concomitant administration of fluoroquinolone antibiotics that have a greater potential for 
significant QT prolongation (i.e., gatifloxacin, moxifloxacin and sparfloxacin) 
• 
Hypokalemia 
Bedaquiline treatment must be discontinued if the patient develops clinically significant ventricular 
arrhythmia. An additive or synergistic effect on QT prolongation of bedaquiline when co-
administered with other medicinal products that prolong the QT interval cannot be excluded. 
Caution is recommended when using bedaquiline concomitantly with medicinal products with a 
known risk of QT prolongation. If co-administration of such medicinal products with bedaquiline is 
necessary, clinical monitoring including frequent ECG assessment is recommended. 
In the DR-TB treatment arm of the present trial, moxifloxacin will be co-administered with 
bedaquiline. This is to prevent the development of resistance to the other drugs in the regimen in 
case the participant’s strain of MTB is resistant to pyrazinamide. ECG assessments will be 
performed on all participants at screening, baseline, and at treatment visits specified in the flow 
chart.   
2.6.1.3 
Hepatic safety 
Increases in transaminases were seen in clinical studies during administration of bedaquiline with 
the background regimen. Participants should be monitored during treatment. 
Other hepatotoxic medicinal products and alcohol should be avoided while taking bedaquiline, 
especially in participants with diminished hepatic reserve. 
2.6.2 
Pretomanid (P) 
The most common side effects or AEs associated with pretomanid exposure include: 
• 
Headache 
• 
Benign, isolated and reversible elevations of serum creatinine 
• 
Stomach discomfort (nausea, vomiting, flatulence, and/or diarrhoea) 
• 
Skin and subcutaneous tissue disorders 
2.6.2.1 
Hepatic Safety 
Hepatic enzyme increases have been seen in participants treated with pretomanid in 
combinations with various other medications during the clinical development program. It is difficult 
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to assign specific causality to any one drug within a regimen; nonetheless, the NC-008 trial will 
include specific monitoring of hepatic enzymes. 
For additional information refer to  pretomanid IB.[15] 
2.6.3 
Moxifloxacin (M) 
In the usual daily doses of 400 mg/day, moxifloxacin is well tolerated.  As stated in the Package 
Insert[19]  the most frequent individual drug related AEs observed in clinical trials with 400 mg oral 
moxifloxacin therapy were nausea (7.5%) and diarrhoea (5.8%).  Fluoroquinolones, including 
moxifloxacin, are associated with an increased risk of tendinitis and tendon rupture in all ages.   
A known but rare side effect of fluoroquinolones, including moxifloxacin is exacerbation of 
myasthenia gravis. In addition, moxifloxacin has been shown to prolong the QT interval of the 
electrocardiogram in some participants.  It should be used with caution in participants being 
treated concomitantly with other drugs where an additive effect on the QT interval cannot be 
excluded.  
Serious and sometimes fatal hypersensitivity reactions, including anaphylactic reactions, as well 
as peripheral neuropathy may occur after the first or subsequent doses of moxifloxacin. For 
additional information, refer to the moxifloxacin package insert.[19] 
2.6.4 
Pyrazinamide (Z) 
The dose of pyrazinamide that will be used in this trial is an approved dosage for the treatment of 
TB. The most serious side-effect of pyrazinamide is hepatotoxicity and its frequency appears to 
be dose-related. Hyperuricemia commonly occurs, occasionally accompanied by arthralgia and 
may lead to attacks of gout.  Photosensitivity and skin rash have been reported less frequently.  
Other side-effects that have been reported are anorexia, nausea and vomiting, malaise, fever, 
sideroblastic anaemia and dysuria.  Pyrazinamide may decrease the efficacy of gout therapy (e.g. 
allopurinol, colchicine, probenecid or sulphinpyrazone) and dosage adjustments of these 
medications may be necessary.  For additional information on pyrazinamide, refer to the 
manufacturer’s package insert.[20] 
2.6.5 
HRZE/HR Control 
The HRZE (isoniazid 75 mg plus rifampicin 150 mg plus pyrazinamide 400 mg plus ethambutol 
275 mg combination tablets) combination will be given the first 8 weeks and the HR (isoniazid 75 
mg plus rifampicin 150 mg combination tablets) combination will be given from Weeks 9 to 26. 
Participants with DS-TB that are randomized to the HRZE/HR control arm in this trial will be 
given standard weight-adjusted doses of HRZE.   
Please see the HRZE and HR Package Inserts[22, 40] for known and potential risks and benefits. 
 
 
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3.0 
Trial Objectives 
3.1 
Primary Endpoint 
To evaluate the time to culture negativity over 8 weeks from the start of the treatment regimens 
in participants with: 
• 
Drug Sensitive TB (DS-TB) 
 
• 
Drug Resistant TB (DR-TB)  
 
DR-TB are defined as participants with: 
1. mono-resistance to rifampicin or isoniazid, OR 
2. resistance to both rifampicin and isoniazid (DR-TB) 
 
3.2 
Secondary Endpoints 
Efficacy: 
 
• 
Incidence of bacteriologic failure or relapse or clinical failure at 52 weeks (12 months) and 104 
weeks (or 24 months) weeks from the start of therapy.  
• 
Proportion of participants with sputum culture conversion to negative status in liquid culture 
(MGIT) at 4, 6, 12 and 17 weeks to be explored as a potential biomarker of outcome at 52 
weeks from start of therapy. 
• 
Change from baseline in weight. 
• 
Change from baseline in TB symptoms. 
• 
Change from baseline in Participant Reported Health Status. 
 
Safety and Tolerability: 
 
• 
Incidence of Treatment Emergent Adverse Events (TEAEs) presented by incidence, severity, 
drug relatedness, seriousness, leading to early withdrawal, and leading to death.  
 
Quantitative and qualitative clinical safety laboratory measurements, including observed 
and change from baseline. 
 
Quantitative and qualitative ECG results (heart rate, RR interval, PR interval, QRS 
interval, QT interval and QTc interval), including observed. QT/QTc intervals, change 
from baseline, will be categorized as these will be centrally read. 
• 
Changes in male reproductive hormones 
• 
Changes in lens opacities. 
 
These data will be presented as descriptive analyses, and no inferential tests will be carried out. 
Pharmacokinetics (PK) and Pharmacokinetics/Pharmacodynamics (PK/PD): 
 
Plasma concentrations from sparse sampling will be used to update existing population PK 
models and derive exposure metrics (e.g., minimum plasma concentration [Cmin], maximum 
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plasma concentration [Cmax], area under curve over a dosing interval [AUC]) for bedaquiline and 
its M2 metabolite, pretomanid, moxifloxacin, and pyrazinamide. Effects of baseline covariates 
on exposure will be assessed; so too, will the effects of concomitant medications, including 
antiretroviral therapy (ART), where feasible.  
 
Data from other trials may be included to enhance the model-based analysis. Relationships will 
be explored between drug exposure and efficacy and safety endpoints. These exploratory 
PK/PD analyses may include HIV status as a covariate. 
3.3 
Exploratory Objectives 
• 
Evaluate whether any of the secondary endpoints predicts relapse free cure. 
• 
Subgroup analysis of populations by HIV status.  
 
 
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4.0 
Trial Design 
4.1 
Summary of Trial Design 
This is a Phase 2c, multi-centre, open-label, partially randomized clinical trial conducted in 3 
treatment groups.  Participants, trial Investigators and staff, including laboratory staff, will not be 
blinded to treatment randomisation and allocation during the treatment phase of the trial. 
The trial will be performed globally at multiple centres located throughout the world.    
A total of 300 DS-TB participants (150 per treatment arm) will be randomized and stratified for co-
infection with HIV and cavitation, with a target of 50% of the participants being HIV positive.  Up 
to 150 DR-TB participants will be enrolled and assigned to the treatment arm described in Table 
4 below.   
Refer to Section 3.0 Trial Objectives above and Section 9.3 Interim Analysis for details of the 
planned interim analysis and potential updates to the trial objectives and sample size. 
 
Participants with Drug Sensitive TB (DS-TB): 
 
Participants with DS-TB will be randomized to one of two treatment arms. These participants will 
receive either BPaMZ daily for 17 Weeks, or HRZE/HR combination tablets daily for 26 Weeks.  
Participants will be stratified for co-infection with human immunodeficiency virus (HIV) and 
cavitation. 
 
Participants with Drug Resistant TB (DR-TB): 
 
Participants with DR-TB will be assigned to receive BPaMZ daily for 26 weeks (6 months). 
Eligible participants who meet all the inclusion criteria and none of the exclusion criteria, aged 18 
and over, male or female will be assigned to one of the 3 treatment groups with a target of 50% 
of the participants being HIV positive.  
 
DR participants will be treated with 6 months of BPaMZ.  DS participants will be randomised using 
an interactive web response system (IWRS) stratifying for cavitation and HIV status to allocate 
participants evenly across the arms after they have given written, informed consent during the 
Screening visit (Days -9 to -1). 
4.2 
Treatment Plan: Schedule of Assessments 
• 
Screening Period (Day -9 to Day -1) 
• 
Treatment Period (Day 1 to Week 17 / Week 26) 
• 
Follow-Up Period (Week 39 to Week 104) 
Refer to: 
• 
Synopsis Flow Chart and Procedures (Section 1.2) for the timing of all procedures and 
laboratory samples to done at each visit.   
• 
Trial Procedures (Section 7.0 Trial Variables and Procedures) for details regarding specific 
procedures or laboratory tests. 
Each participant will receive up to 26 weeks of treatment.  The trial IMP regimens may require 
interruptions/pauses due to toxicities. All dose interruptions/pauses should be discussed with the 
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Sponsor’s Medical Monitor prior to implementation unless an interruption/pause is required 
urgently for a safety concern.  
 
All participants will enter post-treatment follow-up which continues until Week 104 after start of 
treatment / randomisation. 
 
Participants will receive daily dosing, orally. They will be randomized to one of the following arms: 
Table 4: Treatment Groups 
 
Treatment Group 
Treatment 
Duration 
No of 
Participants 
1 Bedaquiline 200 mg daily for 8 weeks  
then 100 mg daily for 9 weeks, together with 
pretomanid 200 mg + moxifloxacin 400 mg + 
pyrazinamide 1500 mg daily 
17 weeks 
(4 months) 
150 DS-TB 
2 HRZE Tablets (Weeks 1-8): (isoniazid 75 mg plus 
rifampicin 150 mg plus pyrazinamide 400 mg plus 
ethambutol 275 mg combination tablets).  
 
Followed by, 
 
HR Tablets (Weeks 9-26): (isoniazid 75 mg plus 
rifampicin 150 mg combination tablets).   
First 8 weeks  
(2 months) 
 
 
then 
 
17 weeks  
(4 months) 
 
Total 6 months 
150 DS-TB 
3 Bedaquiline 200 mg daily for 8 weeks  
then 100 mg daily for 18 weeks, together with 
pretomanid 200 mg + moxifloxacin 400 mg + 
pyrazinamide 1500 mg daily. 
26 weeks 
(6 months) 
Up to 150 
DR-TB 
 
 
 
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5.0 
Trial Population 
The participant must meet all inclusion and no exclusion criteria within the screening period.  
Retesting for any laboratory or ECG parameters is allowed within the screening period.  Sponsor 
may consider replacement of late exclusions. 
5.1 
Inclusion Criteria 
Participants are required to meet all the following inclusion criteria during the screening period to 
be randomized. 
1. Signed written consent prior to undertaking any trial-related procedures. 
2. Male or female, aged 18 years or over. 
3. Body weight (in light clothing and no shoes) ≥ 30 kg. 
4. Sputum positive for tubercule bacilli (at least 1+ on the International Union Against 
Tuberculosis and Lung Disease [IUATLD]/WHO scale (Appendix 1) on smear microscopy) at 
the trial laboratory. 
5. Disease Characteristics - Participants with one of the following pulmonary TB conditions: 
 
DS-TB treatment arm participants should be: 
a. sensitive to rifampicin, isoniazid and fluoroquinolones by rapid sputum-based test 
AND 
b. either newly diagnosed for TB or have a history of being untreated for at least 3 
years after cure from a previous episode of TB. 
DR-TB treatment arm participants should be: 
a. Resistant to rifampicin and/or isoniazid; but sensitive to fluoroquinolones by rapid 
sputum-based test AND  
b. Should not have had previous treatment for DR-TB/MDR-TB, although may have 
been on a DR-TB/MDR-TB treatment regimen for no longer than 3 days at start of 
screening. 
c. Participants with resistance to injectables by rapid sputum-based test are allowed 
in the trial. 
When Phenotypic DST and/or whole genome sequencing (WGS) results on baseline 
samples become available, any results that are discordant with the screening molecular 
test results used to qualify a participant’s eligibility for the trial will be reviewed by the 
Sponsor Medical Monitor in consultation with the Investigator to determine whether that 
participant is unlikely to respond to treatment and should therefore be removed from the 
trial and given alternative treatment.  If a participant is removed from the trial for such a 
reason, they will be classified as a late exclusion. 
6. A chest x-ray, within 6 months prior to or during the Screening visit, which in the opinion of 
the Investigator is compatible with pulmonary TB.  
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7. Contraception: 
Be of non-childbearing potential or using effective methods of birth control, as defined below: 
Non-childbearing potential: 
a. Female participant or male participants female sexual partner - bilateral 
oophorectomy, 
bilateral 
tubal 
ligation 
and/or 
hysterectomy 
or has 
been 
postmenopausal with a history of no menses for at least 12 consecutive months; or  
b. Male participant  
 
Effective birth control methods: 
a. Double barrier method which can include a male condom, diaphragm, cervical cap, or 
female condom; or  
b. Female participant: Barrier method combined with hormone-based contraceptives or 
an intra-uterine device.  
c. Male participants’ female sexual partner: Barrier method combined with hormone-
based contraceptives or an intra-uterine device.  
Both male and female participants must be willing to continue practicing birth control 
methods and are not planning to conceive throughout treatment and for 6 months after 
the last dose of trial IMP or discontinuation from trial IMP in case of premature 
discontinuation.  
Note: Hormone-based contraception alone may not be reliable when taking IMP; therefore, 
hormone-based contraceptives alone cannot be used by female participants to prevent 
pregnancy. 
 
5.2 
Exclusion Criteria 
Participants will be excluded from participation if they meet any of the following criteria: 
Medical History and Concurrent Conditions: 
1. Any non-TB related condition where participation in the trial, as judged by the Investigator, 
could compromise the well-being of the participant or prevent, limit or confound protocol 
specified assessments. 
2. Abuse of alcohol or illegal drugs that in the opinion of the Investigator would compromise 
the participants’ safety or ability to follow through with all protocol-specified restrictions, 
visits and evaluations. 
3. Historical and or current use of local traditional medications/herbs which in the opinion of 
the Investigator would compromise the participants’ safety or ability to follow through with 
all protocol-specified restrictions, visits and evaluations. 
4. Being, or about to be, treated for malaria. 
5. Is critically ill and, in the judgment of the Investigator, has a diagnosis likely to result in 
death during the trial or the follow-up period. 
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6. TB meningitis or other forms of extrapulmonary tuberculosis with high risk of a poor 
outcome, or likely to require a longer course of therapy (such as TB of the bone or joint), 
as judged by the Investigator. 
7. History of allergy or hypersensitivity to any of the trial IMP or related substances, including 
known allergy to any fluoroquinolone antibiotic, history of tendinopathy associated with 
quinolones or suspected hypersensitivity to any rifampicin antibiotics. 
8. For HIV infected participants any of the following: 
 
a. CD4+ count <100 cells/µL  
b. Karnofsky score <60% (Appendix 5)   
c. Received intravenous antifungal medication within the last 90 days 
d. WHO Clinical Stage 4 HIV disease (Appendix 3) 
 
9. Participants who recently started or expected to need to start ART within 1 month after 
randomization. Participants who have been on ARTs for more than 30 days prior to start 
of the Screening visit or expected to start ART greater than 30 days after randomization 
may be included.  
10. Having participated in other clinical trials with investigational agents within 8 weeks prior 
to start of trial IMP or currently enrolled in an investigational trial. 
11. Participants with any of the following at the Screening visit (per measurements and 
reading done by ECG): 
 
a. QTcF interval on ECG >500 msec.  Participants with QTcF > 450 must be 
discussed with the Sponsor Medical Monitor before enrolment. 
b. Heart failure 
c. A personal or family history of congenital QT prolongation 
d. A history of or known, untreated, ongoing hypothyroidism 
e. A history of or ongoing bradyarrhythmia 
f. 
A history of Torsade de Pointe 
 
12. Unstable Diabetes Mellitus which required hospitalization for hyper- or hypo-glycaemia 
within the past year prior to start of screening. 
13. Females who have a positive pregnancy test at the Screening visit or already known to be 
pregnant, breast-feeding, or planning to conceive a child during the trial or within 6 months 
of stopping treatment.  Males planning to conceive a child during the trial or within 6 
months of stopping treatment. 
Previous and Concomitant Therapy 
14. Previous treatment for TB: 
 
• 
For DS-TB participants: Previous treatment for tuberculosis within 3 years prior to the 
Screening visit. Participants who have previously received isoniazid prophylactically 
may be included in the trial if that treatment is/was discontinued at least 7 days at the 
start of the Screening visit. 
• 
For the DR-TB participants: Previous treatment for DR-TB/MDR-TB, although may 
have been on a DR-TB/MDR-TB treatment regimen for no longer than 3 days at the 
start of the Screening visit. 
 
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15. Any diseases or conditions in which the use of the standard TB drugs or any of their 
components is contra-indicated, including but not limited to drug allergy. 
16. Use of any drug within 30 days prior to randomisation known to prolong QTc interval 
(including, but not limited to, amiodarone, amitriptyline, bepridil, chloroquine, 
chlorpromazine, cisapride, clarithromycin, disopyramide dofetilide, domperidone, 
droperidol, erythromycin, halofantrine, haloperidol, ibutilide, levomethadyl, mesoridazine, 
methadone, pentamidine, pimozide, procainamide, quinacrine, quinidine, sotalol, 
sparfloxacin, thioridazine). 
17. Use of systemic glucocorticoids within one year of the start of the Screening visit (topical, 
inhaled or intranasal glucocorticoids are allowed), as they can lead to visual opacities or 
cataracts. 
18. For HIV infected participants: 
 
a. The following antiretroviral therapy (ART) should not be used with either (BPaMZ 
and HRZE/HR) trial regimen: 
 
1. Stavudine  
2. Didanosine  
3. Triple NRTI regimen is not considered optimal for HIV treatment (poor efficacy) 
 
b. In the case where participants are randomized to HRZE arm, rilpivirine and etravirine 
cannot be given with rifampicin due to drug-drug interactions. A standard NRTI 
backbone may be used in combination with one of the following: 
 
1. Efavirenz requires no dose adjustment  
2. Dolutegravir dose adjustment is required – double dose when co-prescribed 
with rifampicin. 
3. Raltegravir requires no dose adjustment 
4. Lopinavir/r dose adjustment is required – double dose when co-prescribed with 
rifampicin 
5. Nevirapine requires no dose adjustment, however, please note that nevirapine 
based regimens are associated with higher ART failure in participants having or 
known to have a previous viral load more than or equal to 100,000/ mL 
 
c. In the case where participants are randomized to the BPaMZ trial regimen, a 
standard NRTI backbone may be combined with the following:  
 
1. Rilpivirine 
2. Dolutegravir  
3. Raltegravir 
4. Nevirapine  
5. Lopinavir/r  
6. Participants who are on efavirenz, atazanavir/r or darunavir/r at the time of 
screening and have an undetectable viral load, should have their ART switched 
to one of the agents listed above (1-5). It would be preferable to switch to 
another permissible ARV within the same class accompanied by the same 
nucleoside backbone. 
 
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d. ART regimen choice should be discussed with the Sponsor Medical Monitors if there 
are any concerns. 
 
Confirmed plans to use Isoniazid prophylaxis for HIV positive participants during the 
treatment and follow up period is not permitted. 
Diagnostic and Laboratory Abnormalities 
19. Participants with the following toxicities at screening as defined by the enhanced Division 
of Microbiology and Infectious Disease (DMID) adult toxicity table (Draft November 2007) 
(Appendix 2) where applicable: 
 
a. platelets <75,000/mm3 
b. creatinine >1.5 times upper limit of normal (ULN)  
c. eGFR ≤ 60 mL/min 
d. haemoglobin <8.0 g/dL 
e. serum potassium less than the lower limit of normal for the laboratory. This may 
be repeated once 
f. GGT: greater than 3 x ULN 
g. AST: 
• 
≥3.0 x ULN to be excluded; 
• 
results between 1.5 x ULN and 3 x ULN must be discussed with and 
approved by the Sponsor Medical Monitor 
h. ALT: 
• 
≥3.0 x ULN to be excluded 
• 
greater than ULN must be discussed with and approved by the Sponsor 
Medical Monitor 
i. 
 ALP: 
• 
≥3.0 x ULN to be excluded 
• 
2.0 – <3.0 x ULN must be discussed with and approved by the Sponsor 
Medical Monitor 
j. 
Total bilirubin: 
• 
>1.5 x ULN to be excluded; 
• 
greater than 1 – 1.5 x ULN must be discussed with and approved by the 
Sponsor Medical Monitor 
k. Direct bilirubin: 
• 
greater than 1x ULN to be excluded 
All the inclusion and none of the exclusion criteria must be met. If no single variable/value is 
outside of the ranges of acceptability, but when multiple values are close to the limits and/or 
whenever the Investigator has reason to suspect that there might be a health problem (other than 
TB), enrolment should only be considered after discussing the case with the Sponsor Medical 
Monitor. 
 No protocol waivers will be granted by the TB Alliance. 
 
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5.3 
Restrictions 
Concomitant medications should be kept to a minimum during the trial. However, if concomitant 
medications are necessary for the participant’s welfare, they may be given at the discretion of the 
Investigator. For any concomitant medications given as a treatment for a new condition or a 
worsening of an existing condition occurring after signing of the informed consent form, the 
condition must be documented on the Adverse Event pages of the electronic Case Report Form 
(eCRF). 
The prescribing information for all concomitant medication should be reviewed carefully. The 
determinations listed in the respective contraindicated, warning, and precaution sections must be 
respected to prevent any potentially serious and/or life-threatening drug interactions. 
The following recommendations should be followed with regards to concomitant medication to 
avoid possible drug interaction with the IMP: 
Participants on a moxifloxacin containing treatment arm: The IMP should be taken either 
4 hours before or 8 hours after taking the following products: 
• 
An antacid, multivitamin, or other product that has magnesium, aluminium, iron or zinc 
• 
Sucralfate 
• 
Didanosine 
Participants on the HRZE/HR treatment arm: 
• 
Any aluminium-containing antacids should be taken at least one hour after the IMP dose. 
The following medicinal products are prohibited from the Screening visit and during the treatment 
period: 
• 
Quinolone antimalarial (e.g., chloroquine and quinacrine). Participants who have malaria 
at screening are to be excluded. However, if a participant develops malaria during the trial, 
the Investigator is advised to consult the Malaria Treatment Guidance document regarding 
the interaction between moxifloxacin and bedaquiline with anti-malarial drugs. 
Investigators may also contact the Sponsor Medical Monitor for further guidance. 
• 
Chronic systemic glucocorticoids (topical, inhaled or intranasal glucocorticoids are 
allowed) due to their potential to cause visual opacities. Short term systemic 
glucocorticoids are allowed for emergency situations (e.g. for treatment of pulmonary 
exacerbation when inhaled glucocorticoids is inadequate). 
• 
Medicinal products used to treat pulmonary TB: including but not limited to gatifloxacin, 
amikacin, cycloserine, rifabutin, kanamycin, para-aminosalicylic acid, rifapentine, 
thioacetazone, capreomycin, other quinolones, thioamides, and metronidazole. 
The following medicinal products should be avoided from Day 1 (Baseline visit) and during the 
treatment period as much as possible (unless this is required for emergency management of the 
participant). Investigators may also contact the Sponsor Medical Monitor for further guidance. 
• 
Any drug known to prolong QTc interval (including but not limited to amiodarone, bepridil, 
chloroquine, 
chlorpromazine, 
cisapride, 
clarithromycin, 
disopyramide 
dofetilide, 
domperidone, droperidol, erythromycin, halofantrine, haloperidol, ibutilide, levomethadyl, 
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mesoridazine, methadone, pentamidine, pimozide, procainamide, quinidine, sotalol, 
sparfloxacin, thioridazine). The exception is moxifloxacin and bedaquiline administered as 
part of the trial IMP, with ECG monitoring, to help ensure participant safety. 
• 
Any 
drug 
known 
to 
be 
hepatotoxic 
(including 
but 
not 
limited 
to 
acetaminophen/paracetamol, acetazolamide, allopurinol, amiodarone, amitriptyline, 
amoxicillin, amprenavir, atorvastatin, augmentin/co-amoxiclav, azathioprine, baclofen, 
bumetanide, captopril, carbamazepine, celecoxib, chlorpromazine, chlorpromazine, 
clindamycin, clopidogrel, co-trimoxazole, darunavir, delavirdine, diclofenac, doxycycline, 
enalapril, fluconazole, fluoxetine, fosamprenavir, furosemide, gliclazide, glimeperide, 
glipizide, 
ibuprofen, 
irbesartan, 
ketoconazole, 
lisinopril, 
loperamide, 
losartan, 
methotrexate, metolazone, mirtazepine, nitrofurantoin, omeprazole, other non-steroidal 
anti-inflammatory 
drugs, 
paroxetine, 
phenobarbital, 
phenothiazines, 
phenytoin, 
pravastatin, 
probenecid, 
prochlorperazine, 
risperidone, 
rosuvastatin, 
sertraline, 
simeprevir, simvastatin, sodium valproate, sotalol, sulfasalazine, sumatriptan, tamsulosin, 
terbinafine, tetracycline, theophyllin/uniphyllin, tipranavir, tolazamide, tolbutamide, 
topiramate, trazodone, tricyclic antidepressants, trimethoprim, verapamil).  
5.4 
Treatment Discontinuation and/or Early Withdrawal  
Any participant for whom the Investigator decides to temporarily discontinue their IMP is to be 
discussed with the Sponsor Medical Monitor and, if applicable, be restarted on IMP as soon as 
possible.  
A participant must be prematurely withdrawn from the trial (during the trial treatment or follow-up 
periods) because of the following: 
• 
Withdrawal of informed consent 
• 
Investigator considers that for safety reasons it is in the best interest of the participant that 
he/she be withdrawn, including a concern that the participant has symptomatic TB and/or 
bacteriological failure/relapse and requires a change in TB treatment 
• 
Pregnancy 
• 
At the specific request of the Sponsor or termination of the trial by the Sponsor 
• 
Lost to follow-up 
• 
When Phenotypic DST and/or whole genome sequencing (WGS) results on baseline 
samples become available, any results that are discordant with the screening molecular 
test results used to qualify a participant’s eligibility for the trial will be reviewed by the 
Sponsor Medical Monitor in consultation with the Investigator to determine whether that 
participant is unlikely to respond to treatment and should therefore be removed from the 
trial and given alternative treatment.  If a participant is removed from the trial for such a 
reason, they will be classified as a late exclusion. 
A participant may withdraw from the trial at any time at his/her request (withdrawal of consent) or 
may be withdrawn at any time at the discretion of the Investigator for safety, behavioural, 
compliance or administrative issues.  
When a participant withdraws consent from the trial, no additional follow-up visits will be 
performed. 
Participants who withdraw from the trial after having received IMP will not be replaced.  
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All participants withdrawn from trial and who received at least one dose of IMP will be requested 
to return for an Early Withdrawal visit and the applicable safety Follow-Up visits, as per the 
Synopsis Flow Chart and Procedures (Section 1.2 footnote c), as well as Table 5. 
5.4.1 
Early Withdrawal 
In case of early withdrawal during the treatment or follow-up period, all efforts shall be made to 
complete the Early Withdrawal assessments.  At the Early Withdrawal visit the following 
information will be collected and procedures performed: 
• 
Sputum sample collection x 2 (one EMS brought from home and one spot at the research 
site under the coaching and observation of the trial staff).  If no EMS was provided by the 
participant, 2 spot samples may be collected at the site, at least 30 minutes apart. 
• 
Urine pregnancy test (women of child bearing potential, whether they are sexually active or 
not) 
• 
Laboratory safety sampling (including male reproductive hormone tests); 
• 
Single 12-lead ECG 
• 
TB Symptoms Profile 
• 
Patient Reported Health Status Questionnaire 
• 
Vital signs 
• 
Full physical examination, including weight 
• 
Ophthalmology examination, if required as described in Table 5 
• 
IMP compliance check (if participant on IMP) 
• 
Concomitant medications 
• 
Adverse events 
Once a participant has been withdrawn early from the trial, they will be requested to attend follow-
up visits as described in Table 5: 
Table 5: Follow-up Visits Required for Early Withdrawal Participants 
Treatment 
Duration at 
EWD visit 
Ophthalmology 
Examination at 
EWDa 
Ophthalmology 
Examination  
 
Visit 3 months 
after EWD Visita 
Week 52  
(Month12) 
Follow-up 
Visit 
Week 104 
(Month 24) 
Follow-up 
Visit 
≤ 14 days 
Not required 
Not required 
Required 
Required 
15 days to      ≤ 
12 weeks 
Not required 
Required 
Required 
Required 
> 12 weeks  
Required 
Required 
Required, if not 
already 
performed 
Required 
a. If an additional visit is required for an ophthalmology examination after EWD, only the 
ophthalmology examination will be performed at this visit, and it will occur 3 months after the EWD 
visit date. 
The Weeks 52 and 104 visits will be performed to collect SAE information (including verification 
of survival) and participant reported TB outcome information.  This visit may be telephonic, a 
home or a site visit at Weeks 52) and/or Week 104 after the participants’ start of treatment date. 
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5.4.2 
Unscheduled Visits 
Any visit which is conducted in addition to those required by the Synopsis Flow Chart and 
Procedures (Section 1.2), should be considered unscheduled regardless of the reason for the 
visit. The assessments which are undertaken as part of an Unscheduled visit should be as 
clinically indicated.  
The following situation/s require an unscheduled visit/s: 
• 
For any medical reason, as determined by the Investigator or participant. 
• 
If both sputum samples (EMS and spot) at Week 8 or later are contaminated, the 
participant should return for an unscheduled visit/s to give additional sputum samples or 
to document that the participant is not able to produce sputum.  
• 
If after having converted to culture negative, the participant has a MTB confirmed 
positive culture at or after the last visit of the treatment period (Week 17 or Week 26), 
the participant should return for unscheduled visit/s to provide additional sputum 
samples, at a minimum of 7 days apart, or to document that the participant is not able to 
produce a sputum sample. 
Determination of the participant’s primary outcome status requires sputum culture results at the 
following time-points during the trial: 
o End of Follow-up Period (Week 52 and 104) 
o Early Withdrawal, if applicable 
At least one of the following criteria should be met at these time-points to confirm a participant’s 
primary outcome status: 
o two sequential negative sputum culture results; or  
o two sequential positive sputum culture results; or  
o has been unable to produce sputum after documentation of two negative sputum 
cultures with no intervening positive and the participant is clinically asymptomatic 
Should the participant’s primary outcome not meet any of the above criteria, the Investigator 
should continue to recall the participant for an Unscheduled visit to collect sputum samples until 
the criteria is met and the primary outcome can be determined. 
Additional sputum samples: Two samples at each visit – ideally, one EMS and one spot sputum 
sample at the research site under the coaching and observation of the trial staff). If no EMS was 
provided by the participant, 2 spot sputum samples may be collected on site, at least 30 minutes 
apart. Additional sputum samples should be collected at least 7 days after the previous sample. 
 
 
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Table 6: Summary of Scenarios Requiring Unscheduled Visits for 
Mycobacteriology Testing 
Time-point 
Scenario 
Unscheduled 
Visit/s 
Required? 
Comment 
Week 8 or later 
Both sputum cultures 
are contaminated 
Yes 
Provide additional samples 
until a positive or negative 
result is reported, or it is 
confirmed that the 
participant is unable to 
produce sputum 
At or after the last 
treatment visit 
(Week 17 or 
Week 26) 
Previously converted to 
culture negative but now 
has an MTB-positive 
culture 
Yes 
Provide additional samples 
at least 7 days after the 
previous sample until the 
result is confirmed, or it is 
confirmed that the 
participant is unable to 
produce sputum.  
End of Follow-up 
Period (Week 52 
and 104)  
Early 
Withdrawal, if 
applicable 
Participant’s primary 
outcome status cannot 
be confirmed by: 
Two sequential negative 
sputum culture results; 
or   
two sequential positive 
sputum culture results; 
or has been unable to 
produce sputum after 
documentation of two 
negative sputum 
cultures with no 
intervening positive and 
are clinically 
asymptomatic 
Yes 
Provide additional samples 
at least 7 days after the 
previous sample until one of 
the criteria is met and the 
primary outcome status can 
be determined.  
 
If the Investigator is unsure of the outcome in any of the above scenarios, the Investigator should 
contact the Sponsor Medical Monitor to discuss and agree on how the participant is to be 
managed. 
5.4.3 
Lost-to-Follow-up 
Every reasonable attempt must be made to minimise Lost-to-Follow-up (LTFU) participants.  A 
minimum of three contact attempts (telephonic/home visit) will be made for participants who do 
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not arrive for their scheduled trial visits. If these attempts are unsuccessful the participant will be 
considered LTFU.  All attempts to contact the participant must be clearly documented in the 
participant’s source documents. 
5.4.4 
Early Withdrawal due to TB 
Ultimately it is the Investigator’s decision whether a participant requires early withdrawal from the 
trial due to a concern that the participant has symptomatic worsening of TB and/or bacteriological 
failure/relapse.  
Early withdrawal is usually not indicated for a single positive culture.  Should a participant have a 
single positive culture result after being culture negative, the Investigator is to evaluate whether 
the participant has signs and symptoms suggestive of active inadequately treated TB and whether 
it is in the participants best interest that he/she be withdrawn. Prior to early withdrawal of a 
participant due to TB, the Investigator must discuss the participant with the Sponsor Medical 
Monitor, unless the Investigator cannot contact the Sponsor Medical Monitor and considers that 
early withdrawal must occur immediately due to immediate safety concerns with respect to the 
participant. 
If the Investigator decides to withdraw a participant due to TB, additional sputum samples may 
need to be collected to ensure the participant’s outcome status as determined in Section 5.5. 
All early withdrawn participants who are confirmed sputum positive (two sequential sputum 
positive cultures) and/or have symptomatic TB will require further TB treatment. These 
participants will be referred to their applicable DS/DR local community TB clinics for standard anti-
tuberculosis chemotherapy according to National TB Treatment Guidelines.  
The participant will be provided with a referral letter from the Investigator to take with them to their 
National Treatment Program (NTP) clinic and the referral letter, at a minimum, should include all 
treatment received by the participant and information about any suspected/confirmed adverse 
event/reaction related to any of the trial IMP’s and or concomitant medications.  A follow-up call 
should be made by the trial site staff to the clinic to ensure the participant attended the NTP clinic.  
5.5 
Participant Progress Definitions  
Table 7: Participant Progress Definitions 
Status 
Treatment 
Follow-Up 
Screen Failure 
Participants from whom informed consent is obtained and is 
documented in writing (i.e., participant signs an informed consent form) 
but who are not randomized 
Completed 
Treatment / 
Completed 
Follow-Up* 
Participants who complete 
the full course of IMP 
Participants who complete all follow-up 
visits 
Completed 
Treatment / 
Discontinued 
Follow-Up 
Participants who complete 
the full course of IMP 
Participants who do not complete all 
applicable follow-up visits, regardless of 
the reason (excluding LTFU) 
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Status 
Treatment 
Follow-Up 
Completed 
Treatment / Lost 
to Follow-Up 
Participants who complete 
the full course of IMP 
Participants who are unable to be 
contacted on or before their final visit 
Discontinued 
Treatment / 
Completed FU 
Participants who discontinue 
IMP prior to completion of 
the protocol-defined 
treatment course 
Participants who complete all applicable 
follow-up visits 
Discontinued 
Treatment / 
Discontinued 
Follow-Up** 
Participants who discontinue 
IMP prior to completion of 
the protocol-defined 
treatment course 
Participants who do not complete all 
applicable follow-up visits, regardless of 
the reason (excluding LTFU) 
Lost to Follow-Up 
Participants who are unable to be contacted on or before their final 
treatment visit and it cannot be confirmed whether treatment was 
completed 
* 
Note that this includes treatment failures who complete all applicable follow-up visits 
** 
Early Withdrawal 
5.6 
Trial Stopping Rules 
There are no trial specific stopping rules.  
The trial or parts of the trial can be stopped by the Sponsor on advice from the Data Safety and 
Monitoring Committee (DSMC) after their review of applicable trial data.  In addition, the Sponsor 
has the right to stop the trial or a specific trial site at any time, although this should only occur 
after consultation between the involved parties.  Should this occur, the local and central Ethics 
Committee/Institutional Review Board (EC/IRB) and Regulatory Authorities will be informed.   
Should a trial site be closed prematurely, all trial materials (except source documentation that 
must remain at the site) will be returned to the Sponsor or applicable vendor.   The Investigator 
will retain all other documents until notification given by the Sponsor for destruction.  Participants 
currently on trial IMP will receive an appropriate regimen and all participants will be referred to 
their applicable DS-TB/DR-TB NTP clinic. 
 
 
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6.0 
Treatment 
6.1 
IMP Administration  
6.1.1 
Instructions for Dosing of Test Regimen (BPaMZ) 
• 
Treatment will be orally administered once daily, to be taken during breakfast, with a full 
glass of water (approximately 240 ml), for 17 weeks (4 months) or 26 weeks (6 months). 
 
6.1.2 
Instructions for Dosing Control Treatment Regimen (HRZE/HR) 
• 
To be taken with a glass of water (approximately 240 ml). 
• 
HRZE or HR should not be taken with a meal (generally, no closer to meals than 1 hour 
before or 2 hours after a meal) in the following dosing schemes. 
HRZE/HR treatment will be administered orally once daily to DS-TB participants as follows: 
Weight Band 
Weight Range 
Number of tablets per 
weight band 
1 
30-39 kg 
2 
2 
40-54 kg 
3 
3 
55-70 kg 
4 
4 
≥ 71 kg 
5 
 
The participant’s weight at the Screening (HRZE) and Week 8 (HR) visits will be used to determine 
which weight band and dose to administer. 
 
A daily supplement of Vitamin B6 will be provided by the trial site to participants randomised to 
the HRZE/HR treatment arm, per each country’s National TB Treatment Guideline.   
6.2 
Participant Compliance 
During site clinic visits, the IMP will be administered by the Investigator(s)/designated site 
personnel and when possible, the check for IMP compliance via the hand-and-mouth procedure 
(both the hand and the mouth of the participant will be checked to ensure that the participant has 
swallowed the IMP). During the trial, sites will be responsible for ensuring participants are taking 
IMP correctly and are fully trained on how the IMP is to be taken, as well as to check the IMP 
cards for unused tablets in the containers at each visit during the treatment phase.  
6.3 
Treatment Modification(s) 
The importance of adherence to the treatment schedule will be reinforced at each visit.  Non-
adherence should prompt the Investigator to identify and address the cause(s) (e.g. side effects).  
 
Participants that do not take: 
 
• 
Up to 7 consecutive doses of IMP doses: restart IMP, no extension of IMP required. 
• 
If more than 7 to ≤ 35 consecutive doses of IMP: restart IMP and extend the IMP 
treatment by the number of consecutive doses missed. The final treatment visit should 
also be pushed out to the date of last dose. It is not necessary to have an unscheduled 
visit at the time when the end of treatment visit would have been.   
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• 
If more than 35 consecutive doses of IMP, discontinue IMP and withdraw participant 
from the trial. 
• 
If the participant misses a total (sum) of 56 cumulative missed doses, discontinue the 
IMP and withdraw the participant from the trial. 
• 
If more than 7 to ≤ 35 consecutive doses are missed, these must be made up with the 
same treatment combination or dose that was missed.  
Any participant for whom the trial IMP is discontinued (including for non-adherence) will be 
discussed with the Sponsor Medical Monitor and, if applicable, the participant will be restarted on 
trial IMP as soon as possible.  
6.4 
IMP Packaging and Labelling 
The complete formulations of the IMP, bedaquiline and pretomanid, are found in the respective 
Investigator Brochures.[8, 15] The complete formulations of moxifloxacin, pyrazinamide, HRZE/HR 
are found in the Package Inserts.[19, 20, 22, 40]  
The IMP will be packaged in weekly or bi-weekly cards as follows: 
Week 1 to 8 Cards: Dispensed Weekly 
IMP 
Strength 
Number of tablets 
Abbreviation 
Bedaquiline 
100 mg 
14 
B 
Pretomanid 
200 mg 
7 
Pa 
Moxifloxacin 
400 mg 
7 
M 
Pyrazinamide 
500 mg 
21 
Z 
 
Week 9 to 17/26 Cards: Dispensed Weekly 
IMP 
Strength 
Number of tablets 
Abbreviation 
Bedaquiline 
100 mg 
7 
B 
Pretomanid 
200 mg 
7 
Pa 
Moxifloxacin 
400 mg 
7 
M 
Pyrazinamide 
500 mg 
21 
Z 
 
Control (HRZE/HR) Group: Dispensed Bi-weekly 
Weight Band 
Weight Range 
Number of tablets 
per weight band 
Number of tablets 
in each card 
1 
30-39 kg 
2 
28 
2 
40-54 kg 
3 
42 
3 
55-70 kg 
4 
56 
4 
≥71 kg 
5 
70 
 
A daily supplement of Vitamin B6 will be provided by the trial site to participants randomised to 
the HRZE/HR treatment arm, per each country’s National TB Treatment Guideline. 
The packaging of each weekly and biweekly cards will be labelled with, at a minimum, the 
following information: 
• 
Name of Sponsor 
• 
Name of medication 
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• 
Dosage, quantity and method of administration  
• 
Reference/lot number 
• 
The statement “For Clinical Trial Use Only” 
• 
Space for completion of name of Investigator and site number 
• 
MedID: medication identification number 
• 
Storage conditions 
• 
Period of use 
• 
The statement “Keep out of reach of children” 
• 
Expiry date 
• 
Directions for use 
• 
Space for completion of participant number and visit/date dispensed 
6.5 
Blinding and Procedures for Breaking the Blind 
As this is an open label trial there is no need for blinding or procedures to break the blind. The 
trial participants, the site staff, Sponsor, and CROs will not be blinded to treatment assignment.  
6.6 
Handling, Storage and Accountability  
The Investigator or designee must confirm that the appropriate temperature conditions as per 
details on IMP labelling, have been maintained during transit for all trial IMP received, and any 
discrepancies are reported and resolved before use of the trial IMP. 
Only participants randomised in the trial may receive trial IMP and only authorized site staff may 
supply or administer trial IMP. All trial IMP’s must be stored in a secure, environmentally 
controlled, and monitored (manual or automated) area in accordance with the labelled storage 
conditions with access limited to the Investigator and authorized site staff. 
The Investigator, institution, or the head of the medical institution (where applicable) is responsible 
for trial IMP accountability, reconciliation, and record maintenance (i.e., receipt, reconciliation, 
and final disposition records).  Upon completion or termination of the trial, all unused and/or 
partially used IMPs must either be returned to Sponsor (or designated vendor: who will arrange 
for destruction) or destroyed at site as agreed by the Sponsor, after final accountability has been 
confirmed. 
The Investigator/designee will immediately inform the Sponsor of any quality issues arising with 
respect to the trial IMP. The Sponsor will take whatever action is required should such a situation 
arise. 
Further guidance and information for the handling, storage, accountability and final disposition of 
unused trial IMPs are provided in the Pharmacy Manual. 
 
 
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7.0 
Trial Variables and Procedures 
The Synopsis Flowchart and Procedures (Section 1.2)  should be referenced for timing, 
sequence of assessments, and specific procedures. 
7.1 
Demographic and Background Variables and Procedures 
The following demographic and background variables will be collected: 
• 
Written Informed Consent 
• 
Visit dates 
• 
Participant disposition 
• 
Demography (date of birth, race and gender) 
• 
Inclusion and exclusion criteria 
• 
Clinically significant medical and TB treatment history (including past and current TB 
diagnosis, smoking and alcohol use) 
• 
Screening coached spot sputum samples: 
o Smear microscopy for acid-fast bacilli  
o Rapid molecular tests for isoniazid, rifampicin, fluoroquinolones resistance (Hain 
MTBDRplus and HainMTBRsl) 
o Liquid Culture (MGIT) for Mycobacterium tuberculosis (MTB), followed by a speciation 
test to detect presence or absence of MTB and obtain time to positivity (TTP) when 
positive. 
• 
Urine pregnancy test: women of childbearing potential only, whether they are sexually 
active or not (non-childbearing potential for a female participant is defined as having 
bilateral oophorectomy, bilateral tubal ligation and/or hysterectomy or has been 
postmenopausal with a history of no menses for at least 12 consecutive months). 
• 
Serology: HIV and CD4 count.  Where required by regulatory authorities or ethics 
committees, a separate (EC/IRB approved) HIV informed consent form will be obtained 
from participants: 
o Prior to HIV testing and on receipt of the results, participants will be counselled on HIV by 
trained counsellors if they have indicated as such on the HIV consent form. If requested 
by the participant, HIV counselling that is provided to the participant by the trial site should 
be clearly documented in the participant’s medical records/source.  Participants have the 
right to decline to know or receive their HIV test results. This decision should be clearly 
documented in the participant’s medical records/source.   
• 
Karnofsky Score (Appendix 5). Only for HIV positive participants. 
• 
Chest X-Ray: A chest X-ray digital image within 6 months prior to or during the Screening 
visit, will be obtained and read locally by the Investigator or designee.  Digital images will 
be provided to the Sponsor; this process will be documented in the Chest X-Ray / 
Radiology Manual.  The investigator is responsible for review and analysis of the chest X-
ray for participant’s inclusion. 
• 
Method of birth control: male and female participants and their sexual partners 
• 
IMP details: randomization 
• 
IMP compliance and actual dosing 
• 
Concomitant medications 
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7.2 
Efficacy Variables and Procedures 
Two spot sputum samples are collected, one EMS brought from home or collected in the hospital 
ward (only if the participant is hospitalised) and one spot sputum sample collected at the research 
site under the coaching and observation of the trial staff or, if no EMS sample was provided by 
the participant, 2 samples may be collected on site at least 30 minutes apart. The 
mycobacteriology sampling methodology and requirements will be described in a separate 
document, the Mycobacteriology Laboratory Manual, which will be provided prior to the trial start. 
Sputum samples may not be obtained by induction. 
The following analyses will be performed: 
• 
Liquid culture (MGIT), to detect presence or absence of MTB and obtain the TTP followed 
by a speciation test when applicable, to confirm MTB. 
 
Using these observed variables, the following derived variables will be assessed for evaluation of 
the efficacy endpoints: 
• 
Bacteriologic failure/relapse 
• 
Time to sputum culture conversion 
• 
Number of participants with sputum culture conversion 
 
Every effort must be made to collect sputum samples. However, in general, the inability to produce 
sputum is treated as being equivalent to having a negative culture (favourable) result.  A 
participant who never achieves culture negative status due to the inability to produce sputum but 
has completed Week 17 or Week 26 and post treatment follow-up (Weeks 39 to 104) and is 
without clinical or biological evidence of relapse, will be considered to have a favourable outcome. 
TB Symptoms Profile:  
• 
The TB Symptoms Profile will record participants’ ratings of the severity of common TB 
symptoms.  
 
Patient Reported Health Status Variables and Procedures:  
• 
The Patient Reported Health Status variables will be collected at the time points described 
in the Synopsis Flow Chart and Procedures (Section 1.2). Patient Reported Health Status 
will be collected using the EQ-5D-5L Health Questionnaire. This descriptive system consists 
of five health-related quality of life dimensions, each of which will be recorded using five 
levels of severity.  
 
Methodology: The Patient Reported Health Status methodology and requirements will be 
described in a separate trial Participant Questionnaires Guideline, which will be provided prior to 
the trial start. 
7.3 
Safety and Tolerability Assessments 
The following safety and tolerability variables will be collected at the time points described in the 
Synopsis Flow Chart and Procedures (Section 1.2) and assessed for evaluation of the safety 
endpoints: 
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• 
The safety laboratory sampling methodology and requirements will be described in a 
separate document, the Safety Laboratory Manual, which will be provided prior to the trial 
start. The following analyses will be performed: 
o Full Blood Count (haemoglobin, haematocrit, red blood cell count, white blood cell 
count with differential, platelet count) 
o Clinical Chemistry (albumin, serum urea, creatinine, direct, indirect and total bilirubin, 
uric acid, total protein, ALP, AST, ALT, lipase, phosphate, sodium, potassium, calcium 
(corrected for albumin), chloride, magnesium, glucose, bicarbonate/CO2, creatine 
phosphokinase (CPK). GGT is only routinely included at the Screening visit (Day -9 to 
-1).  
o When managing participants with elevated liver enzymes at an Unscheduled visit, the 
investigator should request additional tests, in addition to the repeat LFT [e.g. Gamma 
Glutamyl Transferase (GGT), screening for Hepatitis A, B, C; to assist in ruling out 
other causes of a dysfunctional liver test (e.g. alcohol induced hepatic cell injury, 
hepatobiliary disease, hepatic viral infection)]. 
o Hepatitis A, B and C serology test to be performed at Day 1 (baseline) or where 
available, the backup PK sample at Day 1 (pre-dose) will be used to obtain a hepatitis 
A, B and C serology result for all participants already enrolled prior to Protocol V4.0. 
o Urinalysis (pH, specific gravity, protein, glucose, micro-albumin, ketones, bilirubin, 
creatinine, nitrite, sodium, urobilinogen, blood, leukocytes). Microscopy will be 
completed as follow up to abnormal urinalysis per discretion of Investigator 
• 
12-lead ECG: 
o Investigator assessment: normal or abnormal 
o Central cardiologist assessment: heart rate, PR interval, RR interval, QT, corrected 
QT Interval (QTc) (QTcB and QTcF), QRS. 
o Methodology: 
 
Timing (Synopsis Flow Chart and Procedures, Section 1.2) and registration 
technique for ECGs will be standardized for all participants and will be 
described in a separate document which will be provided prior to the trial start 
 
ECGs are to be recorded for 10 seconds 
 
ECGs are to be performed during a single visit 
 
ECGs should be done before any phlebotomy when both included in a visit 
 
For each participant, the ECGs should, to every extent possible, be collected 
at approximately the same time of day (+/- 1 hours) and in the same fed/fast 
state throughout the trial (e.g. 4 hours after lunch) 
o ECGs to be performed prior to pre- and post-dose PK sampling as described below: 
 
Day 1: pre-dose (within 2 hours prior to dosing) 
 
Week 2: pre-dose (within 2 hours prior to dosing), 1.5–3 hours post-dose and 
4-6 hours post-dose 
 
Week 8: pre-dose (within 2 hours prior to dosing), 1.5–3 hours post-dose and 
4-6 hours post-dose 
 
Week 12: pre-dose (within 2 hours prior to dosing)  
 
Week 17 or at early withdrawal if prior to week 17: pre-dose (within 2 hours 
prior to dosing) and 1.5–3 hours post-dose 
• 
Vital signs: 
o Vital signs (should be done before any phlebotomy in light clothing and with no 
shoes) 
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o Systolic and diastolic blood pressure (mmHg) to be measured in a supine position 
(after 5 minutes of rest) using an appropriately sized cuff, and using the same type of 
sphygmomanometer, if possible, by the same observer, at each relevant visit 
o Heart rate (beats per minute) 
o Respiratory rate (breaths per minute)  
o Axillary body temperature (°C) 
• 
Physical Examination:  
o Height (m) is measured at the screening visit only 
o Full (complete) and limited (gross neurological, pulmonary, cardiovascular and 
abdominal) examinations will be performed and any clinically significant findings will 
be recorded 
o Weight (kg) (in light clothing and with no shoes) 
o Using the variables of weight and height, the body mass index (BMI) will be 
calculated 
• 
Ophthalmology Slit Lamp Examination: 
o To be done by an Ophthalmologist trained on Age-Related Eye Disease Scale 2 
(AREDS2) assessment. The ophthalmology slit lamp methodology and requirements 
will be described in a separate document, the Ophthalmology Guideline. The 
following analyses will be performed: AREDS2 opacity typing and grading. 
• 
Adverse events 
• 
Investigator assessment:  
o The Investigator will review the participant status at specified visits in the Synopsis 
Flow Chart and Procedures (Section 1.2), including any time the Investigator 
determines that the participant fulfils the criteria for the primary outcome of treatment 
failure. The Investigator will assess whether TB treatment is considered a “success” 
or “failure”.  If it is considered a failure, the Investigator should specify if the 
assessment is based on bacteriology and/or clinical deterioration and/or radiological 
deterioration. 
7.4 
PK Variables and Procedures 
Plasma concentrations from sparse sampling (Synopsis Flow Chart and Procedures, Section 1.2) 
will be used to update population PK models for bedaquiline and its M2 metabolite, pretomanid 
to further evaluate the effects of covariates on model parameters in this trial population.   
 
PK data from the current trial may be combined with prior data to enhance this population PK 
analysis. The models will be used to estimate individual exposure metrics (e.g., Cmin, Cmax, AUCτ, 
Cmean, and time above minimum inhibitory concentration) for subsequent analyses exploring 
relationships between drug exposure and efficacy and safety endpoints. 
 
If IMP is not administered during Week 2, 8 and or 17, then only a single PK sample is required 
to be obtained at any time during the visit assessment. 
7.5 
Mycobacteriology Characterization Variable and Procedures 
 
• 
Day 1 (Baseline) sputum sample (or any positive sample from Screening to Week 4, if 
the baseline cultures are contaminated or negative); 
• 
MTB confirmed positive cultures (after the participant has previously converted to 
negative) at or after the last visit of the treatment period (Week 17 or Week 26) or visits 
with positive cultures, during the post-treatment follow-up period. 
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• 
Refer to the Mycobacteriology Laboratory Manual for full details. 
Mycobacterial Characterization - MTB isolates (from the first MTB positive culture) will be 
processed for: 
• 
Rapid molecular tests for fluoroquinolones, injectables, isoniazid and rifampicin 
resistance (only on MTB positive cultures in the follow-up period); 
• 
Minimum Inhibitory Concentration (MIC) against bedaquiline, pretomanid, and 
moxifloxacin;  
• 
Drug Susceptibility Testing for streptomycin, rifampicin, isoniazid, ethambutol, 
moxifloxacin, and pyrazinamide in liquid culture;  
• 
Extraction of organismal (MTB) DNA for whole genome sequencing (WGS), and 
comparison of sequences from baseline and relapse isolates. 
 
If the participant’s culture converts to negative and has a MTB positive culture at or after the last 
visit of the treatment period (Week 17 and Week 26), the MTB cultures will be tested at the trial 
mycobacteriology laboratories using Hain MTBDRplus and HainMTBRsl to detect resistance to 
isoniazid, rifampicin, fluoroquinolones and injectables. 
 
All MTB isolates must be stored at the local mycobacteriology laboratories, until trial closure.  In 
addition, MTB isolates as well as extracted MTB DNA from the applicable baseline and follow-up 
cultures will be stored at the central mycobacteriology laboratory for potential further work to 
advance new assay tools and understanding of MTB as a pathogen for a maximum of 5 years 
after trial closure.  
 
 
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8.0 
Adverse Events 
8.1 
Definitions 
8.1.1 
Adverse Event (AE) 
Any untoward medical occurrence in a clinical investigation participant, temporally associated with 
the use of a trial treatment whether or not considered related to trial treatment. An AE can 
therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease (new or exacerbated) temporally associated with the use of a trial treatment, 
whether or not related to the trial treatment. 
8.1.2 
Serious Adverse Event (SAE) 
Any untoward medical occurrence that at any dose: 
• 
Results in death 
• 
Is life threatening (any event in which the participant was at risk of death at the time of the 
event; it does not refer to an event, which hypothetically might have caused death if it were 
more severe) 
• 
Requires inpatient hospitalisation or prolongation of existing hospitalisation; in general, 
hospitalisation signifies that the participant has been detained (usually involving at least 
an overnight stay) at the hospital or emergency ward for observation and/or treatment that 
would not have been appropriate in the physician’s office or outpatient setting. 
Complications that occur during hospitalisation are AEs. If a complication prolongs 
hospitalisation or fulfils any other serious criteria, the event is serious. When in doubt as 
to whether “hospitalisation” occurred, or was necessary, the AE should be considered 
serious. Hospitalisation for elective treatment of a pre-existing condition that did not 
worsen from baseline is not considered an AE. 
• 
Results in persistent or significant disability/incapacity; the term disability means a 
substantial disruption of a person’s ability to conduct normal life functions. This definition 
is not intended to include experiences of relatively minor medical significance such as 
uncomplicated headache, nausea, vomiting, diarrhoea, influenza, and accidental trauma 
(e.g., sprained ankle) which may interfere with or prevent everyday life functions but do 
not constitute a substantial disruption. 
• 
Is a congenital anomaly/birth defect; or 
• 
Is a medically important event 
Note:  Medical and scientific judgment should be exercised in deciding which is a medically 
important event that may not be immediately life-threatening or result in death or hospitalisation 
but may jeopardize the participant or may require medical or surgical intervention to prevent one 
of the outcomes listed above.   
Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias or convulsions that do not result in hospitalisation, or the 
development of drug dependency or drug abuse. A “suspected transmission of infectious agent 
by a medicinal product” is also considered a serious adverse event under the SAE criterion “Other 
medically important condition”.     
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8.1.3 
Attribution/Causality 
• 
The Investigator is obligated to assess the relationship between trial treatment and each 
occurrence of each AE/SAE 
• 
The Investigator will use clinical judgment to determine the relationship 
• 
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to trial IMP administration will be 
considered and investigated 
• 
The Investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment 
• 
For each AE/SAE, the Investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality 
• 
There may be situations in which an SAE has occurred, and the Investigator has minimal 
information to include in the initial report to the Sponsor/designee. However, it is very 
important that the Investigator always assesses causality for every event before the initial 
transmission of the SAE data to the Sponsor/designee. 
• 
The Investigator may change his/her opinion of causality in light of follow-up information 
and send a SAE follow-up report with the updated causality assessment 
 
Table 8: Adverse Events Attribution/Causality Ratings 
Relatedness Rating 
Definition 
Not Related 
An AE, which is not related to the use of the drug. 
Unlikely 
An AE for which an alternative explanation is more likely, e.g., 
concomitant drug(s) or concomitant disease(s), and/or the 
relationship in time suggests that a causal relationship is unlikely. 
Possible 
An AE, which might be due to the use of the drug.  An alternative 
explanation, e.g., concomitant drug(s) or concomitant disease(s), is 
inconclusive.  The relationship in time is reasonable; therefore, the 
causal relationship cannot be excluded. 
Probable 
An AE, which might be due to the use of the drug.  The relationship 
in time is suggestive, e.g., confirmed by de-challenge.  An 
alternative explanation is less likely, e.g., concomitant drug(s) or 
concomitant disease(s). 
Certain 
An AE, which is listed as a possible adverse reaction and cannot be 
reasonably explained by an alternative explanation, e.g., 
concomitant drug(s) or concomitant disease(s).   
 
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8.1.4 
Severity 
Table 9: Definitions for Adverse Event Severity Gradings 
Grade 
Severity Rating 
Definition 
GRADE 1 
Mild 
Transient or mild discomfort (< 48 hours); no medical 
intervention/therapy required. 
GRADE 2 
Moderate 
Mild to moderate limitation in activity - some assistance 
may be needed; no or minimal medical 
intervention/therapy required. 
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. 
 
See Appendix 2 for full DMID Toxicity Tables. Above ratings should be used to estimate the grade 
for abnormalities NOT found elsewhere in the Toxicity Tables. 
8.2 
Reporting 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and non-
leading verbal questioning of the participant is the preferred method to inquire about AE 
occurrences. 
All AEs will be collected by the Investigator from the time a participant signs the Informed Consent 
Form through to their Week 104 follow-up visit. The exception to this is early withdrawal 
participants who will only have SAEs collected from their time of early withdrawal to their Week 
104 follow-up visit at the timepoints specified in the Synopsis Flow Chart and Procedures 
(Section 1.2) and recorded in the CRF.   
Medical occurrences that begin after obtaining informed consent will be recorded as AEs. If an 
AE started before signing of the informed consent, but is ongoing at trial start, it should be 
recorded as medical history.  If the pre-existing medical occurrence worsens during the trial, an 
AE will be recorded. 
All SAEs will be recorded and reported to the Sponsor or designee within 24 hours of the 
information becoming known to the Investigator, as noted in the SAE reporting guidelines. The 
Investigator will submit any updated SAE data to the Sponsor within 24 hours of information 
becoming known to the Investigator.  
The Sponsor/Investigator/designee will inform Regulatory Authorities and/or EC/IRB of all SAEs 
in accordance with local requirements and ICH guidelines for GCP. 
The Sponsor/designee will forward Safety Notification letters to the Investigator for submission to 
the EC/IRB. 
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Investigators are not obligated to actively seek AE or SAE information in former trial participants. 
However, if the Investigator learns of any SAE, including a death, at any time after a participant 
has been discharged from the trial, and he/she considers the event to be reasonably related to 
the trial IMP or trial participation, the Investigator must promptly notify the Sponsor, EC/IRB and 
regulatory authorities in an expedited basis, in accordance with local requirements and ICH GCP 
Guidelines. 
8.2.1 
Follow up of Adverse Events 
All AEs will be followed until: 
• 
Satisfactory clinical resolution or stabilization; or 
• 
The end of the follow-up period; and  
• 
All queries on these AEs have been resolved.   
Certain long-term AEs cannot be followed until resolution within the setting of this protocol. In 
these cases, follow-up will be the responsibility of the Investigator.  However, this will have to be 
agreed upon with the Sponsor Medical Monitor. 
The Investigator is obligated to perform or arrange for the conduct of supplemental measurements 
and/or evaluations as medically indicated or as requested by Sponsor or representative to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may include 
additional laboratory tests or investigations, histopathological examinations, or consultation with 
other health care professionals.  The Investigator should contact the Sponsor/designee to discuss 
appropriate medical follow-up if consultation is required.  
If a participant dies during participation in the trial or during a recognized follow-up period, the 
Investigator will provide the Sponsor/representative with a copy of any post-mortem findings, 
including histopathology. 
New or updated SAE information will be recorded in the originally completed CRF and submitted 
to the Sponsor within 24 hours of receipt, per the eCRF completion guideline. 
8.2.2 
Clinical Laboratory Adverse Events 
Changes in the results of the clinical laboratory assessment results and which the Investigator 
determines are clinically significant will be reported as AEs.  It is the Investigators’ responsibility 
to review the results of all laboratory tests as they become available.  This review must be 
documented by the Investigators’ dated signature on the laboratory report.  For each abnormal 
laboratory test result, the Investigator needs to ascertain and document if this is a clinically 
significant change from baseline for that individual participant.  This determination, however, does 
not necessarily need to be made the first time an abnormal value is observed.  The Investigator 
may repeat the laboratory test or request additional tests to verify the results of the original 
laboratory tests.  If this laboratory value is determined by the Investigator to be a clinically 
significant change from baseline for that participant, it is considered to be an AE. 
8.2.3 
Disease Symptoms During Trial 
Symptoms of the disease under trial (Tuberculosis) experienced by the participant while on the 
trial will be assessed by the Investigator.  If the symptom has: 
• 
worsened while the participant is in the trial; and  
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• 
the Investigator assesses it as clinically significant; 
it will be recorded as an adverse event. If there is: 
• 
no change; and  
• 
the Investigator assesses the symptom as due to the participant’s TB; and  
• 
not clinically significant; 
it will not be recorded as an AE and this will be noted in the participant’s source documentation. 
All TB related symptoms that meet SAE criteria will be recorded and reported as a SAE. 
8.2.4 
Overdose 
Overdose of the IMP experienced by the participant while on the trial, will be assessed by the 
Investigator to determine whether the overdose led to an adverse event, including if the taking of 
the suspected medicine led to suicidal intention and subsequent overdose of the suspected 
medicine, or other medication. In this case it will be recorded as an adverse event. If it does not 
lead to an adverse event, it will not be recorded as an AE and this will be noted in the participant’s 
source documentation. 
8.2.5 
Drug Interaction 
If the Investigator becomes aware that the participant has experienced a drug interaction which 
has resulted in an adverse event, it will be recorded as an adverse event. 
8.2.6 
Pregnancy 
The Investigator will immediately notify the Sponsor of any pregnancy that is discovered during 
IMP administration or which started during IMP administration.  Pregnancy forms will be 
completed for all pregnancies reported during the clinical trial, as defined below. In addition, the 
Investigator will report to the Sponsor any follow up information regarding the outcome of the 
pregnancy, including perinatal and neonatal outcome.  Infants will be followed-up for 6 months.   
All women of childbearing potential will be instructed to contact the Investigator immediately if 
they suspect they might be pregnant (for example, missed or late menses) at any time during the 
trial. 
If a pregnancy is suspected while the participant is receiving IMP, the IMP will be withheld 
immediately until the result of the pregnancy test is known.  If pregnancy is confirmed, the IMP 
will be permanently discontinued in an appropriate manner, the participant withdrawn from the 
trial and referred to the NTP for further management.  
Protocol-required procedures for trial discontinuation and follow-up will be performed unless 
contraindicated by the pregnancy. 
Pregnancy reporting will follow the same timelines for a SAE (see above). Instructions and 
forms will be provided separately. SAE reporting will also occur if the pregnancy outcome is a 
congenital anomaly.  This will follow the reporting procedures described above for SAE reporting. 
8.3 
Monitoring for Specific Toxicities  
Monitoring for specific toxicities is based upon target organs as defined in the preclinical toxicity 
studies of the Investigator’s Brochures[8, 15] and Package Inserts.[19, 20, 22, 40] 
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AEs still ongoing at the end of the treatment period in the trial will be followed until satisfactory 
clinical resolution or stabilization, or until the end of the follow-up period and until all queries on 
these AEs have been resolved.   
Grade 3 and Grade 4 laboratory abnormalities, and laboratory abnormalities considered clinically 
significant should be followed until satisfactory resolution or stabilization. 
Note: For Grade 3 or 4 laboratory toxicities, participants should have a confirmatory 
measurement within 48 hours, where possible. The recommendations for managing 
participants below assumes that the laboratory abnormalities of concern have been confirmed. 
 
8.3.1 
ALT, AST and Bilirubin Elevations 
The Investigator should refer to the Hepatoxicity Management Guideline, to appropriately monitor 
significant elevations of AST, ALT or Bilirubin. A separate Hepatoxicity Management Guideline 
document has been developed to aid investigators in the management of participants. 
When managing participants with elevated liver enzymes at an Unscheduled visit, the Investigator 
should request additional tests, in addition to the repeat LFT [e.g. Gamma Glutamyl Transferase 
(GGT), screening for Hepatitis A, B, C; to assist in ruling out other causes of a dysfunctional liver 
test (e.g. alcohol induced hepatic cell injury, hepatobiliary disease, hepatic viral infection)]. 
8.3.2 
Lipase 
Grade 3 (> 2.0 to ≤ 5.0 x ULN) or Grade 4 (> 5.0 x ULN): 
• 
Contact the Sponsor Medical Monitor to review. Participants with confirmed Grade 3 or 
4 elevations of lipase, the Investigator should consider pausing the full regimen, pending 
further evaluation. 
8.3.3 
Musculoskeletal System and Cardiac Muscle Myalgia 
Grade 2 (muscle tenderness at a site other than sites of injection and/or venepuncture or with 
moderate impairment of activity) or Grade 3 (severe muscle tenderness with marked impairment 
of activity) or Grade 4 (frank myonecrosis): 
• 
Participants with Grade 2 signs and symptoms should be followed closely. Participants 
with Grade 3 or 4 signs and symptoms should be discussed with the Sponsor Medical 
Monitor to consider pausing trial IMP, pending further evaluation. 
8.3.4 
Cardiac Rhythm Disturbances 
Cardiac rhythm disturbances that are Grade 3 (recurrent, persistent, symptomatic arrhythmia 
requiring treatment) or Grade 4 (unstable dysrhythmia requiring treatment): 
• 
Participants should be monitored closely.  The Investigator should discuss with the 
Sponsor Medical Monitor to consider pausing the full regimen, pending further evaluation. 
QTc prolongation  
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If QTcF is equal to or greater than 500 msec, the ECG should be repeated, and serum electrolytes 
should be evaluated. If the second ECG also has a QTcF of > 500 msec, the Sponsor Medical 
Monitor should be consulted to consider pausing the full regimen, pending further evaluation. 
New left bundle branch block (LBBB) or Mobitz type 2 or complete heart block. Recordings with 
artefacts that interfere with the interpretation of the ECG should be repeated to confirm the 
findings. If the finding is from the centralized ECG machine reading the result is to be checked 
and confirmed by the Investigator.  If this is confirmed by the Investigator, dosing is to be paused 
until the reading has been confirmed by the central cardiologist and the participant is to be treated 
per the Investigator’s clinical judgment. If it is confirmed by the central cardiologist, the participant 
is to be withdrawn from the full regimen.  Contact Sponsor Medical Monitor to review.  
8.4 
Safety Monitoring by Data Monitoring Committee 
A Data Safety Monitoring Committee (DSMC) will be appointed for the trial. The primary 
responsibility of the DSMC will be to act in an advisory capacity to the Sponsor to safeguard the 
interests of trial participants by monitoring participant safety, assess participant risk versus 
benefit, and assess data quality and general evaluation of the trial progress. Its activities will be 
delineated in a DSMC Charter that will define the membership, responsibilities and the scope and 
frequency of data reviews.  
The DSMC will operate on a conflict-free basis independently of the Sponsor and the trial team. 
It will comprise at least 3 voting members that include at least 2 clinicians and one statistician.   
The DSMC may have an organizational meeting prior to commencement of the trial. The DSMC 
will have meetings where it will review unblinded data during a closed session. These meetings 
will be planned at regular intervals.  
The Sponsor or the DSMC may convene ad hoc meetings based on rates of SAEs and/or to 
review results of the futility analysis, or if safety concerns arise during the trial.  After its 
assessment, the DSMC will recommend to the Sponsor continuation, modification or termination 
of the clinical trial.  
 
 
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9.0 
Statistical Analysis 
The statistical analysis plan (SAP), which will contain details of the analyses specified in this 
section, will be written and signed off prior to the interim analysis. 
There will be 3 data analyses and trial reports generated for this trial:  
 
1. When all participants have completed 8 weeks (2 months) of treatment from baseline.  
2. When all participants have completed 52 weeks (12 months) follow-up from start of 
therapy. 
3. When all participants have completed 104 weeks (24 months) follow-up from start of 
therapy.  
9.1 
Analysis Populations 
There will be three main analyses of the primary efficacy endpoint: An intent to treat (ITT) analysis; 
a modified intent to treat (mITT) analysis and a per protocol (PP) analysis: 
• 
The ITT population is defined as all randomized participants excluding late screening 
failures. Late screening failures are participants withdrawn from treatment because they 
were found to be ineligible (late exclusions from the trial), based on data collected prior to 
randomization. 
• 
The mITT population is defined as the ITT population with extra exclusions (described in 
the SAP). 
• 
The PP population is defined as the mITT population with extra exclusions (described in 
the SAP). 
• 
The mITT analysis will be considered primary, with consistent findings required from the 
other main analysis populations to support the primary conclusion. 
9.2 
Sample Size 
For the primary endpoint, time-to-culture conversion at 8 weeks,150 participants per arm (DS-TB 
participants) will provide at more than 90% power (5% 2-sided significance) to detect a hazard 
ratio (HR) of at least 2 assuming 50% of control participants are culture negative by 8 weeks. If 
only 25% of the control arm remain culture positive at 8 weeks, then this sample size will still 
retain more than 90% power to detect a HR of least 2.  This sample size also allows for one 
planned interim analysis of the primary endpoint (See Section 9.4.1) 
For the key secondary endpoint of clinical outcome at 12 months from randomization, 150 patients 
per arm will provide 74% power based on assumptions using data from the largest most recent 
and completed phase 3 TB treatment trial which used the same control arm.[41]  That is, assuming 
16% unfavourable (see Section 9.4.2) in the control arm and 13% unassessable (see Section 9.6) 
at 52 weeks post randomization. A 12% margin of non-inferiority was chosen to preserve at least 
75% of the estimated control arm effect against placebo (estimated to be 54%)[41, 42] which is 
considered an acceptable proportion on which to declare non-inferiority of the test regimen. 
9.3 
Interim Analyses 
There is one planned interim efficacy analysis which will occur after approximately 60 assessable 
participants have been randomised to the control arm and have reached the 8-week primary 
endpoint. Time to culture negative status in liquid media up to 8 weeks will be analysed using a 
Cox regression model, censoring for death and lost to follow up/withdrawal to estimate the hazard 
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ratio (HR). Following a review of these interim findings, the following considerations will be given 
to modify the trial objectives and sample size: 
If the observed HR (time to culture negativity, experimental arm vs. HRZE control arm) is >2, the 
sample size may be increased to adequately power the trial on the key secondary efficacy 
endpoint (clinical and microbiological outcome at 52 weeks from randomization), which will then 
become the primary efficacy endpoint. The trial efficacy objectives will be updated as follows: 
- 
Primary Objective 
To determine the incidence of bacteriologic failure or relapse or clinical failure at 52 weeks 
from the start of treatment / randomisation.  
- 
Secondary Objectives 
To evaluate the time to culture negativity over 8 weeks, from the start of treatment / 
randomisation. 
All other trial objectives will remain unchanged. 
To achieve 90% power and overall 5% 2-sided significance after adjusting for the interim analysis, 
this will mean increasing the sample size to 225 participants per randomised arm, i.e., to a total 
of 450 DS-TB participants (and up to 225 DR-TB participants). This adaptation is based on the 
Multi-arm Multi-stage (MAMS) framework [46, 47, 48] and full details are provided in the Statistical 
Analysis Plan.  
9.4 
Primary and Secondary Efficacy Endpoint Analysis 
9.4.1 
Primary Efficacy Endpoint, Time to Culture Conversion at 8 Weeks 
The primary analysis will be conducted using culture results from liquid culture (MGIT) media. 
Participants will be classified as being culture positive, culture negative, dead or unassessable at 
8 weeks.  The proportion culture negative will be those classified as being culture negative divided 
by the total considered culture negative, culture positive or have died. This proportion will be 
estimated from the Kaplan Meier estimates from the time to culture conversion to negative status 
analysis and groups compared using a hazard ratio and 95% confidence interval. 
Non-inferiority of the key secondary endpoint of clinical outcome will be assessed using the upper 
bound of the one-sided 97.5% confidence interval for the difference between the proportion of 
participants who are classified as having an unfavourable status on the intervention less the 
control regimen.  If the upper bound of the one-sided 97.5% confidence limit for this difference in 
proportions is less than 12% (the margin of inferiority) the intervention will be non-inferior to the 
control arm. 
9.4.2 
Key Secondary Efficacy Endpoint, Clinical Outcome at 52 Weeks from 
Randomization  
For the key secondary endpoint of clinical outcome (bacteriologic failure or relapse or clinical 
failure), participants will be classified as having a favourable, unfavourable or unassessable 
outcome status which will be defined in detail in the SAP.  In general, participants achieving and 
maintaining culture negative status without any additional treatment will be considered favourable; 
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participants who fail on treatment or relapse in follow-up will be considered unfavourable and 
participants who are not assessable (and who have not already been declared as unfavourable) 
will be considered unassessable and excluded from the analysis. 
9.4.3 
Other Secondary Efficacy Endpoints 
The secondary efficacy endpoints and analyses are as follows are: 
• 
Clinical outcome (bacteriologic failure or relapse or clinical failure) at 104 weeks from the 
start of therapy.  
• 
Proportion of participants with sputum culture conversion to negative status in liquid 
culture (MGIT) at 4, 6, 12 and 17 weeks to be explored as a potential biomarker of outcome 
at 52 weeks from start of therapy. 
• 
Change from baseline in weight will be summarised and presented. 
• 
Proportion of participants experiencing a change from baseline in TB symptoms. 
• 
Change from baseline in Patient Reported Health Status will be summarised and 
presented. 
9.5 
Safety and Tolerability Assessments 
The incidence of all-cause mortality will be summarized.  All adverse events will be coded using 
the Medical Dictionary for Regulatory Activities (MedDRA) and will be presented by Preferred 
Term within each MedDRA System Organ Class (SOC).  
Treatment-emergent adverse events (TEAEs) are defined as any AE occurring or worsening with 
an onset date on or after the date of the first dose of the study medication and within 14 days after 
the date of the last dose. Any adverse event that started beyond this timeframe and assessed as 
possibly related to study drug is considered treatment-emergent. The incidence of the following 
events will be summarized for further medical analysis: 
• 
Incidence of TEAEs; 
• 
Incidence of TEAEs by Severity; 
• 
Incidence of TEAEs by DMID toxicity grade; 
• 
Incidence of Drug-Related TEAEs; 
• 
Incidence of Serious TEAEs; 
• 
Incidence of TEAEs Leading to Early Withdrawal; 
• 
Incidence of TEAEs leading to Death. 
9.6 
Pharmacokinetics 
For each analyte and each scheduled sampling time/window, the plasma concentration will be 
summarized by descriptive statistics including the mean, SD, coefficient of variation (CV), median, 
minimum, maximum, geometric mean and geometric CV (%). 
In addition, mean and/or median concentration-versus-time graphs will be provided, with error 
bars and/or scatter plots as appropriate. 
Plasma concentrations from sparse sampling will be used to update existing population PK 
models and derive exposure metrics (e.g., Cmin, Cmax, AUC) for bedaquiline and its M2 metabolite, 
pretomanid, moxifloxacin, and pyrazinamide. Effects of baseline covariates on exposure will be 
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assessed; so, too, will the effects of concomitant medications including ART, as feasible. Data 
from other trials may be included to enhance the model-based analysis.  
Detailed plans for the PopPK analysis will be outlined in a separate modelling plan, and results 
will be reported in separate modelling report. 
9.7 
Pharmacokinetics/Pharmacodynamics 
Relationships will be explored between drug exposure and efficacy and safety endpoints. These 
exploratory PK/PD analyses may include HIV status as a covariate. Planning details and results 
will be included in the separate modelling plan and report. 
 
 
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10.0 Records Management 
10.1 Data Collection 
All relevant CRF/eCRF pages will be completed for each participant who receives any amount of 
IMP, depending on visits attended.  For screening failure participants, specific eCRF pages will 
be completed as described in the eCRF Completion Guidelines. For participants who are 
prematurely withdrawn, all the visits the participant attended including withdrawal and follow-up 
visits need to be completed. 
10.2 Source Documents 
Source documents are defined as all information in original records and certified copies of original 
records of clinical findings, observations, or other activities in a clinical trial necessary for the 
reconstruction and evaluation of the trial.  Source documents will include, but are not limited to, 
progress notes, in-patient hospital records, electronic data, screening logs, and recorded data 
from automated instruments. 
All source documents pertaining to this trial will be maintained by the Investigators.  The 
Investigator 
must 
permit 
trial 
related 
monitoring, 
audits, 
Independent 
Ethics 
Committee/Institutional Review Board (EC/IRB) review and regulatory inspections providing 
authorized personnel direct access to source documents, including documents required to confirm 
inclusion/exclusion and relevant in-patient records while participants are on trial treatment. 
10.3 File Management at the Trial Centre 
It is the responsibility of the Investigators to ensure that the trial centre files are maintained in 
accordance with International Good Clinical Practice Guidelines and the ethical principles that 
have their origin in the Declaration of Helsinki. 
10.4 Records Retention at the Trial Centre 
The Investigator is obliged to retain records and data from the trial for safety reasons and for audit 
and inspection after trial completion.  The essential documents should be retained for not less 
than 2 years after the last approval of a marketing application and until there are no pending or 
contemplated marketing applications or at least 2 years have elapsed since the formal 
discontinuation of clinical development of the IMP.  Investigator should notify the 
Sponsor/designees prior to destroying any records pertaining to the trial. 
 
 
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11.0 Quality Control and Assurance  
11.1 Site Procedures 
The Investigator undertakes to perform the clinical trial in accordance with this protocol, local 
regulations, International GCP, and the ethical principles that have their origin in the Declaration 
of Helsinki. 
The Investigator undertakes to complete the CRFs according to the Sponsor’s requirements, in a 
timely, accurate and legible manner. CRF entries will be verifiable to source documentation other 
than the CRF. 
Site Standard Operating Procedures (SOPs), where available, will be adhered to for all clinical 
and bioanalytical activities relevant to the quality of the trial.  Participant compliance will be 
monitored throughout the trial. 
The Investigator will sign and date any analysis results (e.g., laboratory, ECG, etc.) to verify that 
the results have been reviewed. 
The Investigator may appoint other sub-Investigators to assist with the trial. However, the 
Investigator maintains responsibility for the trial and will supervise the sub-Investigators. Written 
EC/IRB approval of the trial will be obtained prior to involvement in the trial. 
The Investigator will ensure that all site personnel are adequately trained in GCP, local 
regulations, the protocol, IBs/package inserts and all trial procedures and requirements. 
11.2 Monitoring 
The Investigator is responsible for the validity of all data collected at the clinical site and must 
accept the various monitoring procedures employed by the Sponsor.  The purpose of monitoring 
is to verify that the rights and well-being of human participants are protected; that trial data are 
accurate, complete and verifiable with source data; and that the trial is conducted in compliance 
with the protocol, International GCP, the ethical principles that have their origin in the Declaration 
of Helsinki and the applicable regulatory requirements.  
Monitors assigned by the Sponsor will conduct regular site visits before, during and after the trial 
for monitoring various aspects of the trial, and to assure appropriate conduct of the trial in 
accordance with ICH GCP.  Visits will take place usually within a predetermined interval, but this 
may vary during the trial.  The Investigator and site staff will allow the trial monitor and authorized 
representatives of the Sponsor to (1) inspect all CRFs, written informed consent documents and 
corresponding source documents (e.g., original medical records), patient records and laboratory 
raw data, site SOPs, training records, facilities and other trial related systems/processes, and (2) 
access clinical supplies, dispensing and storage areas.  The Investigator and site staff should 
also (1) agree to assist with monitoring activities if requested and (2) provide adequate time and 
space for monitoring visits.  
The monitor will query any missing, confusing, spurious, or otherwise ambiguous data with the 
Investigator.  All queries should be resolved in a timely manner.  A monitoring log will be 
maintained recording each visit, the reason for the visit, the monitor’s signature and Investigator 
or designee’s confirmation signature. 
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11.3 Protocol Deviations 
A protocol deviation is any noncompliance with the clinical trial protocol and GCP requirements. 
The noncompliance may be either on the part of the participant, the Investigator, or the trial site 
staff. Because of deviations, corrective actions are to be developed by the site and implemented 
promptly.  
It is the responsibility of the site to use continuous vigilance to identify and report deviations. All 
deviations must be addressed in trial source documents and reported to Sponsor/designee. 
Protocol deviations must be sent to the local IRB per their guidelines. The site PI/trial staff is 
responsible for knowing and adhering to their IRB requirements. 
11.4 Auditing 
For compliance with International GCP and regulatory agency guidelines, it may be necessary for 
Sponsor-authorized Quality Assurance personnel and/or authorized personnel from an external 
regulatory agency to conduct an audit or inspection of the investigational site.  The purpose of an 
audit is to assess the quality of data about accuracy, adequacy and consistency, and to assure 
that trials are in accordance with the guidelines.  Having the highest quality data from trials is an 
essential aspect of drug development.  
The Investigator and site staff will be given sufficient notice to prepare for such visits, which will 
usually last between one and two days and may be conducted at any stage during the trial.  The 
audit will involve the review of all trial-related documentation required by GCP to be maintained 
by each site; drug storage, dispensing and return; all trial-related supplies; and source documents 
against the CRFs to assure the adequacy and accuracy of the information which has been 
recorded, including the verification of any AEs which have occurred. The auditors or inspectors 
may also review site SOPs, training records, site facilities and other trial related 
systems/processes. 
In the event of the site being notified of a Regulatory Inspection, the Sponsor will help with 
preparation.  It is essential that the Sponsor be notified of the inspection as soon as possible. 
 
 
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12.0 Ethics and Regulatory 
12.1 Basic Principles 
This research will be carried out in accordance with International GCP, the ethical principles that 
have their origin in the Declaration of Helsinki and the applicable regulatory requirements. 
12.2 Independent Ethics Committee/Institutional Review Board (EC/IRB) Review 
The protocol and required trial related documents will be reviewed by the sites respective EC/IRB.  
The trial will not start until the EC/IRB has approved the protocol, written informed consent, any 
written information to be provided to the participant or any modification thereof, plus any other 
trial related documents required for review.  The EC/IRB shall be constituted and shall operate in 
accordance with International GCP, the ethical principles that have their origin in the Declaration 
of Helsinki. The Investigator will maintain an accurate and complete record of all submissions 
made to, and responses from the IRB/EC.  The records should be filed in the Investigator’s Trial 
File, and copies will be sent to the Sponsor. 
12.3 Regulatory Authorities 
The Regulatory Authorities will receive the protocol, amendments, reports on SAEs, and the 
Integrated Clinical Trial Report according to national regulations.  As required by local legislation, 
written approval will be obtained from the Regulatory Authorities prior to commencement of the 
trial and implementation of e.g. amendments as applicable. 
12.4 Informed Consent 
Written informed consent will be obtained from all participants (or legally acceptable 
representative) before any trial-related procedures (including any screening or pre-treatment 
procedures) are performed.  Investigators may discuss the availability of the trial and the 
opportunity for entry with a potential participant without first obtaining consent.  However, informed 
consent must be obtained and documented prior to initiation of any procedures that are performed 
solely for determining eligibility for research, including withdrawal from current medication(s).  
When this is done in anticipation of, or in preparation for, the research, it is part of the research. 
The Investigators have both ethical and legal responsibility to ensure that each participant being 
considered for inclusion in this trial is given a full explanation of the protocol.  Participants must 
be informed that their participation is voluntary.  The Investigator or his/her representative will 
explain the nature of the trial to the participant or his/her legally authorized representative and 
answer all questions regarding the trial. This shall be documented on a written informed consent 
form that shall be approved by the same EC/IRB responsible for approval of this protocol.  Each 
informed consent form shall include the elements required by the international GCP and must 
adhere to the ethical principles that have their origin in the Declaration of Helsinki.  
The trial will be included and updated in the appropriate Country registry and referenced in the 
informed consent forms (ICF). 
Once the appropriate essential information has been provided to the participant and fully 
explained by the Investigators (or qualified designees) and it is felt that the participant 
understands the implications of participating, the EC/IRB approved written ICF will be signed and 
dated by both the participant and the person obtaining consent (Investigators or designees), and 
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by any other parties required by the EC/IRB. Ongoing participants must be re-consented to the 
most current version of the ICF(s) during their participation in the trial. 
The original signed ICFs will be kept with the trial records and a copy of signed ICF will be provided 
to the participant or the participant’s legally authorized representative.  Another copy of the signed 
ICF and a source document identifying the trial and recording the dates of participation will be 
placed in the participant’s medical record. 
The monitor will inspect the original completed ICFs for all participants. 
12.5 Confidentiality 
All site staff, the Sponsor, and any Sponsor representatives will preserve the confidentiality of all 
participants taking part in the trial, in accordance with International GCP, applicable local 
legislation/regulations. Subject to the requirement for source data verification by the trial 
personnel by reference to the participant’s notes, confidentiality of all participant identities will be 
maintained.  Unique identifiers will be used on the CRF and in all trial correspondence, as 
permitted.  No material bearing a participant’s name will be kept on file by the Sponsor. The written 
informed consent will contain a clause granting permission for review of the participants’ source 
data by the Sponsor or designees. 
 
 
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13.0 Publication Policy 
The definition of publication for this purpose is any public presentation of the data emerging from 
this trial.  
All unpublished information given to the Investigator by the Sponsor shall not be published or 
disclosed to a third party, other than to the responsible EC/IRB, within the understanding of the 
confidentiality of their nature, without the prior written consent of the Sponsor. 
Results of this research will be submitted for publication as soon as feasible upon completion of 
the trial in the form of a joint publication(s) between Sponsor and Investigator(s), including site 
clinical and laboratory Investigators, as appropriate. Publication and authorship will be in accord 
with the International Association of Journal Editors.[43]  
Because the trial is funded, in whole or in part, by the Bill and Melinda Gates Foundation (the 
“Foundation”), all peer-reviewed published research relating to the Trial must comply with the 
Foundation’s 
Open 
Access 
Policy 
as 
described 
from 
time 
to 
time 
at 
http://www.gatesfoundation.org/How-We-Work/General-Information/Open-Access-Policy. 
Specifically, (a) all peer-reviewed published research relating to the trial must be submitted for 
publication by TB Alliance through the Chronos Open Access Publishing Service established by 
the Foundation to ensure the immediate and unrestricted access and reuse of all peer-reviewed 
published research funded, in whole or in part, by the Foundation without any embargo period, 
and (b) all data underlying the peer-reviewed published research results must be immediately 
made accessible and open to the public in accordance with the Foundation’s Open Access Policy. 
14.0 Protocol Amendment Policy 
Any change to the protocol will be affected by means of a protocol amendment.  Any changes 
which affect participant safety or welfare will be submitted to the EC/IRB and Regulatory 
Authorities prior to implementation.  The Investigator, EC/IRB, and Sponsor must agree on all 
amendments.  No amendment will be implemented until approved by the relevant authorities 
and/or EC/IRB and signed by all required parties.  Exceptions to this are when the Investigator 
considers that the participant’s safety is compromised.  
Protocol amendments detailing minor administrative changes should be submitted by the 
Investigator to the EC/IRB and Regulatory Authorities, either for notification purposes or approval 
as appropriate. 
15.0 Sponsor, Financial Aspects, Insurance and Indemnity 
The trial Sponsor is the TB Alliance (TBA).  The TB Alliance is a not for profit, product development 
partnership accelerating the discovery and development of new TB drugs that will shorten 
treatment, be effective against susceptible and resistant strains, be compatible with antiretroviral 
therapies for those HIV-TB participants currently on such therapies and improve treatment of 
latent infection. 
The TB Alliance works with public and private partners worldwide.  It is committed to ensuring 
that approved new regimens are affordable, adopted and available to those who need them. 
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The TB Alliance operates with funding mainly from the Bill & Melinda Gates Foundation, the 
Netherlands Ministry of Foreign Affairs (DGIS), the United Kingdom Department for International 
Development (DFID), and the United States Agency for International Development (USAID). 
The participants will not receive any incentives for their involvement in the trial.  The Sponsor has 
made provision to reimburse the participants for out-of-pocket expenses such as travelling to and 
from the trial site and other miscellaneous costs as a result of their trial participation. 
The Sponsor certifies that it has liability insurance coverage for itself and will provide an 
associated certificate upon request.  The insurance does not relieve the Investigators of the 
obligation to maintain their own liability insurance as required by applicable law. The Sponsor 
does not assume any obligation for the medical treatment of other injuries and illnesses.
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16.0 References 
1. 
Maggi N, Pasqualucci CR, Ballotta R, Sensi P. Rifampicin: a new orally active rifamycin. 
Chemotherapy. 1966;11(5):285-292. 
2. 
Jindani A, Aber VR, Edwards EA, Mitchison DA. The early bactericidal activity of drugs in 
patients with pulmonary tuberculosis. Am Rev Respir Dis. 1980;121(6):939-949. 
3. 
Dietze R, Teixeira L, Rocha LM, Palaci M, Johnson JL, Wells C, et al. Safety and 
bactericidal activity of rifalazil in patients with pulmonary tuberculosis. Antimicrob Agents 
Chemother. 2001;45(7):1972-1976. 
4. 
Donald PR, Sirgel FA, Venter A, Parkin DP, Seifart HI, van de Wal BW, et al. Early 
bactericidal activity of antituberculosis agents. Expert Rev Anti Infect Ther. 2003;1(1):141-
155. 
5. 
Johnson JL, Hadad DJ, Boom WH, Daley CL, Peloquin CA, Eisenach KD, et al. Early and 
extended early bactericidal activity of levofloxacin, gatifloxacin and moxifloxacin in 
pulmonary tuberculosis. Int J Tuberc Lung Dis. 2006;10(6):605-612. 
6. 
Rustomjee R, Diacon AH, Allen J, Venter A, Reddy C, Patientia RF, et al. Early bactericidal 
activity and pharmacokinetics of the diarylquinoline TMC207 in treatment of pulmonary 
tuberculosis. Antimicrob Agents Chemother. 2008;52(8):2831-2835. 
7. 
Package insert: Sirturo.  Janssen Therapeutics, September 2014 Available at: 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/204384s000lbl.pdf. 
8. 
Investigator’s Brochure: TMC207 (bedaquiline).  Edition 10. Janssen Research and 
Development, 02 Dec 2016. 
9. 
Koul A, Dendouga N, Vergauwen K, Molenberghs B, Vranckx L, Willebrords R, et al. 
Diarylquinolines target subunit c of mycobacterial ATP synthase. Nat Chem Biol. 
2007;3(6):323-324. 
10. 
Andries K, Verhasselt P, Guillemont J, Gohlmann HW, Neefs JM, Winkler H, et al. A 
diarylquinoline drug active on the ATP synthase of Mycobacterium tuberculosis. Science. 
2005;307(5707):223-227. 
11. 
Huitric E, Verhasselt P, Andries K, Hoffner SE. In vitro antimycobacterial spectrum of a 
diarylquinoline ATP synthase inhibitor. Antimicrob Agents Chemother. 2007;51(11):4202-
4204. 
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12. 
Koul A, Vranckx L, Dendouga N, Balemans W, Van den Wyngaert I, Vergauwen K, et al. 
Diarylquinolines are bactericidal for dormant mycobacteria as a result of disturbed ATP 
homeostasis. J Biol Chem. 2008;283(37):25273-25280. 
13. 
Nuermberger E, Rosenthal I, Tyagi S, Williams KN, Almeida D, Peloquin CA, et al. 
Combination chemotherapy with the nitroimidazopyran PA-824 and first-line drugs in a 
murine model of tuberculosis. Antimicrob Agents Chemother. 2006;50(8):2621-2625. 
14. 
Nuermberger E, Tyagi S, Tasneen R, Williams KN, Almeida D, Rosenthal I, et al. Powerful 
bactericidal and sterilizing activity of a regimen containing PA-824, moxifloxacin, and 
pyrazinamide in a murine model of tuberculosis. Antimicrob Agents Chemother. 
2008;52(4):1522-1524. 
15. 
Investigator's Brochure: Pretomanid (PA-824).  Global Alliance for TB Drug Development, 
22 December 2016. 
16. 
Stover CK, Warrener P, VanDevanter DR, Sherman DR, Arain TM, Langhorne MH, et al. 
A small-molecule nitroimidazopyran drug candidate for the treatment of tuberculosis. 
Nature. 2000;405(6789):962-966. 
17. 
Lenaerts AJ, Gruppo V, Marietta KS, Johnson CM, Driscoll DK, Tompkins NM, et al. 
Preclinical testing of the nitroimidazopyran PA-824 for activity against Mycobacterium 
tuberculosis in a series of in vitro and in vivo models. Antimicrob Agents Chemother. 
2005;49(6):2294-2301. 
18. 
Tyagi S, Nuermberger E, Yoshimatsu T, Williams K, Rosenthal I, Lounis N, et al. 
Bactericidal activity of the nitroimidazopyran PA-824 in a murine model of tuberculosis. 
Antimicrob Agents Chemother. 2005;49(6):2289-2293. 
19. 
Package insert: Moxifloxacin.  MacLeods Pharmaceuticals Ltd., January 2014. 
20. 
Package insert: Pyrazinamide.  MacLeods Pharmaceuticals Ltd., November 2012. 
21. 
Zhang Y, Mitchison D. The curious characteristics of pyrazinamide: a review. Int J Tuberc 
Lung Dis. 2003;7(1):6-21. 
22. 
Package insert: HRZE Combination Tablets.  MacLeods Pharmaceuticals Ltd., September 
2011. 
23. 
World Health Organization. Global tuberculosis report 2012.  2015. WHO Press, Geneva, 
Switzerland. 
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24. 
Pym AS, Diacon AH, Tang S-J, Conradie F, Danilovits M, Chuchottaworn C, et al. 
Bedaquiline safety data in a broad patient population treated for drug-resistant TB 
including XDR-TB (C209 trial). Tuberculosis. 2016;47:394-402. 
25. 
Lee M, Lee J, Carroll MW, Choi H, Min S, Song T, et al. Linezolid for treatment of chronic 
extensively drug-resistant tuberculosis. N Engl J Med. 2012;367(16):1508-1518. 
26. 
A Phase 3 Trial Assessing the Safety and Efficacy of Bedaquiline Plus PA-824 Plus 
Linezolid in Subjects With Drug Resistant Pulmonary Tuberculosis. ClinicalTrials.gov,  
Available at: https://www.clinicaltrials.gov/ct2/show/NCT02333799, Updated 28 February 
2017. 
27. 
Mdluli K, Nuermberger E. Pre-Clinical Drug Combination Trials to Identify Novel Regimens 
for TB.  2009. in Recent Advances in TB Drug Development Symposium. 40th Union World 
Conference, International Union Against TB and Lung Disease. Cancun, Mexico. 
28. 
Tasneen R, Li SY, Peloquin CA, Taylor D, Williams KN, Andries K, et al. Sterilizing activity 
of novel TMC207- and PA-824-containing regimens in a murine model of tuberculosis. 
Antimicrob Agents Chemother. 2011;55(12):5485-5492. 
29. 
Singh R, Manjunatha U, Boshoff HI, Ha YH, Niyomrattanakit P, Ledwidge R, et al. PA-824 
kills nonreplicating Mycobacterium tuberculosis by intracellular NO release. Science. 
2008;322(5906):1392-1395. 
30. 
Manjunatha U, Boshoff HI, Barry CE. The mechanism of action of PA-824: Novel insights 
from transcriptional profiling. Commun Integr Biol. 2009;2(3):215-218. 
31. 
Manjunatha UH, Boshoff H, Dowd CS, Zhang L, Albert TJ, Norton JE, et al. Identification 
of a nitroimidazo-oxazine-specific protein involved in PA-824 resistance in Mycobacterium 
tuberculosis. Proc Natl Acad Sci U S A. 2006;103(2):431-436. 
32. 
Nuermberger E, Tyagi S, Williams KN, Rosenthal I, Bishai WR, Grosset JH. Rifapentine, 
moxifloxacin, or DNA vaccine improves treatment of latent tuberculosis in a mouse model. 
Am J Respir Crit Care Med. 2005;172(11):1452-1456. 
33. 
Tasneen R, Betoudji F, Tyagi S, Li SY, Williams K, Converse PJ, et al. Contribution of 
Oxazolidinones to the Efficacy of Novel Regimens Containing Bedaquiline and 
Pretomanid in a Mouse Model of Tuberculosis. Antimicrob Agents Chemother. 
2015;60(1):270-277. 
34. 
Diacon AH, Dawson R, du Bois J, Narunsky K, Venter A, Donald PR, et al. Phase II dose-
ranging trial of the early bactericidal activity of PA-824. Antimicrob Agents Chemother. 
2012;56(6):3027-3031. 
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35. 
Burman WJ, Goldberg S, Johnson JL, Muzanye G, Engle M, Mosher AW, et al. 
Moxifloxacin versus ethambutol in the first 2 months of treatment for pulmonary 
tuberculosis. Am J Respir Crit Care Med. 2006;174(3):331-338. 
36. 
Rustomjee R, Lienhardt C, Kanyok T, Davies GR, Levin J, Mthiyane T, et al. A Phase II 
trial of the sterilising activities of ofloxacin, gatifloxacin and moxifloxacin in pulmonary 
tuberculosis. Int J Tuberc Lung Dis. 2008;12(2):128-138. 
37. 
Conde MB, Efron A, Loredo C, De Souza GR, Graca NP, Cezar MC, et al. Moxifloxacin 
versus ethambutol in the initial treatment of tuberculosis: a double-blind, randomised, 
controlled phase II trial. Lancet. 2009;373(9670):1183-1189. 
38. 
Dorman SE, Johnson JL, Goldberg S, Muzanye G, Padayatchi N, Bozeman L, et al. 
Substitution of moxifloxacin for isoniazid during intensive phase treatment of pulmonary 
tuberculosis. Am J Respir Crit Care Med. 2009;180(3):273-280. 
39. 
Investigator's Brochure: Bayer HealthCare AG, moxifloxacin.  01 October 2011. 
40. 
Package insert: HR Combination Tablets.  MacLeods Pharmaceuticals Ltd., September 
2011. 
41. 
Gillespie SH, Crook AM, McHugh TD, Mendel CM, Meredith SK, Murray SR, et al. Four-
month moxifloxacin-based regimens for drug-sensitive tuberculosis. N Engl J Med. 
2014;371(17):1577-1587. 
42. 
Tiemersma EW, van der Werf MJ, Borgdorff MW, Williams BG, Nagelkerke NJ. Natural 
history of tuberculosis: duration and fatality of untreated pulmonary tuberculosis in HIV 
negative patients: a systematic review. PLoS One. 2011;6(4):e17601. 
43. 
Recommendations for the Conduct, Reporting, Editing, and Publication of Scholarly work 
in Medical Journals.  Available at: http://www.icmje.org/icmje-recommendations.pdf, 
Updated December 2016. 
44.  
Reuben A (2004). “Hy’s Law”. Landmarks in Hepatology 39(2): 574-578. 
45. 
Temple RJ (2006). “Hy’s Law: predicting serious hepatotoxicity”. Pharmacoepidemoiology 
and Drug Safety 15: 241-243. 
46. 
Parmar, M.K., et al., Testing many treatments within a single protocol over 10 years at 
MRC Clinical Trials Unit at UCL: Multi-arm, multi-stage platform, umbrella and basket 
protocols. Clin Trials, 2017. 14(5): p. 451-461. 
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47. 
Bratton, D.J., P.P. Phillips, and M.K. Parmar, A multi-arm multi-stage clinical trial design 
for binary outcomes with application to tuberculosis. BMC Med Res Methodol, 2013. 13: 
p. 139. 
48. 
Royston, P., et al., Designs for clinical trials with time-to-event outcomes based on 
stopping guidelines for lack of benefit. Trials, 2011. 12: p. 81. 
 
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Appendices 
Appendix 1: The IUATLD Scale 
The IUATLD scale proposes five groups for reporting the results of reading smears for acid fast 
bacilli. They should be recorded as follows: 
FINDING 
RECORDING 
No acid-fast bacilli found in at least 100 fields 
negative 
1 to 9 acid-fast bacilli per 100 fields 
scanty positive 
10 to 99 acid-fast bacilli per 100 fields 
+ 
1 to 10 acid-fast bacilli per field in at least 50 
fields 
++ 
More than 10 acid-fast bacilli per field in at least 
20 fields 
+++ 
Reference: The Public Health Service National Tuberculosis Reference Laboratory and the 
National Laboratory Network. Minimum Requirements, Role and Operation in a Low-Income 
Country. International Union Against Tuberculosis and Lung Disease 1998. 
 
 
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Appendix 2: Division of Microbiology and Infectious Disease (DMID) Toxicity 
Table 
Source:  U.S. National Institute of Allergy and Infectious Diseases, DMID, November 2007 (Draft) 
ABBREVIATIONS:  Abbreviations utilized in the Table: 
ULN = Upper Limit of Normal 
LLN = Lower Limit of Normal 
Rx = Therapy 
Req = Required 
Mod = Moderate 
IV = Intravenous 
ADL = Activities of Daily Living 
Dec = Decreased 
 
ESTIMATING SEVERITY GRADE 
For abnormalities NOT found elsewhere in the Toxicity Tables use the scale below to estimate 
grade of severity: 
Grade 
Severity Rating 
Definition 
GRADE 1 
Mild 
Transient or mild discomfort (< 48 hours); no medical 
intervention/therapy required. 
GRADE 2 
Moderate 
Mild to moderate limitation in activity - some assistance may be 
needed; no or minimal medical intervention/therapy required. 
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. 
 
SERIOUS OR LIFE-THREATENING AEs 
ANY clinical event deemed by the clinician to be serious or life-threatening should be considered 
a grade 4 event. Clinical events considered to be serious or life-threatening include, but are not 
limited to: seizures, coma, tetany, diabetic ketoacidosis, disseminated intravascular coagulation, 
diffuse petechiae, paralysis, acute psychosis, severe depression. 
COMMENTS REGARDING THE USE OF THESE TABLES 
• 
Standardized and commonly used toxicity tables (Division of Acquired Immune Deficiency 
Syndrome (AIDS), NCI’s Common Toxicity Criteria (CTC), and World Health Organization 
(WHO)) have been adapted for use by the DMID and modified to better meet the needs of 
participants in DMID trials. 
• 
For parameters not included in the following Toxicity Tables, sites should refer to the “Guide 
For Estimating Severity Grade” located above. 
• 
Criteria are generally grouped by body system. 
• 
Some protocols may have additional protocol specific grading criteria, which will supersede 
the use of these tables for specified criteria. 
 
 
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HEMATOLOGY 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Hemoglobin 
9.5 - 10.5 gm/dL 
8.0  - 9.4gm/dL 
6.5 - 7.9 gm/dL 
< 6.5 gm/dL 
Absolute Neutrophil 
Count 
1000-1500/mm3 
750-999/mm3 
500-749/mm3 
<500/mm3 
Platelets 
75,000- 
99,999/mm3 
50,000- 
74,999/mm3 
20,000- 
49,999/mm3 
<20,000/mm3 
WBCs 
11,000-13,000/ 
mm3 
13,000-15,000 
/mm3 
15,000- 
30,000/mm3 
>30,000 or <1,000 
/mm3 
% Polymorphonuclear 
Leucocytes + Band 
Cells 
> 80% 
90 – 95% 
>95% 
---------- 
Abnormal Fibrinogen 
Low: 
100-200 
mg/dL High: 
400-600 mg/dL 
Low: 
<100 
mg/dL 
High: 
>600 mg/dL
Low: 
< 50 mg/dL 
---------- 
Fibrinogen 
associated with 
gross bleeding or 
with 
disseminated 
Fibrin Split Product 
20-40 mcg/ml 
41-50 mcg/ml 
51-60 mcg/ml 
> 60 mcg/ml 
Prothrombin Time (PT) 
1.01 - 1.25 x ULN 
1.26-1.5 x ULN 
1.51 -3.0 x ULN 
>3 x ULN 
Activated 
Partial 
Thromboplastin (APPT) 
1.01 -1.66 x ULN 
1.67 - 2.33 x ULN 
2.34 - 3 x ULN 
> 3 x ULN 
Methemoglobin 
5.0 - 9.9 % 
10.0 - 14.9 % 
15.0 - 19.9% 
> 20.0 % 
 
CHEMISTRIES 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Hyponatremia 
130-135 mEq/L 
123-129 mEq/L 
116-122 mEq/L 
< 116 mEq/L or abnormal 
sodium with mental 
status changes or 
Hypernatremia 
146-150 mEq/L 
151-157 mEq/L 
158-165 mEq/L 
> 165 mEq/L or abnormal 
sodium with mental 
status changes or 
Hypokalemia 
3.0 - 3.4 mEq/L 
2.5 - 2.9 mEq/L 
2.0 - 2.4 mEq/L or 
intensive 
replacement 
therapy or 
hospitalization 
required 
< 2.0 mEq/L or abnormal 
potassium with paresis, ileus 
or life-threatening arrhythmia 
Hyperkalemia 
5.6 - 6.0 mEq/L 
6.1 - 6.5 mEq/L 
6.6 - 7.0 mEq/l 
> 7.0 mEq/L or 
abnormal potassium 
with life- threatening 
Hypoglycemia 
55-64 mg/dL 
40-54 mg/dL 
30-39 mg/dL 
<30 mg/dL or abnormal 
glucose with mental status 
changes or coma 
Hyperglycemia 
(non-fasting and no 
prior diabetes) 
116 - 160 mg/dL 
161- 250 mg/dL 
251 - 500 mg/dL 
> 500 mg/dL or abnormal 
glucose with ketoacidosis 
or seizures 
 
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Hypocalcemia 
(corrected for 
albumin) 
8.4 - 7.8 mg/dL 
7.7 - 7.0 mg/dL 
6.9 - 6.1 mg/dL 
< 6.1 mg/dL or abnormal 
calcium with life 
threatening arrhythmia or 
Hypercalcemia 
(correct for albumin) 
10.6 - 11.5 mg/dL 
11.6 - 12.5 
mg/dL 
12.6 - 13.5 mg/dL 
> 13.5 mg/dL or abnormal 
calcium with life 
threatening arrhythmia 
Hypomagnesemia 
1.4 - 1.2 mEq/L 
1.1 - 0.9 mEq/L 
0.8 - 0.6 mEq/L 
< 0.6 mEq/L or 
abnormal magnesium 
with life- threatening 
Hypophosphatemia 
2.0 - 2.4 mg/dL 
1.5 -1.9 mg/dL 
or replacement 
Rx required 
1.0 -1.4 mg/dL 
intensive therapy or 
hospitalization 
required 
< 1.0 mg/dL or 
abnormal phosphate 
with life- threatening 
arrhythmia
Hyperbilirubinemia 
(when accompanied 
by any increase in 
other liver function 
test) 
1.1 - <1.25 x ULN 
1.25 - <1.5 x 
ULN 
1.5 – 1.75 x ULN 
> 1.75 x ULN 
Hyperbilirubinemia 
(when 
other 
liver 
function are in the 
normal range) 
1.1 - <1.5 x ULN 
1.5 - <2.0 x ULN 
2.0 – 3.0 x ULN 
> 3.0 x ULN 
BUN 
1.25 - 2.5 x ULN 
2.6 - 5 x ULN 
5.1 - 10 x ULN 
> 10 x ULN 
Hyperuricemia (uric 
acid) 
7.5 – 10.0 mg/dL 
10.1 – 12.0 
mg/dL 
12.1 – 15.0 mg/dL 
>15.0 mg/dL 
Creatinine 
1.1 - 1.5 x ULN 
1.6 - 3.0 x ULN 
3.1 - 6 x ULN 
> 6 x ULN or dialysis 
required 
 
ENZYMES 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
AST (SGOT) 
1.1 - <2.0 x ULN 
2.0 – <3.0 x ULN 
3.0 – 8.0 x ULN 
> 8 x ULN 
ALT (SGPT) 
1.1 - <2.0 x ULN 
2.0 – <3.0 x ULN 
3.0 – 8.0 x ULN 
> 8 x ULN 
GGT 
1.1 - <2.0 x ULN 
2.0 – <3.0 x ULN 
3.0 – 8.0 x ULN 
> 8 x ULN 
Alkaline Phosphatase 
1.1 - <2.0 x ULN 
2.0 – <3.0 x ULN 
3.0 – 8.0 x ULN 
> 8 x ULN 
Amylase 
1.1 - 1.5 x ULN 
1.6 - 2.0 x ULN 
2.1 - 5.0 x ULN 
> 5.1 x ULN 
Lipase 
1.1 - 1.5 x ULN 
1.6 - 2.0 x ULN 
2.1 - 5.0 x ULN 
> 5.1 x ULN 
 
URINALYSIS 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Proteinuria 
1+ or 200 mg - 1 
gm loss/day 
2-3+ or 1- 2 gm 
loss/day 
4+ or 2-3.5 gm 
loss/day 
nephrotic 
syndrome or > 
3.5 gm loss/day 
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Hematuria 
microscopic only 
<10 rbc/hpf 
gross, no clots >10 
rbc/hpf 
gross, with or 
without clots, 
OR red blood 
cell casts 
obstructive 
or required 
transfusion 
 
CARDIOVASCULAR 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Cardiac Rhythm 
asymptomatic, 
transient signs, no 
Rx required 
recurrent/persistent 
; symptomatic Rx 
required 
unstable 
dysrythmia; 
hospitalization and 
treatment required 
Hypertension 
transient increase 
> 20 mm/Hg; no 
treatment 
recurrent, chronic 
increase 
> 
20mm/Hg. 
/treatment required 
acute 
treatment 
required; 
outpatienttreatm 
ent 
or 
hospitalization 
possible 
end organ damage 
or 
hospitalization 
required 
Hypotension 
transient 
orthostatic 
hypotension with 
heart 
rate 
increased by <20 
beat/min 
or 
decreased by <10 
mm Hg systolic 
BP, No treatment 
required 
symptoms due to 
orthostatic 
hypotension or BP 
decreased by <20 
mm 
Hg 
systolic; 
correctable with oral 
fluid treatment 
requires IV fluids; 
no hospitalization 
required 
mean 
arterial 
pressure <60mm/ 
Hg or end organ 
damage or shock; 
requires 
hospitalization and 
vasopressor 
treatment 
Pericarditis 
minimal effusion 
mild/moderate 
asymptomatic 
effusion, 
no 
treatment 
symptomatic 
effusion; pain; EKG 
changes 
tamponade; 
pericardiocentesis 
or surgery required 
Hemorrhage, 
Blood Loss 
microscopic/occult 
mild, no transfusion 
gross blood loss; 
1-2 
units 
transfused 
massive blood 
loss; > 3 units 
transfused 
 
RESPIRATORY 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Cough 
Transient - no 
treatment 
persistent 
cough; 
treatment responsive 
Paroxysmal 
cough; 
uncontrolled with 
-------------------- 
Bronchospasm, 
Acute 
transient; no 
treatment; 70% 
- 
80% FEV1 of 
peak flow
requires treatment; 
normalizes with 
bronchodilator; 
FEV1 
50% - 70% (of 
no normalization 
with 
bronchodilator;FEV1 
25% - 50% of 
peak flow; or 
cyanosis: FEV1 
< 25% of peak 
flow or 
intubation 
necessary
Dyspnea 
dyspnea on exertion 
dyspnea with normal 
activity 
dyspnea at rest 
dyspnea requiring 
Oxygen therapy 
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GASTROINTESTINAL 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Nausea 
mild or transient; 
maintains 
reasonable intake 
moderate 
discomfort; intake 
decreased 
significantly; some 
activity limited 
no 
significant 
intake; requires IV 
fluids 
hospitalization 
required; 
Vomiting 
1 episode in 24 
hours 
2-5 episodes in 24 
hours 
>6 episodes in 24 
hours or needing 
IV fluids 
physiologic 
consequences 
requiring 
hospitalization 
or 
requiring 
parenteral nutrition 
Constipation 
requiring 
stool 
softener or dietary 
modification 
requiring laxatives 
obstipation 
requiring manual 
evacuation 
or 
enema 
obstruction or toxic 
megacolon 
Diarrhea 
mild or transient; 3- 
4 loose stools/day 
or mild diarrhea 
last < 1 week 
moderate 
or 
persistent; 5-7 loose 
stools/day 
or 
diarrhea lasting >1 
week 
>7 loose stools/day 
or bloody diarrhea; 
or 
orthostatic 
hypotension 
or 
electrolyte 
imbalance or >2L 
IV fluids required 
hypotensive shock 
or 
physiologic 
consequences 
requiring 
hospitalization 
Oral 
Discomfort/Dysphagia 
mild discomfort; no 
difficulty 
swallowing 
some limits on 
eating/drinking 
eating/talking very 
limited; unable to 
swallow solid foods 
unable to drink 
fluids; requires IV 
fluids 
 
NEUROLOGICAL 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Neuro-Cerebellar 
slight 
incoordination 
dysdiadochokinesis 
intention 
tremor, 
dysmetria, slurred 
speech; nystagmus 
locomotor ataxia 
incapacitated 
Psychiatric 
mild anxiety or 
depression 
moderate anxiety or 
depression; therapy 
required; change in 
normal routine 
severe 
mood 
changes requiring 
therapy; or suicidal 
ideation; 
or 
aggressive ideation 
acute 
psychosis 
requiring 
hospitalization;  or 
suicidal 
gesture/attempt or 
hallucinations 
Muscle Strength 
Subjective 
weakness 
no 
objective 
symptoms/ signs 
mild 
objective 
signs/symptoms no 
decrease in function 
objective 
weakness function 
limited 
paralysis 
Paresthesia (burning, 
tingling, etc.) 
mild discomfort; no 
treatment required 
moderate 
discomfort; 
non- 
narcotic analgesia 
required 
severe discomfort; 
or 
narcotic 
analgesia required 
with symptomatic 
improvement 
incapacitating; or 
not responsive to 
narcotic analgesia 
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Neuro-sensory 
mild impairment in 
sensation 
(decreased 
sensation, 
e.g., 
vibratory, pinprick, 
hot/cold in great 
toes) in focal area 
or 
symmetrical 
distribution; 
or 
change in taste, 
smell, vision and/or 
hearing 
moderate 
impairment 
(mod 
decreased 
sensation, 
e.g., 
vibratory, pinprick, 
hot/cold to ankles) 
and/or joint position 
or mild impairment 
that 
is 
not 
symmetrical 
severe impairment 
(decreased or loss 
of 
sensation 
to 
knees or wrists) or 
loss of sensation of 
at 
least 
mod 
degree in multiple 
different 
body 
areas (i.e., upper 
and 
lower 
extremities) 
sensory 
loss 
involves limbs and 
trunk; paralysis; or 
seizures 
 
MUSCULOSKELETAL 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Arthralgia (joint pain) 
mild pain not 
interfering with 
function 
moderate 
pain, 
analgesics 
and/or 
pain interfering with 
function but not with 
activities of daily 
living 
severe pain; pain 
and/or analgesics 
interfering 
with 
activities of daily 
living 
disabling pain 
Arthritis 
mild pain 
with 
inflammation, 
erythema or joint 
swelling – but not 
interfering 
with 
function 
moderate pain with 
inflammation, 
erythema 
or 
joint 
swelling – interfering 
with function, but not 
with 
activities 
of 
daily living 
severe pain with 
inflammation, 
erythema or joint 
swelling 
–and 
interfering 
with 
activities of daily 
living 
permanent and/or 
disabling 
joint 
destruction 
Myalgia 
myalgia with no 
limitation of activity 
muscle tenderness 
(at 
other 
than 
injection site) or with 
moderate 
impairment 
of 
activity 
severe 
muscle 
tenderness 
with 
marked impairment 
of activity 
frank 
myonecrosis 
 
SKIN 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Mucocutaneous 
erythema; pruritus 
diffuse, maculo 
papular rash, dry 
desquamation 
vesiculation or moist 
desquamation 
or 
ulceration 
exfoliative 
dermatitis, mucous 
membrane 
involvement 
or 
erythema, 
multiforme 
or 
suspected Stevens- 
Johnson 
or 
necrosis 
requiring 
surgery 
Induration 
< 15mm 
15-30 mm 
>30mm 
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Erythema 
< 15mm 
15-30 mm 
>30mm 
Edema 
< 15mm 
15-30 mm 
>30mm 
Rash at Injection 
Site 
< 15mm 
15-30 mm 
>30mm 
Pruritus 
slight itching at 
injection site 
moderate itching at 
injection extremity 
itching over entire 
body 
 
SYSTEMIC 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Allergic Reaction 
pruritus without rash 
localized urticaria 
generalized 
urticaria; 
angioedema 
anaphylaxis 
Headache 
mild, no treatment 
required 
transient, moderate; 
treatment required 
severe; responds to 
initial 
narcotic 
therapy 
intractable; requires 
repeated 
narcotic 
therapy 
Fever: oral 
37.7 - 38.5 C or 
100.0 - 101.5 F 
38.6 - 39.5 C or 
101.6 - 102.9 F 
39.6 - 40.5 C or 103 
- 105 F 
> 40 C or > 105 F 
Fatigue 
normal 
activity 
reduced < 48 hours 
normal 
activity 
decreased 25- 50% 
> 48 hours 
normal 
activity 
decreased > 50% 
can’t work 
unable to care for 
self 
 
 
 
 
 
 
 
 
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Appendix 3: Who Clinical Staging of HIV/AIDS for Adults and Adolescents  
Primary HIV Infection 
Asymptomatic 
Acute retroviral syndrome 
Clinical Stage 1 
Asymptomatic 
Persistent generalized lymphadenopathy 
Clinical Stage 2 
Moderate unexplained weight loss (<10% of presumed or measured body weight) 
Recurrent respiratory infections (sinusitis, tonsillitis, otitis media, and pharyngitis) 
Herpes zoster 
Angular cheilitis 
Recurrent oral ulceration 
Papular pruritic eruptions 
Seborrheic dermatitis 
Fungal nail infections 
Clinical Stage 3 
Unexplained severe weight loss (>10% of presumed or measured body weight) 
Unexplained chronic diarrhea for >1 month 
Unexplained persistent fever for >1 month (>37.6ºC, intermittent or constant) 
Persistent oral candidiasis (thrush) 
Oral hairy leukoplakia 
Pulmonary tuberculosis (current) 
Severe presumed bacterial infections (e.g., pneumonia, empyema, pyomyositis, bone 
or joint infection, meningitis, bacteremia) 
Acute necrotizing ulcerative stomatitis, gingivitis, or periodontitis 
Unexplained anemia (hemoglobin <8 g/dL) 
Neutropenia (neutrophils <500 cells/µL) 
Chronic thrombocytopenia (platelets <50,000 cells/µL) 
Clinical Stage 4 
HIV wasting syndrome 
Pneumocystis pneumonia 
Recurrent severe bacterial pneumonia 
Chronic herpes simplex infection (orolabial, genital, or anorectal site for >1 month or 
visceral herpes at any site) 
Esophageal candidiasis (or candidiasis of trachea, bronchi, or lungs) 
Extrapulmonary tuberculosis 
Kaposi sarcoma 
Cytomegalovirus infection (retinitis or infection of other organs) 
Central nervous system toxoplasmosis 
HIV encephalopathy 
Cryptococcosis, extrapulmonary (including meningitis) 
Disseminated nontuberculosis mycobacteria infection 
Progressive multifocal leukoencephalopathy 
Candida of the trachea, bronchi, or lungs 
Chronic cryptosporidiosis (with diarrhea) 
Chronic isosporiasis 
Disseminated mycosis (e.g., histoplasmosis, coccidioidomycosis, penicilliosis) 
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Protocol Number:  NC-008 (B-Pa-M-Z) 
Protocol Version: V4.0 / 30 SEP 2019 
Protocol Name:  
SimpliciTB 
 
 
CONFIDENTIAL 
Page 104 of 106 
Recurrent nontyphoidal Salmonella bacteremia 
Lymphoma (cerebral or B-cell non-Hodgkin) 
Invasive cervical carcinoma 
Atypical disseminated leishmaniasis 
Symptomatic HIV-associated nephropathy 
Symptomatic HIV-associated cardiomyopathy 
Reactivation of American trypanosomiasis (meningoencephalitis or myocarditis) 
 
REF: World Health Organization. WHO Case Definitions of HIV for Surveillance and Revised Clinical Staging and Immunological 
Classification of HIV-Related Disease in Adults and Children; 2007 
Vital Signs 
The following abnormalities will be defined for vital signs: 
Abnormality Code 
Vital Signs Parameter 
 
Pulse 
DBP 
SBP 
RR 
Abnormalities on actual values 
“Abnormally low” 
≤ 50 bpm 
≤ 50 mmHg 
≤ 90 mm Hg 
<12 
Breaths per minute 
“Grade 1 or mild” 
- 
> 
90 
mmHg-
<100 mmHg 
> 140 mmHg-
<160 mmHg 
17-20 
Breaths per minute 
“Grade 2 or moderate” 
- 
≥ 100 mmHg-
<110 mmHg 
≥ 160 mmHg-
<180 mmHg 
21-25 
Breaths per minute 
“Grade 3 or severe” 
- 
≥ 110 mmHg 
≥ 180 mmHg 
>25 
Breaths per minute 
“Abnormally high or Grade 
4” 
≥ 120 bpm 
- 
- 
Intubation 
 
 
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TB Alliance 
Protocol Number:  NC-008 (B-Pa-M-Z) 
Protocol Version: V4.0 / 30 SEP 2019 
Protocol Name:  
SimpliciTB 
 
 
CONFIDENTIAL 
Page 105 of 106 
Appendix 4: Cardiovascular Safety 
CARDIOVASCULAR 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Cardiac 
Rhythm 
 
asymptomatic, 
transient signs, 
no Rx required 
recurrent/persistent; 
symptomatic Rx 
required 
unstable 
dysrythmia; 
hospitalization and 
treatment required 
Hypertension 
transient increase > 
20 mm/Hg; no 
treatment 
recurrent, 
chronic increase 
> 20mm/Hg. 
/treatment 
required 
acute treatment 
required; outpatient 
treatment or 
hospitalization 
possible 
end organ damage 
or hospitalization 
required 
Hypotension 
transient orthostatic 
hypotension with 
heart rate increased 
by <20 beat/min or 
decreased by <10 
mm Hg systolic BP, 
no treatment 
required. 
symptoms due 
to orthostatic 
hypotension or 
BP decreased 
by <20 mm Hg 
systolic; 
correctable with 
oral fluid 
treatment 
requires IV fluids; 
no hospitalization 
required 
mean arterial 
pressure <60mm/ 
Hg or end organ 
damage or shock; 
requires 
hospitalization and 
vasopressor 
treatment 
Pericarditis 
minimal effusion 
mild/moderate 
asymptomatic 
effusion, no 
treatment 
symptomatic 
effusion; pain; EKG 
changes 
tamponade; 
pericardiocentesis 
or surgery required 
Hemorrhage, 
Blood Loss 
microscopic/occult 
mild, no 
transfusion 
gross blood loss; 1-
2 units transfused 
massive blood loss; 
> 3 units transfused 
All-important abnormalities from the ECG readings will be reported. 
The percentage of participants with increases in QTc of <30, 30-60, or > 60 ms from baseline will 
also be tabulated at each time point. 
Abnormality Code 
ECG parameter 
 
HR 
PR 
QRS 
QTcorrected 
Abnormalities on actual values 
“Abnormally low” 
≤ 50 bpm 
NAP 
≤ 50 ms 
- 
“Abnormally high” 
≥ 120 bpm 
≥ 210 ms 
≥ 120 ms 
- 
“]450 ms, 480 ms] 
- 
- 
- 
450 ms < QTc ≤ 480 ms 
“]480 ms, 500 ms] 
- 
- 
- 
480 ms < QTc ≤ 500 ms 
“More than 500 ms 
- 
- 
- 
QTc > 500 ms 
Abnormalities on changes from baseline 
“[30; 60] ms” 
- 
- 
- 
[30; 60] ms 
“> 60 ms” 
- 
- 
- 
> 60 ms 
 
 
 
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Protocol Number:  NC-008 (B-Pa-M-Z) 
Protocol Version: V4.0 / 30 SEP 2019 
Protocol Name:  
SimpliciTB 
 
 
CONFIDENTIAL 
Page 106 of 106 
Appendix 5: Karnofsky Performance Status Scale Definitions Rating (%) Criteria 
Description 
% 
Able to carry on normal activity 
and to work; no special care 
needed. 
Normal no complaints; no evidence of disease. 
100 
Able to carry on normal activity; minor signs or 
symptoms of disease. 
90 
Normal activity with effort; some signs or symptoms 
of disease.  
80 
Unable to work; able to live at 
home 
and 
care 
for 
most 
personal needs; varying amount 
of assistance needed. 
Cares for self; unable to carry on normal activity or 
to do active work. 
70 
Requires occasional assistance, but is able to care 
for most of his personal needs. 
60 
Requires considerable assistance and frequent 
medical care.  
50 
Unable to care for self; requires 
equivalent of institutional or 
hospital care; disease may be 
progressing rapidly. 
Disabled; requires special care and assistance. 
40 
Severely disabled; hospital admission is indicated 
although death not imminent. 
30 
Very sick; hospital admission necessary; active 
supportive treatment necessary. 
20 
Moribund; fatal processes progressing rapidly. 
10 
Dead 
0 
 
Ref: Oxford Textbook of Palliative Medicine, Oxford University Press.  1993; 109. 
 
471 of 852


 
 
TB Alliance 
Protocol Number: NC-008 
Protocol Amendment No.: 3 / 30-Sep-2019 
Protocol Name: SimpliciTB 
Protocol Amendment 
or Administrative Change 
 
TMP-C-SOP01-C V1.0 30-Nov-2018 
CONFIDENTIAL 
This document is proprietary and shall not be reproduced without prior written permission from TB Alliance. 
Trial Number 
Trial Name
NC-008 
SimpliciTB 
X Protocol Amendment Number 3, Dated 30/SEP/2019 
 Protocol Administrative Change Number _ _, Dated _ _/_ _ _/_ _ _ _ 
Summary - Protocol section changed 
Does amendment / 
administrative change 
affect any of the 
elements listed? 
YES
NO
A 
Purpose of trial 
 
X  
B 
Design of trial 
 
X  
C 
Informed consent 
 
X  
D 
Recruitment procedure 
 
X  
E 
Measures of efficacy 
 
X  
F 
Schedule of samples 
 
X  
G 
Addition or deletion of tests or measures 
X 
 
H 
Number of participants 
 
X  
I 
Age range of participants 
 
X  
J 
Inclusion criteria 
 
X  
K 
Exclusion criteria 
 
X  
L 
Safety monitoring 
X 
 
M 
Duration of exposure to the investigational medicinal product(s) 
 
 
N 
Change of posology of the investigational medicinal product(s) 
 
X  
O 
Change of comparator 
 
X  
P 
Statistical analysis 
 
X  
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TB Alliance 
Protocol Number: NC-008 
Protocol Amendment No.: 3 / 30-Sep-2019 
Protocol Name: SimpliciTB 
Protocol Amendment 
or Administrative Change 
 
TMP-C-SOP01-C V1.0 30-Nov-2018 
CONFIDENTIAL 
This document is proprietary and shall not be reproduced without prior written permission from TB Alliance. 
Reasons for Protocol Amendment or Administrative Change: 
1  
Change: 
TB Alliance logo has been changed on page 1, due to updated company logo that was implemented in Jul 2019. 
2  
Clarify:  
Per Memo #3, Slit lamp ophthalmic examination to be performed at Week 17 and 26 for the 4-month treatment arm, and 
 
 
only at  Week 26 for the 6-month treatment arms (Section 1.2, Synopsis Flow Chart and Procedures update, only) to  
 
 
ensure consistency with protocol Section 1.2 Flow Chart and Procedures footnote p. 
3  
Clarify:  
Per Memo #5, ECG to be performed at Week 12 (Section 1.2, Synopsis Flow Chart and Procedures update, only) to ensure 
 
 
consistency with the protocol Section 1.2 Flow Chart and Procedures footnote n, and Section 7.3 Safety and Tolerability 
 
 
Assessments. 
4  
Clarify:  
Per Memo #6, Male Reproductive Hormone testing to be performed at the end of each 4 and 6-month treatment period 
 
 
(Section 1.2, Synopsis Flow Chart and Procedures update, only) in alignment with the protocol intention to perform this 
 
 
assessment at the end of each treatment period. 
5  
Clarify:  
Per Memo #7, Male Reproductive Hormone testing to be performed at the early withdrawal visit (Section 1.2, Synopsis Flow 
 
 
Chart and Procedures update, only), to ensure consistency with the Section 5.4.1 Early Withdrawal. 
6  
Clarify:  
Per Memo #8, pregnancy testing is to be performed on all female participants of childbearing potential.  Females of non- 
 
 
childbearing potential are: Female participant or male participants  female sexual partner  bilateral oophorectomy, bilateral 
 
 
tubal ligation and/or hysterectomy or has been postmenopausal with a history of no menses for at least 12 consecutive 
 
 
months (Inclusion criteria #5.1.7 updated, only), to ensure consistency with the Section 1.2 Synopsis and Flow Chart and 
 
 
Procedures footnote k, Section 5.4.1 Early Withdrawal (urine pregnancy test) and Section 7.1 Demographic and Background 
 
 
Variables and Procedures (urine pregnancy test). 
7  
Change: 
should (changed from 
 
 
 (Section 1.2, Synopsis Flow Chart and Procedures footnote l; Section 7.3 Safety and  
 
 
Tolerability Assessments; Section 8.3.1 ALT, AST and Bilirubin Elevations) to improve safety monitoring and management 
 
 
of participants. 
8  
Add: 
 
Hepatitis A, B and C serology test to be performed at Day 1 (baseline) or where available, the backup PK sample at Day 1 
 
 
(pre-dose) will be used to obtain a hepatitis A, B and C serology result for all participants already enrolled prior to Protocol 
 
 
V4.0, to improve safety monitoring and management of participants (Section 1.2, Synopsis Flow Chart and Procedures 
 
 
footnote l; Section 7.3 Safety and Tolerability Assessments). 
9  
Add: 
 
Where available, the backup PK sample at Day 1 (pre-dose) will be used to obtain a hepatitis A, B and C result for all  
 
 
participants already enrolled prior to Protocol V4.0 , to improve safety monitoring and management of participants (Section 
 
 
1.2, Synopsis Flow Chart and Procedures footnote s). 
10  
Add: 
 
/ or whole genome sequencing (WGS) results on baseline samples become available, any 
 
 
results that are discordant with the screening molecular test results
wording updated, as Phenotypic DST results are 
2 of 12
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TB Alliance 
Protocol Number: NC-008 
Protocol Amendment No.: 3 / 30-Sep-2019 
Protocol Name: SimpliciTB 
Protocol Amendment 
or Administrative Change 
 
TMP-C-SOP01-C V1.0 30-Nov-2018 
CONFIDENTIAL 
This document is proprietary and shall not be reproduced without prior written permission from TB Alliance. 
 
 
more readily available when this review and decision needs to be made, on an ongoing basis (Section 5.1.5  
 
 
 
Inclusion Criteria and 5.4 Treatment Discontinuation and/or Early Withdrawal). 
11  
Change: 
Treatment-emergent adverse events (TEAEs) are defined as any AE occurring or worsening with an onset date on or after 
 
 
the date of the first dose of the study medication and within 14 days after the date of the last dose, changed from 
 
 
the last scheduled visit / assessment / measurement
in Section 9.5 Safety and Tolerability Assessments, to be consistent 
 
 
with the Statistical Analysis Plan (SAP) definition of  TEAEs. 
# 
Section 
Previous Text 
Version 3.0, dated 14-Jan-19 
 
Amended Text 
Version 4.0, dated 30-Sep-19 
Additional text - bold font. Deleted text  strike-
through. 
Reason for 
Change 
Insert 
reason # 
from table 
above 
1 
Page 1, title 
page 
 
 
1 
2 
Section 1.2 
Synopsis Flow 
Chart and 
Procedures 
X-mark present at Week 17 for the 6-month 
treatment arms 
X-mark has been removed from Week 17 for the 
6-month treatment arms, for the Ophthalmic 
examination assessment 
2 
3 
Section 1.2 
Synopsis Flow 
Chart and 
Procedures 
X-mark not present  
X-mark has been included at Week 12, for the 
assessment of the 12-lead ECG 
3 
4 
Section 1.2 
Synopsis Flow 
Chart and 
Procedures 
X-marks present at Week 17 for the 6-month 
treatment arms, and at Week 26 for the 4-month 
treatment arm 
X-mark has been included at Week 17 for the 4-
month and at Week 26 for the 6-month treatment 
arms, for the assessment of the Male Reproductive 
Hormone Tests 
4 
5 
Section 1.2 
Synopsis Flow 
Chart and 
Procedures 
X-mark not present 
X-mark has been included at Early Withdrawal, 
for the assessment of the Male Reproductive 
Hormone Tests  
5 
3 of 12
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TB Alliance 
Protocol Number: NC-008 
Protocol Amendment No.: 3 / 30-Sep-2019 
Protocol Name: SimpliciTB 
Protocol Amendment 
or Administrative Change 
 
TMP-C-SOP01-C V1.0 30-Nov-2018 
CONFIDENTIAL 
This document is proprietary and shall not be reproduced without prior written permission from TB Alliance. 
# 
Section 
Previous Text 
Version 3.0, dated 14-Jan-19 
 
Amended Text 
Version 4.0, dated 30-Sep-19 
Additional text - bold font. Deleted text  strike-
through. 
Reason for 
Change 
Insert 
reason # 
from table 
above 
6 
Inclusion 
Criteria #5.1.7 
a. Participant - not heterosexually active or 
practice sexual abstinence; or 
b. Female participant or male participants female 
sexual partner  bilateral oophorectomy, 
bilateral tubal ligation and/or hysterectomy or 
has been postmenopausal with a history of no 
menses for at least 12 consecutive months; or 
c. Male participant or female participants male 
sexual partner - vasectomised or has had a 
bilateral orchidectomy at least three months 
prior to screening; 
 
a. Participant - not heterosexually active or practice 
sexual abstinence; or 
b. Female participant or male participants female 
sexual partner  bilateral oophorectomy, bilateral 
tubal ligation and/or hysterectomy or has been 
postmenopausal with a history of no menses for 
at least 12 consecutive months; or 
c. Male participant or female participants male 
sexual partner - vasectomised or has had a 
bilateral orchidectomy at least three months prior 
to screening; 
 
6 
7 
Section 1.2, 
Synopsis Flow 
Chart and 
Procedures 
footnote l; 
Section 7.3 
Safety and 
Tolerability 
Assessments; 
Section 8.3.1 
ALT, AST and 
Bilirubin 
Elevations 
When managing participants with elevated liver 
enzymes at an Unscheduled visit, the investigator 
should request additional tests, in addition to the 
repeat LFT [e.g. Gamma Glutamyl Transferase 
(GGT), screening for Hepatitis A, B, C; to assist in 
ruling out other causes of a dysfunctional liver test 
(e.g. alcohol induced hepatic cell injury, 
hepatobiliary disease, hepatic viral infection)]. 
 
When managing participants with elevated liver 
enzymes at an Unscheduled visit, the investigator 
can should request additional tests, in addition to 
the repeat LFT [e.g. Gamma Glutamyl Transferase 
(GGT), screening for Hepatitis A, B, C; to assist in 
ruling out other causes of a dysfunctional liver test 
(e.g. alcohol induced hepatic cell injury, 
hepatobiliary disease, hepatic viral infection)]. 
 
7 
4 of 12
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TB Alliance 
Protocol Number: NC-008 
Protocol Amendment No.: 3 / 30-Sep-2019 
Protocol Name: SimpliciTB 
Protocol Amendment 
or Administrative Change 
 
TMP-C-SOP01-C V1.0 30-Nov-2018 
CONFIDENTIAL 
This document is proprietary and shall not be reproduced without prior written permission from TB Alliance. 
# 
Section 
Previous Text 
Version 3.0, dated 14-Jan-19 
 
Amended Text 
Version 4.0, dated 30-Sep-19 
Additional text - bold font. Deleted text  strike-
through. 
Reason for 
Change 
Insert 
reason # 
from table 
above 
8 
Section 1.2, 
Synopsis Flow 
Chart and 
Procedures 
footnote l; 
Section 7.3 
Safety and 
Tolerability 
Assessments 
No previous text 
Hepatitis A, B and C serology test to be 
performed at Day 1 (baseline) or where available, 
the backup PK sample at Day 1 (pre-dose) will be 
used to obtain a hepatitis A, B and C serology 
result for all participants already enrolled prior 
to Protocol V4.0 
8 
9 
Section 1.2, 
Synopsis Flow 
Chart and 
Procedures 
footnote s 
No previous text 
Where available, the backup PK sample at Day 1 
(pre-dose) will be used to obtain a hepatitis 
serology result for all participants already 
enrolled prior to Protocol V4.0 
9 
10  
Section 5.1.5 
Inclusion 
Criteria and 
5.4 Treatment 
Discontinuatio
n and/or Early 
Withdrawal 
When Phenotypic DST and whole genome 
sequencing (WGS) results on baseline samples 
become available, any results that are discordant 
with the screening molecular test results used to 
reviewed by the Sponsor Medical Monitor in 
consultation with the Investigator to determine 
whether that participant is unlikely to respond to 
treatment and should therefore be removed from 
the trial and given alternative treatment.  If a 
participant is removed from the trial for such a 
reason, they will be classified as a late exclusion. 
When Phenotypic DST and / or whole genome 
sequencing (WGS) results on baseline samples 
become available, any results that are discordant 
with the screening molecular test results used to 
reviewed by the Sponsor Medical Monitor in 
consultation with the Investigator to determine 
whether that participant is unlikely to respond to 
treatment and should therefore be removed from the 
trial and given alternative treatment.  If a participant 
is removed from the trial for such a reason, they will 
be classified as a late exclusion. 
10 
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TB Alliance 
Protocol Number: NC-008 
Protocol Amendment No.: 3 / 30-Sep-2019 
Protocol Name: SimpliciTB 
Protocol Amendment 
or Administrative Change 
TMP-C-SOP01-C V1.0 30-Nov-2018 
CONFIDENTIAL 
This document is proprietary and shall not be reproduced without prior written permission from TB Alliance. 
# 
Section 
Previous Text 
Version 3.0, dated 14-Jan-19 
Amended Text 
Version 4.0, dated 30-Sep-19 
Additional text - bold font. Deleted text  strike-
through. 
Reason for 
Change 
Insert 
reason # 
from table 
above 
11 
Section 9.5 
Safety and 
Tolerability 
Assessments 
Treatment-emergent adverse events (TEAEs) are 
defined as AEs which started at or after the first 
administration of IMP and includes those events 
started prior to the first administration of IMP but 
which worsened after the first intake.  Adverse 
events starting after the last administration of IMP 
until the last scheduled 
visit/assessment/measurement will be regarded as 
treatment-emergent. 
Treatment-emergent adverse events (TEAEs) are 
defined as AEs which started at or after the first 
administration of IMP and includes those events 
started prior to the first administration of IMP but 
which worsened after the first intake.  Adverse 
events starting after the last administration of IMP 
until the last scheduled 
visit/assessment/measurement will be regarded as 
treatment-emergent. any AE occurring or 
worsening with an onset date on or after the date 
of the first dose of the study medication and 
within 14 days after the date of the last dose. 
Any adverse event that started beyond this 
timeframe and assessed as possibly related to 
study drug is considered treatment-emergent 
11 
6 of 12
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TB Alliance 
Protocol Number: NC-008 
Protocol Amendment No.: 3 / 30-Sep-2019 
Protocol Name: SimpliciTB 
Protocol Amendment 
or Administrative Change 
 
TMP-C-SOP01-C V1.0 30-Nov-2018 
CONFIDENTIAL 
This document is proprietary and shall not be reproduced without prior written permission from TB Alliance. 
Sponsor 
I agree to the terms of this Protocol Amendment or Administrative Change. 
Signature of Study Physician 
 
Printed name 
 
Date 
Principal Investigator 
I hereby confirm I have read the above Protocol Amendment or Protocol Administrative Change and agree to conduct this clinical trial as 
outlined in the above. I will provide copies of the Protocol Amendment or Protocol Administrative Change and access to all of the information 
required to conduct the clinical trial according to the above Protocol Amendment or Protocol Administrative Change to the site personnel under 
my supervision. I will discuss this material with them and ensure they are fully informed on all trial requirements.  
Signature of Principal Investigator 
 
Printed name 
 
Date 
7 of 12
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Certificate Of Completion
Envelope Id: DDB90083451842C4B8D597D6B0BC588A
Status: Completed
Subject: Please DocuSign: 2019.09.30 Amendment 3.docx
Source Envelope: 
Document Pages: 7
Signatures: 1
Envelope Originator: 
Certificate Pages: 5
Initials: 0
Leandra Lombard
AutoNav: Enabled
EnvelopeId Stamping: Disabled
Time Zone: (UTC-08:00) Pacific Time (US & Canada)
40 Wall St FL 24
New York, NY  10005
Leandra.Lombard@tballiance.org
IP Address: 102.182.198.156
Record Tracking
Status: Original
             01 October 2019 | 03:11
Holder: Leandra Lombard
             Leandra.Lombard@tballiance.org
Location: DocuSign
Signer Events
Signature
Timestamp
Morounfolu Olugbosi
morounfolu.olugbosi@tballiance.org
Senior Director, Clinical Development
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(Required)
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3DABF6C3-410E-4B8F-85E1-D6E511FA5A5F
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   I approve this document
Sent: 01 October 2019 | 03:12
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Signed: 01 October 2019 | 03:29
Electronic Record and Signature Disclosure: 
      Accepted: 27 September 2017 | 05:45
      ID: 8028570c-617d-4406-b419-ac9d8a5cc392
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17 April 2020 
Memo to: 
Investigators and Site Staff, TB Alliance Project Team, Ethics Committees and Regulatory 
Authorities 
RE: 
SimpliciTB NC-008 (BPaMZ), Protocol Memo #9 
Global Protocol Version 4.0 dated 30 September 2019 and RUS Protocol V3.0 dated 1 October 
2019, Section 9.0 Statistical Analysis:  
To Whom It May Concern: 
This memo serves to clarify that the Week 8 data analysis and trial report referenced in Section 9.0 of the protocol 
Statistical Analysis, will be performed when all participants have completed 52 Weeks (12 Months) of follow-up, from 
the start of therapy.  
Protocol Section 9.0 Statistical Analysis will be revised at the next protocol update, to reflect this information. 
As this data analysis and trial report will be performed when all participants have completed 52 Weeks (12 Months) 
follow-up from start of therapy, it is determined that there is no impact on participant safety or integrity of the study 
data. 
Regards 
Dr Morounfolu Olugbosi, MD MSc 
SimpliciTB Study Physician  
Senior Director, Clinical Development/Head of South Africa Office, TB Alliance 
Cc: 
Trial Master File, Investigator Site Files 
Ethics Committees and Regulatory Authorities (as required) 
Investigator Acknowledgement of Receipt: 
I confirm receipt of this Memo #9 dated 16 April 2020, my understanding thereof and agree to implement it 
accordingly. 
Principal Investigator Name 
Signature 
Date 
1 of 1
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CONFIDENTIAL 
Page 1 of 99 
 
 
 
Protocol Number: 
NC-008 (B-Pa-M-Z) 
Title: 
An Open-Label, Partially Randomized Trial to Evaluate the 
Efficacy, Safety and Tolerability of a 4-month Treatment of 
Bedaquiline 
plus 
Pretomanid 
plus 
Moxifloxacin 
plus 
Pyrazinamide (BPaMZ) Compared to a 6-month Treatment of 
HRZE/HR (Control) in Adult Participants with Drug-Sensitive 
Smear-Positive Pulmonary Tuberculosis (DS-TB) and a 6-month 
Treatment of BPaMZ in Adult Participants with Drug Resistant, 
Smear-Positive Pulmonary Tuberculosis (DR-TB). 
Drug(s)/Combination(s): 
Bedaquiline tablets (B), pretomanid tablets (Pa), moxifloxacin 
tablets (M), pyrazinamide tablets (Z), HRZE tablets [isoniazid 
(H), rifampicin (R), pyrazinamide (Z) and ethambutol (E)] and HR 
tablets [isoniazid (H) plus rifampicin (R) combination tablets] 
Protocol Version/Date: 
 
Russia V1.0 / 10 July 2018, Incorporating Protocol V2.0 / 21 
February 2018 
Protocol Name: 
SimpliciTB 
 
 
 
 
 
485 of 852


Global Alliance for TB Drug Development
Protocol Number: NC-008 (B-Pa-M-Z)
Protocol Version:
Russia V1.0 / 10 Jul 2018, Incorporating Protocol V2.0 / 21 Feb 2018
Protocol Name:
SimpliciTB
Confidential
Page 2 of 99
PROTOCOL SIGNATURE PAGE
Protocol Title:  An Open-Label, Partially Randomized Trial to Evaluate the Efficacy, 
Safety and Tolerability of a 4-month Treatment of Bedaquiline plus Pretomanid plus 
Moxifloxacin plus Pyrazinamide (BPaMZ) Compared to a 6-month Treatment of 
HRZE/HR (Control) in Adult Participants
with Drug-Sensitive Smear-Positive 
Pulmonary Tuberculosis (DS-TB) and a 6-month Treatment of BPaMZ in Adult 
Participants with Drug Resistant, Smear-Positive Pulmonary Tuberculosis (DR-TB).
Protocol Number: 
NC-008 (B-Pa-M-Z)
Protocol Date:
Russia V1.0 / 10 July 2018, Incorporating Protocol V2.0 / 21 
February 2018
Protocol Name:
SimpliciTB
SPONSOR:
Global Alliance for TB Drug Development
I agree to the terms of this trial protocol.
Morounfolu Olugbosi, MD MSc
Signature of Study Physician
Printed Name
40 Wall Street, 24th Floor
New York, NY 10005
Phone +27 87 700 3900 / +27 79 045 4917
E-mail: morounfolu.olugbosi@tballiance.org
Date
LEAD INVESTIGATOR
I agree to the terms of this trial protocol. I will conduct the trial according to the procedures 
specified herein and in accordance to the principles of Good Clinical Practice (GCP) and 
local regulations.
Signature 
Printed Name
Date
486 of 852


Global Alliance for TB Drug Development 
Protocol Number: NC-008 (B-Pa-M-Z) 
Protocol Version: Russia V1.0 / 10 Jul 2018, Incorporating Protocol V2.0 / 21 Feb 2018 
Protocol Name: 
SimpliciTB 
Confidential 
Page 3 of 99 
 
PRINCIPAL INVESTIGATOR PROTOCOL SIGNATURE PAGE 
 
An Open-Label, Partially Randomized Trial to Evaluate the Efficacy, Safety and 
Tolerability of a 4-month Treatment of Bedaquiline plus Pretomanid plus Moxifloxacin 
plus Pyrazinamide (BPaMZ) Compared to a 6-month Treatment of HRZE/HR (Control) in 
Adult Participants with Drug-Sensitive Smear-Positive Pulmonary Tuberculosis 
(DS-TB) and a 6-month Treatment of BPaMZ in Adult Participants with Drug Resistant, 
Smear-Positive Pulmonary Tuberculosis (DR-TB). 
Protocol Number:  
NC-008 (B-Pa-M-Z) 
Protocol Date:  
Russia V1.0 / 10 July 2018, Incorporating Protocol V2.0 / 21 
 
February 2018 
Protocol Name:  
SimpliciTB 
 
I hereby confirm that I have read the above protocol and agree to conduct this clinical trial as 
outlined in the above protocol. I will provide copies of the protocol and access to all the 
information required to conduct the clinical trial according to the above protocol to the site 
personnel under my supervision. I will discuss this material with them and ensure they are fully 
informed on all trial requirements. 
 
 
 
 
 
Signature 
 
Printed Name 
 
 
 
Date 
 
 
 
 
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Protocol Name: 
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Confidential 
Page 4 of 99 
TABLE OF CONTENTS .................................................................................................. Page 
1.0 
Synopsis .................................................................................................................... 10 
1.1 
Synopsis Summary ................................................................................................ 10 
1.2 
Synopsis Flow Chart and Procedures .................................................................... 16 
2.0 
Introduction and Rationale ......................................................................................... 21 
2.1 
Tuberculosis Disease ............................................................................................. 21 
2.2 
Tuberculosis Clinical Research .............................................................................. 21 
2.3 
Trial Rationale ........................................................................................................ 23 
2.3.1 
Trial Design Rationale ...................................................................................................................... 23 
2.3.2 
Trial Drug Regimen Rationale .......................................................................................................... 24 
2.4 
Agents used within SimpliciTB ............................................................................... 24 
2.5 
Background of Agents to be Studied in SimpliciTB................................................. 27 
2.5.1 
Bedaquiline (B) ................................................................................................................................. 27 
2.5.2 
Pretomanid (P) ................................................................................................................................. 33 
2.5.3 
Moxifloxacin (M) .............................................................................................................................. 39 
2.5.4 
Pyrazinamide (Z) .............................................................................................................................. 41 
2.6 
Overall Benefit/Risk Assessment ........................................................................... 42 
2.6.1 
Bedaquiline (B) ................................................................................................................................. 42 
2.6.2 
Pretomanid (P) ................................................................................................................................. 43 
2.6.3 
Moxifloxacin (M) .............................................................................................................................. 44 
2.6.4 
Pyrazinamide (Z) .............................................................................................................................. 44 
2.6.5 
HRZE/HR Control .............................................................................................................................. 44 
3.0 
Trial Objectives .......................................................................................................... 44 
3.1 
Primary Objectives ................................................................................................. 44 
3.2 
Secondary Objectives ............................................................................................ 45 
3.3 
Exploratory Objectives ........................................................................................... 45 
4.0 
Trial Design ............................................................................................................... 46 
4.1 
Summary of Trial Design........................................................................................ 46 
4.2 
Treatment Plan: Schedule of Assessments ............................................................ 46 
5.0 
Trial Population ......................................................................................................... 47 
5.1 
Inclusion Criteria .................................................................................................... 47 
5.2 
Exclusion Criteria ................................................................................................... 49 
5.3 
Restrictions ............................................................................................................ 52 
5.4 
Treatment Discontinuation and/or Early Withdrawal ............................................... 53 
5.4.1 
Early Withdrawal ............................................................................................................................. 54 
5.4.2 
Unscheduled Visits ........................................................................................................................... 55 
5.4.3 
Lost-to-Follow-up ............................................................................................................................. 56 
5.4.4 
Early Withdrawal due to TB ............................................................................................................. 56 
5.5 
Participant Progress Definitions ............................................................................. 56 
5.6 
Trial Stopping Rules ............................................................................................... 57 
6.0 
Treatment .................................................................................................................. 57 
6.1 
IMP Administration ................................................................................................. 57 
6.1.1 
Instructions for Dosing of Test Regimen (BPaMZ): .......................................................................... 57 
6.1.2 
Instructions for Dosing Control Treatment Regimen (HRZE/HR): .................................................... 57 
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Protocol Name: 
SimpliciTB 
Confidential 
Page 5 of 99 
6.2 
Participant Compliance .......................................................................................... 58 
6.3 
Treatment Modification(s) ...................................................................................... 58 
6.4 
IMP Packaging and Labelling ................................................................................. 58 
6.5 
Blinding and Procedures for Breaking the Blind ..................................................... 59 
6.6 
Handling, Storage and Accountability..................................................................... 59 
7.0 
Trial Variables and Procedures ................................................................................. 60 
7.1 
Demographic and Background Variables and Procedures ..................................... 60 
7.2 
Efficacy Variables and Procedures ........................................................................ 61 
7.3 
Safety and Tolerability Assessments ..................................................................... 62 
7.4 
PK Variables and Procedures ................................................................................ 63 
7.5 
Mycobacteriology Characterization Variable and Procedures ................................ 63 
8.0 
Adverse Events ......................................................................................................... 64 
8.1 
Definitions .............................................................................................................. 64 
8.1.1 
Adverse Event (AE) ........................................................................................................................... 64 
8.1.2 
Serious Adverse Event (SAE) ............................................................................................................. 64 
8.1.3 
Attribution/Causality ....................................................................................................................... 65 
8.1.4 
Severity ............................................................................................................................................ 66 
8.2 
Reporting ............................................................................................................... 66 
8.2.1 
Follow up of Adverse Events ............................................................................................................ 67 
8.2.2 
Clinical Laboratory Adverse Events .................................................................................................. 67 
8.2.3 
Disease Symptoms During Trial ....................................................................................................... 68 
8.2.4 
Overdose .......................................................................................................................................... 68 
8.2.5 
Drug Interaction ............................................................................................................................... 68 
8.2.6 
Pregnancy ........................................................................................................................................ 68 
8.3 
Monitoring for Specific Toxicities ............................................................................ 69 
8.3.1 
ALT, AST and Bilirubin Elevations ..................................................................................................... 69 
8.3.2 
Lipase ............................................................................................................................................... 69 
8.3.3 
Neurological ..................................................................................................................................... 69 
8.3.4 
Musculoskeletal System and Cardiac Muscle Myalgia .................................................................... 70 
8.3.5 
Cardiac Rhythm Disturbances .......................................................................................................... 70 
8.4 
Safety Monitoring by Data Monitoring Committee .................................................. 70 
9.0 
Statistical Analysis ..................................................................................................... 71 
9.1 
Analysis Populations .............................................................................................. 71 
9.2 
Sample Size........................................................................................................... 71 
9.3 
Interim Analyses .................................................................................................... 71 
9.4 
Primary and Secondary Efficacy Endpoint Analysis ............................................... 71 
9.4.1 
Primary Efficacy Endpoint, Time to Culture Conversion at 8 Weeks ................................................ 71 
9.4.2 
Key Secondary Efficacy Endpoint, Clinical Outcome at 52 Weeks from Randomization .................. 72 
9.4.3 
Other Secondary Efficacy Endpoints ................................................................................................ 72 
9.5 
Safety and Tolerability Assessments ..................................................................... 72 
9.6 
Pharmacokinetics................................................................................................... 73 
9.7 
Pharmacokinetics/Pharmacodynamics ................................................................... 73 
10.0 
Records Management ............................................................................................... 73 
10.1 
Data Collection ...................................................................................................... 73 
10.2 
Source Documents ................................................................................................ 73 
10.3 
File Management at the Trial Centre ...................................................................... 74 
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Global Alliance for TB Drug Development 
Protocol Number: NC-008 (B-Pa-M-Z) 
Protocol Version: Russia V1.0 / 10 Jul 2018, Incorporating Protocol V2.0 / 21 Feb 2018 
Protocol Name: 
SimpliciTB 
Confidential 
Page 6 of 99 
10.4 
Records Retention at the Trial Centre .................................................................... 74 
11.0 
Quality Control and Assurance .................................................................................. 74 
11.1 
Site Procedures ..................................................................................................... 74 
11.2 
Monitoring .............................................................................................................. 74 
11.3 
Protocol Deviations ................................................................................................ 75 
11.4 
Auditing .................................................................................................................. 75 
12.0 
Ethics and Regulatory ............................................................................................... 76 
12.1 
Basic Principles ..................................................................................................... 76 
12.2 
Independent Ethics Committee/Institutional Review Board (EC/IRB) Review ......... 76 
12.3 
Regulatory Authorities ............................................................................................ 76 
12.4 
Informed Consent .................................................................................................. 76 
12.5 
Confidentiality ........................................................................................................ 77 
13.0 
Publication Policy ...................................................................................................... 77 
14.0 
Protocol Amendment Policy ....................................................................................... 78 
15.0 
Sponsor, Financial Aspects, Insurance and Indemnity ............................................... 78 
16.0 
References ................................................................................................................ 79 
Appendices .......................................................................................................................... 83 
 
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Protocol Version: Russia V1.0 / 10 Jul 2018, Incorporating Protocol V2.0 / 21 Feb 2018 
Protocol Name: 
SimpliciTB 
Confidential 
Page 7 of 99 
List of Tables 
Table 1.  Bedaquiline Adverse Drug Reactions .................................................................... 31 
Table 2.  Key findings of Pretomanid in Safety and Toxicity Trials........................................ 35 
Table 3.  Summary of Phase 2b trials in which moxifloxacin were administered as part of a 
four-drug regimen during the intensive phase of treatment (total treatment duration: 2 months)
 ............................................................................................................................................ 40 
Table 4: Treatment Groups .................................................................................................. 47 
Table 5: Follow-up Visits Required for Early Withdrawal Participants ................................... 54 
Table 6: Adverse Events Attribution/Causality Ratings ......................................................... 66 
Table 7: Definitions for Adverse Event Severity Gradings .................................................... 66 
 
List of Figures 
Figure 1.  Unified Drug Sensitive/Drug Resistant Regimen Development Path .................... 22 
Figure 2.  Log10 CFU Counts in Lungs ................................................................................ 34 
Figure 3.  Mean log Colony Forming Unit Values over Time Trial CL-010 ............................ 37 
 
List of Appendices 
Appendix 1: The IUATLD Scale ........................................................................................... 83 
Appendix 2: Division of Microbiology and Infectious Disease (DMID) Toxicity Table ............ 84 
Appendix 3: Who Clinical Staging of HIV/AIDS for Adults and Adolescents ......................... 91 
Appendix 4: Cardiovascular Safety ...................................................................................... 93 
Appendix 5: Karnofsky Performance Status Scale Definitions Rating (%) Criteria ................ 94 
Appendix 6: Tuberculosis Symptoms Profile ........................................................................ 95 
Appendix 7: Patient Reported Health Status Questionnaire ................................................. 96 
 
 
 
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Protocol Name: 
SimpliciTB 
Confidential 
Page 8 of 99 
Abbreviations and Definition of Terms 
3TC 
Lamivudine 
ABC 
Abacavir 
AE  
Adverse Event  
AFB 
Acid-fast bacilli 
AIDS 
Acquired Immune Deficiency Syndrome 
ALP 
Alkaline Phosphatase 
ALT 
Alanine aminotransferase 
AREDS2 
Age Related Eye Disease Scale 2 
ART 
Anti-Retroviral Therapy 
AST 
Aspartate aminotransferase 
AUCτ 
Area Under Curve over a dosing interval 
B 
Bedaquiline 
BA 
Bacterial activity 
BMI 
Body Mass Index 
BPaMZ 
Combination of bedaquiline plus pretomanid plus moxifloxacin plus 
pyrazinamide 
C 
Clofazimine 
CFU 
Colony Forming Units 
C(max), (min) 
plasma Concentration (maximum), (minimum) 
CO2 
Carbon dioxide 
CPK 
Creatine Phosphokinase 
CYP3A4 
Cytochrome P450 3A4 
DMID 
Division of Microbiology and Infection Disease 
DNA 
Deoxyribonucleic Acid 
DR-TB 
Drug-resistant tuberculosis 
For this particular protocol defined as TB participants with  
1. mono-resistance to rifampicin or isoniazid, OR 
2. resistance to both rifampicin and isoniazid (MDR-TB) 
(participants with fluoroquinolone resistance are excluded) 
DS-TB 
Drug-sensitive tuberculosis 
DSMC 
Data Safety and Monitoring Committee 
E 
Ethambutol 
EBA 
Early Bactericidal Activity 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
EFV 
Efavirenz 
(e)CRF 
(electronic) Case Report Form 
EMS 
Early Morning Sputum 
EWD 
Early Withdrawal 
FTC 
Emtricitabine 
FSH 
Follicle-stimulating hormone 
GCP  
Good Clinical Practice 
GMR 
Geometric Mean Ratio 
H 
Isoniazid 
hERG 
Human Ether-à-go-go Related Gene 
HIV  
Human Immunodeficiency Virus 
HRZE 
Isoniazid, Rifampicin, Pyrazinamide, Ethambutol 
HR 
Isoniazid plus rifampicin combination tablet 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
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Protocol Name: 
SimpliciTB 
Confidential 
Page 9 of 99 
IMP 
Investigational Medicinal Product 
IRB 
Institutional Review Board 
ITT 
Intent to Treat 
IUATLD 
International Union Against Tuberculosis and Lung Disease 
IWRS 
Interactive Web Randomization System 
kg 
Kilogram 
L 
Linezolid 
LH 
Luteinizing hormone 
LLN 
Lower Limit of Normal 
LPV 
Lopinavir 
LTFU 
Long term follow-up  
M 
Moxifloxacin 
MBD 
Minimum Bactericidal Dose 
MIC 
Minimum Inhibitory Concentration 
MTB 
Mycobacterium tuberculosis 
MDR-TB 
Multi Drug Resistant Tuberculosis 
MGIT 
Mycobacterial Growth Inhibiting Tube 
mITT 
Modified Intent to Treat 
ms 
millisecond 
NVP 
Nevirapine 
NO 
Nitric Oxide 
NOAEL 
No Observed Adverse Effect Level 
NRTI 
(Triple) Nucleosidase Reverse Transcriptase Inhibitor 
Pa 
Pretomanid 
PD 
Pharmacodynamic 
PP 
Per Protocol 
PK 
Pharmacokinetic 
PR 
PR interval 
R 
Rifampicin 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SSCC 
Serial sputum colony counting 
TB 
Tuberculosis 
TDF 
Tenofovir 
TEAE 
Treatment Emergent Adverse Events 
TTP 
Time to Positivity  
ULN 
Upper Limit of Normal 
WHO 
World Health Organization 
XDR-TB 
Extensively Drug Resistant Tuberculosis 
μg(/ml) 
micrograms (per millilitre) 
Z 
Pyrazinamide (tablets) 
 
 
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Protocol Name: 
SimpliciTB 
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Page 10 of 99 
1.0 
Synopsis 
1.1 
Synopsis Summary 
Synopsis 
Description  
Name of 
Sponsor/Company 
Global Alliance for TB Drug Development 
Name of Finished 
Products 
Bedaquiline tablets (B), pretomanid tablets (Pa), moxifloxacin 
tablets (M), pyrazinamide tablets (Z), HRZE tablets [isoniazid (H), 
rifampicin (R), pyrazinamide (Z) and ethambutol (E)] and HR 
tablets [isoniazid (H) plus rifampicin (R) combination tablets] 
Protocol Number/Title 
NC-008 / (B-Pa-M-Z)/ An Open-Label, Partially Randomized Trial 
to Evaluate the Efficacy, Safety and Tolerability of a 4-month 
Treatment of Bedaquiline plus Pretomanid plus Moxifloxacin plus 
Pyrazinamide (BPaMZ) Compared to a 6-month Treatment of 
HRZE/HR (Control) in Adult Participants with Drug-Sensitive 
Smear-Positive Pulmonary Tuberculosis (DS-TB) and a 6-month 
Treatment of BPaMZ in Adult Participants with Drug Resistant, 
Smear-Positive Pulmonary Tuberculosis (DR-TB) 
Treatment Indication 
Pulmonary Tuberculosis (TB) 
Trial Objective(s) 
To evaluate the efficacy, safety and tolerability at 8 weeks (2-
months), 52 weeks (12-months), and 104 Weeks (24-months) 
post the start of the following treatment regimens in participants 
with: 
 
Drug Sensitive TB (DS-TB) 
– 
BPaMZ given for 17 Weeks (4 months), or 
– 
Standard HRZE/HR treatment given for 26 weeks (6 
 
months) 
 
Drug Resistant TB (DR-TB)  
– 
BPaMZ given for 26 Weeks (6 months) 
 
DR-TB Defined as participants with  
1. mono-resistance to rifampicin or isoniazid, OR 
2. resistance to both rifampicin and isoniazid (MDR-TB) 
Trial Design 
Phase 2c multi-centre, open-label, partially randomized clinical 
trial in DS-TB and DR-TB participants.  
 
All participants will enter post-treatment follow-up which continues 
until Week 104 (24 months) after start of treatment / 
randomisation. 
 
Participants with Drug Sensitive TB (DS-TB): 
 
Participants with DS-TB will be randomized to one of two 
treatment arms. These participants will receive either BPaMZ daily 
for 17 weeks (4 months), or HRZE/HR tablets daily for 26 weeks 
(6 months). Participants will be stratified for co-infection with 
human immunodeficiency virus (HIV) and cavitation. 
 
Participants with Drug Resistant TB (DR-TB): 
 
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Protocol Name: 
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Page 11 of 99 
Synopsis 
Description  
Participants with DR-TB will be assigned to receive BPaMZ daily 
for 26 weeks (6 months). 
Patient Population 
A total of up to 450 male and female participants, diagnosed with 
DS-TB or DR-TB, aged 18 years and over with a target of up to 
50% being HIV positive. 
 
300 DS-TB participants (150 per treatment arm) will be 
randomized and stratified for co-infection with HIV and cavitation. 
 
Up to 150 DR-TB participants will be enrolled. 
Test product, Dose and 
Mode of Administration 
The Test Treatment Regimen (BPaMZ) consists of a combination 
of the following products and will be supplied as: 
 
Product 
Tablet Strength 
Abbreviation  
Bedaquiline 
100 mg  
(B) 
Pretomanid 
200 mg  
(Pa) 
Moxifloxacin 
400 mg 
(M) 
Pyrazinamide 
500 mg 
(Z) 
 
Instructions for Dosing of Test Regimen (BPaMZ):  
Treatment will be administered orally once daily, to be taken 
during breakfast, with a full glass of water (approximately 240 ml), 
for 17 weeks (4 months) or 26 weeks (6 months) in the following 
dosing schemes: 
 
Participants with Drug Sensitive TB: (DS-TB) 
Bedaquiline 200 mg daily for 8 weeks then 100 mg daily for 9 
weeks, together with pretomanid 200 mg + moxifloxacin 400 mg + 
pyrazinamide 1500 mg daily for 17 weeks (Total treatment 
duration 4 months)  
 
OR 
 
Participants with Drug Resistant TB: (DR-TB) 
Bedaquiline 200 mg daily for 8 weeks then 100 mg daily for 18 
weeks, together with pretomanid 200 mg + moxifloxacin 400 mg + 
pyrazinamide 1500 mg daily for 26 weeks (Total treatment 
duration 6 months) 
Positive Control 
Product, Dose and 
Mode of Administration 
The Control Treatment Regimen (HRZE/HR) will be supplied as:  
 
HRZE Tablets: (isoniazid 75 mg plus rifampicin 150 mg plus 
pyrazinamide 400 mg plus ethambutol 275 mg combination 
tablets). This combination will be given for the first 8 weeks. 
 
AND 
 
HR Tablets: (isoniazid 75 mg plus rifampicin 150 mg combination 
tablets). This combination will be given from Weeks 9 to 26. 
 
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Protocol Name: 
SimpliciTB 
Confidential 
Page 12 of 99 
Synopsis 
Description  
Instructions 
for 
Dosing 
Control 
Treatment 
Regimen 
(HRZE/HR): 
 
To be taken with a glass of water (approximately 240 ml).  HRZE 
or HR should not be taken with a meal (generally, no closer to 
meals than 1 hour before or 2 hours after a meal) in the following 
dosing schemes: 
 
Treatment will be administered orally once daily to the HRZE/HR 
randomized DS-TB participants as follows: 
 
 
Weeks 1-26: HRZE/HR tablets daily dose per the 
 
participant’s weight as follows:  
 
 
Weight Band 
Weight Range 
Number of 
tablets  
1 
30-39 kg 
2 
2 
40-54 kg 
3 
3 
55-70 kg 
4 
4 
≥ 71 kg 
5 
 
Vitamin B6 daily supplement to be taken with the HRZE/HR 
treatment, per each country’s TB Treatment Guidelines.  
Treatment 
Interruptions/Pauses 
For All Trial Regimens:  
The trial treatment regimens may require interruptions/pauses due 
to toxicities. All dose interruptions/pauses should be discussed 
with the Sponsor’s Medical monitor prior to implementation, unless 
an interruption/pause is required urgently for a safety concern.   
Action required for participants missing the following number of 
doses within the trial treatment regimens:  
• 
Up to 7 consecutive doses: restart treatment, no extension 
of treatment required 
• 
Greater than 7 and to ≤ 35 consecutive doses: restart 
treatment, extend the treatment by the number of 
consecutive doses missed, before the end of the treatment 
period (week 17/26). In this case, the last visit of the 
treatment period should also be pushed out to the date of 
the last dose 
• 
Greater than 35 consecutive doses: discontinue treatment 
and withdraw participant from the trial  
• 
If the participant misses a total (sum of) of 56 cumulative 
missed doses, discontinue IMP and withdraw participant 
from the trial. 
 
Any participant for whom the trial medication is discontinued 
(including for non-adherence) will be discussed with the Sponsor 
Medical Monitor and, if applicable, the participant will be restarted 
on trial medication as soon as possible. 
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Protocol Name: 
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Page 13 of 99 
Synopsis 
Description  
Statistical Methods: 
A general description of the statistical methods planned to be used to analyse efficacy data is 
outlined below. Specific details will be provided in the statistical analysis plan (SAP,) which 
will be written and signed off prior to the first participant enrolled in the trial. 
 
The primary analysis will be conducted using culture results from liquid culture (in the 
Mycobacterial Growth Indicator Tube (MGIT) system). 
 
Criteria for Evaluation: 
 
The primary efficacy endpoint will be time to culture negativity over 8 weeks. The 
primary hypothesis to be evaluated is:  
 
In the participants with DS-TB in the experimental BPaMZ treatment regimen, the time to 
culture negativity by 8 weeks will be superior, compared to the participants who are 
treated with the standard HRZE regimen. 
 
There will be three main analyses.  A modified Intent to Treat (mITT) analysis will be primary. 
A per-protocol (PP) analysis and an ITT analysis will also be performed for the secondary 
endpoint. These will be examined for consistency with the mITT analysis.  
 
Note:  Culture conversion requires at least 2 consecutive culture negative samples, at least 7 
days apart (after positive baseline confirmation).  Participants who are documented at a visit 
as unable to produce sputum and who are clinically considered to be responding well to 
treatment will be considered culture negative at that visit.  
 
Secondary Endpoints 
 
A key secondary endpoint will be the proportion of participants experiencing bacteriologic 
failure or relapse or clinical failure (unfavourable outcome) at 52 weeks (12 months). The 
hypothesis to be evaluated for this endpoint is: 
 
In the participants with DS-TB in the experimental BPaMZ treatment regimen, the 
proportion experiencing an unfavourable outcome will be non-inferior compared to the 
participants who are treated with the standard HRZE regimen. 
 
Other Secondary Endpoints 
 
Efficacy: 
• 
Incidence of bacteriologic failure or relapse or clinical failure at 104 weeks from the 
start of therapy.  
• 
Proportion of participants with sputum culture conversion to negative status in liquid 
culture (MGIT) at 4, 6, 12 and 17 weeks to be explored as a potential biomarker of 
outcome at 52 weeks from start of therapy. 
• 
Change from baseline in weight. 
• 
Change from baseline in TB symptoms. 
• 
Change from baseline in Participant Reported Health Status. 
 
Safety and Tolerability: 
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Protocol Name: 
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Page 14 of 99 
Synopsis 
Description  
• 
Incidence of Treatment Emergent Adverse Events (TEAEs) presented by incidence, 
severity, drug relatedness, seriousness, leading to early withdrawal, and leading to 
death.  
o Quantitative and qualitative clinical safety laboratory measurements, including 
observed and change from baseline. 
o Quantitative and qualitative electrocardiogram (ECG) results (heart rate, RR 
interval, PR interval, QRS interval, QT interval and QTc interval), including 
observed. QT/QTc intervals, change from baseline, will be categorized as 
these will be centrally read. 
• 
Changes in male reproductive hormones and lens opacities. 
 
These data will be presented as descriptive analyses, and no inferential tests will be carried 
out. 
 
Pharmacokinetics (PK) and Pharmacokinetics/Pharmacodynamics (PK/PD): 
Plasma concentrations from sparse sampling will be used to update existing population PK 
models and derive exposure metrics (e.g., minimum plasma concentration [Cmin], maximum 
plasma concentration [Cmax], area under curve over a dosing interval [AUC]) for bedaquiline 
and its M2 metabolite, pretomanid, moxifloxacin, and pyrazinamide. Effects of baseline 
covariates on exposure will be assessed; so too, will the effects of con-medications, including 
antiretroviral therapy (ART), where feasible. Data from other trials may be included to 
enhance the model-based analysis. Relationships will be explored between drug exposure 
and efficacy and safety endpoints. These exploratory PK/PD analyses may include HIV status 
as a covariate. 
 
Exploratory: 
Evaluate whether any of the secondary endpoints predict relapse free cure. Subgroup 
analysis of populations by HIV status will be performed. 
 
No formal statistical comparisons will be made for the participants enrolled with DR-TB. The 
responses of participants with DR-TB receiving BPaMZ will be compared for consistency with 
those responses of the DS-TB participants on the same regimen.   
 
Sample Size 
Primary endpoint: 150 participants per arm (DS-TB patients) will provide at least 90% power 
(5% 2-sided significance) to detect a hazard ratio (HR) of at least 2 assuming 50% of control 
participants are culture negative by 8 weeks.  
 
Additional efficacy parameters will be evaluated including the incidence of bacteriologic failure 
or relapse or clinical failure (unfavourable outcome) at 52 weeks and 104 weeks from the start 
of treatment. Time to unfavourable outcome from assignment of trial treatment through follow-
up as a function of time will be analysed using Kaplan-Meier analysis. 
 
Trial Duration: 
Approximately 4 years (18-month enrolment period for DS-TB participants, up to 26 week-
treatment, and follow-up until week 104 from start of treatment. Depending on the DR-TB 
recruitment rate, enrolment into this arm may continue after enrolment into the DS-TB arms is 
complete.  
 
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Protocol Name: 
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Page 15 of 99 
Synopsis 
Description  
There will be 3 database locks, data analyses and trial reports generated for this trial:  
 
1. When all participants have completed 8 weeks (2 months) of treatment from baseline.  
2. When all participants have completed 52 weeks (12 months) follow-up from start of 
therapy. 
3. When all participants have completed 104 weeks (24 months) follow-up from start of 
therapy.  
 
 
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Page 16 of 99 
1.2 
Synopsis Flow Chart and Procedures 
Period 
Screen-
inga 
Treatment 
Follow-Upc 
Visitb 
Day -9 to -1 
Day 1 
(Baseline)d 
Day 7 (Week 1) 
Week 2 
Week 3 
Week 4 
Week 5 
Week 6 
Week 7 
Week 8  
Week 12 
Week 17 
4-mth treatmente 
Week 17  
6-mth treatmente 
Week 22  
Week 26  
4-mth treatmente 
Week 26  
6-mth treatmente 
Week 39 
Week 52 
Week 65 
Week 78 
Week 104 
Early 
Withdrawalc 
Visit Windowv 
N/A 
+/- 3 Days 
+/- 5 Days 
+/- 14 Days 
Written Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/Treatment/ Smoking History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sputum Samplingf,g 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HIV Statush and CD4 Counti 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Karnofsky Score 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Drug Screenj 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Pregnancy Testk 
X 
X 
 
 
 
 
 
 
 
X 
 
X 
X 
 
X 
X 
 
 
 
 
 
X 
Laboratory Safety Testl 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
 
 
 
 
X 
Male Reproductive Hormone Testsm 
X 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
 
 
 
 
12-lead ECGn 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
X 
 
 
 
 
X 
Chest X-Rayo 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TB Symptoms Profile 
X 
X 
 
X 
 
X 
 
 
 
X 
 
X 
X 
 
X 
X 
 
X 
 
 
X 
X 
Patient Reported Health Status  
X 
X 
 
X 
 
X 
 
 
 
X 
 
X 
X 
 
X 
X 
 
X 
 
 
X 
X 
Vital Signs and weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Ophthalmic Examinationp 
X 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
X 
X 
X 
 
 
 
 
X 
Physical Examination – fullq 
X 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
Physical Examination – limitedr 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
Pharmacokinetic Samplings 
 
X 
 
X 
 
 
 
 
 
X 
X 
X 
X 
 
 
 
X 
 
X 
X 
X 
 
IMP Randomization/ Assignmentt 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IMP Compliance Checku 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 Xe 
 
X 
 
 
 
 
 
Xt 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Investigator Assessmentv 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
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GENERAL: Vital signs, ECGs and blood draws are to be performed pre-dosing 
unless otherwise specified. Vital signs and/or ECGs should be done prior to blood 
draws (safety and PK) on days with those assessments. 
 
a. Screening: Screening assessments can occur on different days within nine days prior 
to Day 1 dosing (randomisation).  
b. Visit Schedule (due to unforeseen circumstances): If the duration of treatment is 
extended due to dose interruptions / pauses, the last visit of the treatment period 
should also be pushed out to the date of last dose. It is not necessary to have an 
unscheduled visit at the time that the last visit of the treatment period would have been.   
c. Follow-up Visits for Early Withdrawal Participants: Once a participant has been 
permanently withdrawn from the trial, they will be required to attend Early Withdrawal, 
Week 52 (if not already performed) and Week 104 follow-up visits. The Week 52 and 
Week 104 visits will be to collect Serious Adverse Event (SAE) information (including 
verification of survival) and participant reported TB outcome information only and may 
be telephonic, a home or a site visit. Visits will occur at Week 52 and/or Week 104 after 
the participant’s start of treatment date.  Refer to Table 5 for additional guidance. 
d. Day 1 (Baseline): All procedures are to be completed prior to dosing.  
e. Last Visit of the Treatment Period: Investigational Medicinal Product (IMP) 
Compliance Check is not performed at the Week 22 visit for participants who have 
completed treatment at Week 17. 
f. Sputum Sampling: The sputum sampling methodology/requirements and tests will be 
described in a separate document, the Mycobacteria Laboratory Manual. 
• 
Days -9 to -1 (Screening). Two spot sputum samples taken 30 minutes apart will 
be collected at the research site under the coaching and observation of the trial 
staff. The following analyses will be performed on the first of these samples: 
o Smear microscopy for acid-fast bacilli (AFB); 
o Rapid molecular tests for fluoroquinolones, isoniazid and rifampicin 
resistance;  
o Liquid Culture (MGIT) for Mycobacterium tuberculosis (MTB), followed by 
a speciation test to detect presence or absence of MTB and obtain time to 
positivity (TTP) when positive. 
o The second sample is collected as a back-up sample to the first sample in 
case it is technically not possible to obtain a result/s from the first sample. 
If the Day -9 to -1 (Screening) spot sputum smear shows an indeterminate 
result or is AFB negative, the test may be repeated on the back-up sample 
or on a freshly collected spot sputum/s and that result will be used.  
• 
Baseline to Week 104, including any unscheduled visits:  
o Two sputum samples (ideally one early morning brought from home and 
one spot at the research site under the coaching and observation of the trial 
staff. If the participant forgets to bring in the Early Morning Sputum (EMS), 
then two spots are to be collected at the site, at least 30 min apart, and this 
altered sample collection is captured within case report form [CRF]).   
o If both sputum samples at Weeks 8, 17 (4-month treatment arm), 26 (6-
month treatment arm), 52 or 104 are contaminated, the participant should 
return for an unscheduled visit(s) to give additional samples or to document 
that the participant is not able to produce sputum. If there is a MTB 
confirmed positive culture at or after the last visit of the treatment period 
(Week 17 for the 4-month treatment arms and Week 26 for the 6-month 
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Protocol Version: Russia V1.0 / 10 Jul 2018, Incorporating Protocol V2.0 / 21 Feb 2018 
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Confidential 
Page 18 of 99 
treatment arms), the participant should return for an unscheduled visit(s) to 
give additional sputum samples a minimum of 7 days after the previous 
sample, or to document that the participant is not able to produce sputum.  
• 
Additional samples may be required to define a participants’ primary outcome 
status as described in Section 7.2.  
• 
Liquid Culture (MGIT) for MTB, followed by a speciation test to detect presence or 
absence of MTB and obtain TTP when positive, will be performed on all samples. 
g. Mycobacteriology Characterisation Tests performed: 
• 
Day 1 (baseline) sputum sample (or any positive sample from screening out to 
Week 4 if the baseline cultures are contaminated or negative); 
• 
MTB confirmed positive cultures at or after Week 17 (4-month treatment arms) or 
Week 26 (6-month treatment arms). 
Refer to Mycobacteria Laboratory Manual for full details.   
Mycobacterial Characterization - MTB isolates will be processed for: 
o Minimum Inhibitory Concentration (MIC) against bedaquiline, pretomanid, 
and moxifloxacin;  
o Drug Susceptibility Testing for streptomycin, rifampicin, isoniazid, 
ethambutol, moxifloxacin, pyrazinamide and second line TB drugs 
including, but not limited to fluoroquinolones, and injectables using an 
indirect susceptibility test in liquid culture;  
o Extraction of organismal (MTB) DNA for whole genome sequencing, and 
comparison of sequences from baseline and relapse isolates. 
h. HIV Testing: If HIV status is a confirmed known positive, a repeated HIV test is not 
needed provided that a documented HIV test result is available. If HIV status is 
unknown or suspected negative, a HIV test will be requested. If an ELISA and/or 
Western Blot and/or Electro-Chemiluminescence based HIV test was performed within 
4 weeks prior to screening, it should not be repeated if documentation of testing 
method and negative HIV results can be provided. Repeated HIV testing, during the 
Screening period is permitted for indeterminate HIV results. 
i. 
CD4 Count: Required for all HIV-positive participants.  
j. 
Urine 
Drug 
Screen: 
Cannabinoids, 
cocaine, 
amphetamines, 
opiates, 
benzodiazepines, barbiturates, at Screening only. Investigator to utilize this result to 
determine whether participant meets Exclusion criteria 2. Positive results will not 
automatically exclude a participant from the trial. 
k. Urine Pregnancy Test: Women of childbearing potential only, whether they are 
sexually active or not.  
l. 
Safety Laboratory Assessments: The Safety Laboratory sampling methodology and 
requirements will be described in a separate document, the Safety Laboratory Manual, 
which will be provided prior to the trial start. The following analyses will be performed: 
• 
Full Blood Count (haemoglobin, haematocrit, red blood cell count, white blood cell 
count with differential, platelet count).  
• 
Clinical Chemistry (albumin, serum urea, creatinine, direct, indirect and total 
bilirubin, uric acid, total protein, alkaline phosphatase [ALP], aspartate 
aminotransferase [AST], alanine aminotransferase [ALT], lipase, phosphate, 
sodium, potassium, calcium (corrected for albumin), chloride, magnesium, 
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Page 19 of 99 
glucose, bicarbonate/carbon dioxide [CO2], creatine phosphokinase [CPK]). GGT 
is only routinely included at the Screening visit (Day -9 to -1).  
• 
Urinalysis (pH, specific gravity, protein, glucose, micro-albumin, ketones, bilirubin, 
creatinine, nitrite, sodium, urobilinogen, blood, leukocytes). Microscopy will be 
completed as follow-up to abnormal urinalysis per discretion of Investigator.  
• 
When managing participants with elevated liver enzymes at an Unscheduled visit, 
the investigator can request additional tests, in addition to the repeat LFT [e.g. 
Gamma Glutamyl Transferase (GGT), screening for Hepatitis A, B, C; to assist in 
ruling out other causes of a dysfunctional liver test (e.g. alcohol induced hepatic 
cell injury, hepatobiliary disease, hepatic viral infection)]. 
m. Male Reproductive Hormone Tests: Testosterone, follicle-stimulating hormone 
(FSH), luteinizing hormone (LH) and Inhibin B to be done on male participants in ALL 
treatment groups. 
n. Single 12-Lead ECG: To every extent possible, this should be performed at 
approximately the same time of day as the trial procedures (+/-1 hour). Central ECG 
analysis will be performed. Results from central reading of Day -9 to -1 (Screening) 
ECG must be used to determine eligibility.  
o. Chest X-Ray: A chest x-ray (digital image only) within 6 months prior to or at the 
Screening visit, will be obtained and read locally by the Investigator or designee. Digital 
images will be provided to the Sponsor and this process will be described in a separate 
document, the Radiology Manual. 
p. Slit Lamp Ophthalmic Examination: Slit lamp examination will be done at the 
Screening visit, the last visit of the treatment period, Week 17 or 26, and at Week 39 
(9 months) for both treatment groups.  An additional slit lamp at 6 months will be done 
for the 4-month treatment group. Slit lamp ophthalmology examination will be 
performed by an Ophthalmologist with AREDS2 training. Ophthalmology examinations 
may occur at any time within the window period for the applicable visit i.e. they do not 
have to be performed on the same day as the trial procedures. 
q. Physical Examination – Full: Height (m) will only be collected at Day -9 to -1 
(Screening).  
r. Physical Exam – Limited: Limited physical exams will include weight and gross 
neurological, pulmonary, cardiovascular and abdominal exam(s). 
s. Pharmacokinetic (PK) Sampling: This process will be described in a separate 
document, the PK Sampling Manual. No PK samples will be collected for the HRZE-
HR treatment arm.  Blood draws for PK samples collected pre-dose must be done after 
the ECG is performed.  The dates and times of the two doses of IMP taken prior to all 
pre-dose PK samples will be collected.  Specific PK blood draws will be obtained as 
follows: 
• 
Day 1: pre-dose (within 2 hours prior to dosing) 
• 
Week 2: pre-dose (within 2 hours prior to dosing), 1.5–3 hours post-dose and 4-6 
hours post-dose 
• 
Week 8: pre-dose (within 2 hours prior to dosing), 1.5–3 hours post-dose and 4-6 
hours post-dose 
• 
Week 12: pre-dose (within 2 hours prior to dosing)  
• 
Week 17 or at early withdrawal if prior to week 17: pre-dose (within 2 hours prior 
to dosing) and 1.5–3 hours post-dose 
• 
Weeks 39, 65, 78 and 104 (for bedaquiline, bedaquiline metabolite M2): PK 
samples are to be obtained at any time on the day of the scheduled visit 
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t. Investigational 
Medicinal 
Product 
(IMP) 
Randomization/Assignment: 
Randomization may occur once all the Screening results are available and the 
Investigator has determined that the participant is eligible for the trial. 
u. IMP/Compliance Check: IMP administration will be supervised per local site practice 
to assure compliance to regimen. Performed at all visits and Early Withdrawal (EWD), 
if during the treatment period.  
v. Investigator Assessment: Investigator to review participant status and assess 
whether IMP or TB treatment at current visit is considered a “success” or “failure”.  If 
considered a failure, the Investigator should specify if based on bacteriology and/or 
clinical deterioration and/or radiological deterioration. Investigator Assessment to be 
completed, as shown on the flowchart, and at any time Investigator determines that 
participant fulfils criteria for outcome of treatment failure. 
w. Visit Windows: The windows noted on the flowchart for timing of visit also apply to 
timing within a visit.  Procedures should be performed within +/- 3 days of scheduled 
visit from Day 1 to Week 8 or +/- 5 Days of scheduled visit from Week 12 to Week 26 
or +/- 14 days of scheduled visit at or after Week 39.  Sites should make every effort 
to ensure all procedures are done on the same day, when possible. 
 
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Protocol Version: Russia V1.0 / 10 Jul 2018, Incorporating Protocol V2.0 / 21 Feb 2018 
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2.0 
Introduction and Rationale 
2.1 
Tuberculosis Disease 
Although some progress has been made in recent years in controlling tuberculosis (TB) 
globally, TB has remained a persistent problem in the developing countries of Africa, Asia and 
South America.  TB is currently one of the top three killer infectious diseases, and there is 
more TB in the world today than at any other time in history.  The current first-line anti-
tuberculosis agents have been in use for over 40 years and are relatively ineffective in 
controlling TB as a public health problem.  Although the current regimens and drugs have 
been very successful in controlled clinical trials resulting in the permanent cure of more than 
95% of trial participants, treatment takes 6 months or more to complete. This, long duration 
treatment plus side effects, result in poor adherence which particularly occurs after the 
second month of treatment.  
The current TB treatment regimens and treatments for drug-sensitive TB are decades old. The 
available treatments have a lengthy duration of treatment, involve multi-drug therapy, and 
require large commitments of resources and infrastructure. High rates of noncompliance are 
common, which often results in increased mortality and chronic, infectious, drug-resistant 
cases. The present TB epidemic and the challenge of current treatment options demonstrate 
the clear need for effective novel TB drugs and drug regimens that are safe for drug sensitive 
and drug resistant TB disease and that are well-tolerated and will shorten the current treatment 
duration for patients. 
The full application of the Directly Observed Treatment, Short-Course strategy is becoming 
more and more difficult in the developing countries of the world that are also battling to control 
the HIV-epidemic.  Because of poor treatment adherence, drug resistance is becoming more 
common and fears of an epidemic with virtually untreatable strains of TB are growing.  Since 
the discovery of the rifamycins,[1] and their introduction into standard antituberculosis 
regimens, very few new classes of drugs have been evaluated with a view to their registration 
as antituberculosis agents.  On December 28, 2012 the U.S. Food and Drug Administration 
approved bedaquiline (B) as part of combination therapy to treat adults with multi-drug 
resistant (MDR) pulmonary tuberculosis (TB) when other alternatives are not available. 
Following the declaration of TB as a global emergency by the World Health Organization 
(WHO) in 1993, there has been a resurgence of efforts to develop improved TB therapies and 
several promising new agents are presently in or approaching clinical evaluation.   
New combination regimens are desperately needed for two reasons: to shorten treatment to 
a duration more easily manageable by patients and public health services, and to provide 
more efficacious, safer and better tolerated, affordable treatments for the growing number of 
patients suffering from multidrug-resistant and extensively drug-resistant tuberculosis. 
2.2 
Tuberculosis Clinical Research 
TB currently must be treated with multiple drugs to achieve maximal efficacy and prevent 
resistance. To transform treatment, novel TB regimens are needed. To telescope the time, it 
takes to develop novel, tolerable multi-drug treatments, it is necessary to use the regimen 
development paradigm. This approach tests promising combinations of drugs together to find 
the most impactful treatment once the individual drug candidates have been tested in a robust 
pre-clinical program and the establishment of the individual drug candidates’ safety and 
efficacy have been evaluated.  It evaluates novel combinations of TB drugs — instead of single 
drugs — as part of a single development program, enabling the development of novel TB drug 
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Page 22 of 99 
regimens that have potential to transform treatment for drug-sensitive and drug-resistant 
tuberculosis. This approach offers the potential to reduce the time previously needed to 
develop a novel treatment regimen by up to 75%, shortening the clinical development from 
decades to years. The steps followed in this development model are shown in Figure 1 
Between each step on the unified development pathway a decision is made as to whether to 
proceed. 
Figure 1.  Unified Drug Sensitive/Drug Resistant Regimen Development Path 
 
Early Bactericidal Activity (EBA) Trials 
EBA trials are the backbone clinical trials to quantify the bactericidal action of anti-tuberculosis 
agents alone or in combination by either trialling the fall in the number of colony forming units 
(CFU) or measuring the TTP in liquid culture of M. tuberculosis (MTB) present in the sputum 
of participants with microscopy smear-positive pulmonary TB. EBA trials have been conducted 
over 2, 5, 7 and 14 days.[2]. A review of EBA trials conducted on the key anti-TB drugs has 
shown the value these trials offer to demonstrate the early anti-TB effect that a new therapeutic 
agent may have and to explore the relationships between dose, pharmacokinetics and 
bactericidal activity in participants.[3] 
8-week Bactericidal Activity (BA) Trials 
EBA methodology of quantitative colony counting on solid medium has been adapted to Phase 
2, 8-week TB treatment trials based on serial sputum colony counting (SSCC) or measurement 
of TTP liquid culture to provide a more sensitive efficacy endpoint than the previously used 
binary endpoint of rate of sputum conversion measured after 8 weeks of treatment.[4-6] Such 
trials are conducted to provide data on which to base the selection of treatment-shortening 
regimens.  
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2.3 
Trial Rationale 
This trial (SimpliciTB) will evaluate and support that, in additional to previous studies evaluated 
with BPaMZ, this drug regimen (BPaMZ) will be safe and effective, is well-tolerated and could 
potentially shorten the current treatment duration compared to Standard HRZE/HR treatment 
for patients with drug sensitive TB disease. This trial will also evaluate if this drug regimen 
(BPaMZ) given for 6 months will be safe and effective in drug resistant TB disease. 
Therefore, the trial design addresses the need to find and evaluate a potentially effective and 
shorter regimen compared to regimens (Standard HRZE/HR) that are currently being used. 
2.3.1 
Trial Design Rationale 
NC-008 (B-Pa-M-Z) trial - [SimpliciTB] - is a Phase 2c multi-centre, open-label, partially 
randomized clinical trial in DS-TB and DR-TB participants. This trial is to evaluate the 
combination regimen of Bedaquiline (B) plus Pretomanid (Pa) plus Moxifloxacin (M) plus 
Pyrazinamide (Z), (BPaMZ) in participants with pulmonary TB. 
All participants will enter post-treatment follow-up which continues until Week 104 (24 months) 
after start of treatment / randomisation. 
 
Participants with Drug Sensitive TB (DS-TB): 
Participants with DS-TB will be randomized to one of two treatment arms. These 
participants will receive either BPaMZ daily for 17 weeks (4 months),  
 
or  
HRZE/HR combination tablets daily for 26 weeks (6 months). Participants will be stratified 
for co-infection with HIV and cavitation. 
Participants with Drug Resistant TB (DR-TB) are defined as: 
1. mono-resistance to rifampicin or isoniazid, OR 
2. resistance to both rifampicin and isoniazid (multi-drug resistant tuberculosis [MDR-TB]) 
Up to 150 participants with DR-TB will be assigned to receive BPaMZ daily for 26 weeks (6 
months).  Approximately 300 DS-TB participants (150 per treatment arm) will be randomized 
and stratified for co-infection with HIV and cavitation to either BPaMZ for 4 months or 
HRZE/HR for 6 months.  
 
The trial is sufficiently statistically powered to not only show superiority of 2 months’ culture 
conversion, but should also demonstrate non-inferiority for cure at 12 months. (This is in the 
participants with DS-TB in the experimental BPaMZ treatment regimen, the proportion 
experiencing an unfavourable outcome will be non-inferior compared to the participants who 
are treated with the standard HRZE regimen). 
 
As previously described in the background information, in order to telescope the time it takes 
to develop novel, tolerable multi-drug treatments, it is necessary to use the regimen 
development paradigm and utilize data generated in non-clinical and clinical studies regarding 
combining of anti-tuberculosis agents which could contribute significantly to the sterilization of 
lesions and thus treatment shortening. Therefore, the trial design and proposed trial regimen 
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Page 24 of 99 
(BPaMZ) which is supported with previous non-clinical and clinical studies outlined below 
should address the need and manner of evaluating an effective shorter regimen compared to 
regimes that are currently being used. 
2.3.2 
Trial Drug Regimen Rationale 
The BPaMZ regimen has been studied singularly and in different combinations as outlined 
above. Moxifloxacin has been added to the B-Pa-Z regimen because of the high rate of 
pyrazinamide resistance seen in MDR-TB participants in the NC-002 trial. It essentially 
provides protection against the development of new resistance to the B-Pa-Z drugs. Based on 
the exciting and promising results seen in NC-005, this regimen can be initiated in drug 
sensitive and drug resistant TB participants whom are sensitive to the individual drugs in the 
regimen (excluding extensively drug-resistant tuberculosis [XDR-TB]) and has the potential to 
shorten TB treatment to less than 4 months in drug sensitive TB. These are also oral regimens, 
removing the need for injectables as part of MDR-TB treatment and also project to be markedly 
less expensive than current MDR-TB therapy. Additionally, these regimens can be 
administered in a fixed dose for all patients, and will therefore be simpler for health systems 
to deliver and patients to use. 
2.4 
Agents used within SimpliciTB 
Bedaquiline (TMC207; SirturoTM package insert)[7]  is a novel agent approved for TB 
treatment. As detailed in the Investigator’s Brochure,[8] bedaquiline is a diarylquinoline that 
offers a novel mechanism of anti-tuberculosis action by specifically inhibiting mycobacterial 
adenosine triphosphate synthase.[9, 10]) In vitro, bedaquiline potently inhibits both drug-
sensitive and drug-resistant M. Tb isolates,[10, 11], and is also bactericidal against non-
replicating M. Tb.[12] In the murine model of TB, bedaquiline was as active as the triple 
combination of isoniazid (H), rifampin (R), and pyrazinamide (Z). Addition of bedaquiline to 
HRZ results in accelerated clearance of M. Tb.[3, 4] There appears to be a synergistic 
interaction with pyrazinamide: 100% of mice were culture negative after 8 weeks of treatment 
with bedaquiline and pyrazinamide compared to 0% of mice treated with the standard regimen 
of rifampicin, isoniazid and pyrazinamide.[13] Collectively, these findings in the mouse model 
have led to the suggestion that regimens containing bedaquiline and pyrazinamide could be 
effective in the treatment of both DS- and MDR-TB and shorten treatment duration in patients. 
While the combination of bedaquiline and pretomanid in the murine model of TB appeared 
somewhat antagonistic relative to bedaquiline alone, it was as active as the triple combination 
of HRZ[13] and in a subsequent trial it was more active in the mouse model than HRZ.[14] Thus, 
a novel regimen with a bedaquiline plus pretomanid core could be effective in the treatment of 
MDR-TB by providing two novel drugs for which there is no known pre-existing resistance.  
Pretomanid, (Pa)[15]  is a new chemical entity being developed by TB Alliance for the treatment 
of TB.  It is a member of a class of compounds known as nitroimidazo-oxazines, which possess 
significant anti-tuberculosis activity and a unique mechanism of action.[16] PRETOMANID has 
been under development for several years, and entered clinical trials in 2005. Several trials of 
pretomanid have also been conducted previously in healthy volunteers.  Collectively, these 
trials in participants with active TB and healthy participants have defined the efficacy, safety 
and pharmacokinetic features of the drug.  Overall, pretomanid has mycobactericidal activity 
in participants and is well tolerated and bioavailable after oral dosing.  Pretomanid 
demonstrated in vitro activity against both drug-sensitive (DS) and MDR-TB,[17] and in vivo 
activity in a mouse model of TB[17, 18] with a significant promise for shortening treatment of 
active TB. 
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Moxifloxacin (M)[19]  is a microbial compound, approved in most countries around the world 
for the treatment of acute bacterial sinusitis, acute bacterial exacerbation of chronic bronchitis, 
community-acquired pneumonia, skin and soft tissue infections.  Clinical studies have been 
carried out for many additional indications (urinary tract infections, pelvic infections, 
pharyngitis/tonsillitis, and tuberculosis). Moxifloxacin is an 8-methoxyquinolone whose oral 
formulation (which will be used in this trial) has enhanced activity against Gram-positive 
pathogens, and anaerobes while retaining useful activity against Gram-negative organisms. 
Moxifloxacin is not metabolized by or induces the cytochrome P450 system, thus the risk of 
clinically relevant drug interactions is reduced. It has a positive safety profile within the 
fluoroquinolone class at the approved daily dose of 400 mg. Moxifloxacin while not approved 
for TB by most regulatory authorities, it is regularly used in second line MDR-TB treatment. 
The WHO TB Treatment Guidelines place moxifloxacin in the category of Group 3 drugs and 
notes that “all patients [with MDR-TB] should receive a Group 3 medication if the MTB strain 
is susceptible or if the agent is thought to have efficacy. One of the higher generation 
fluoroquinolones, such as levofloxacin or moxifloxacin, is the fluoroquinolone of choice.[5]” It is 
currently in late stage clinical development for first-line TB treatment in combination with other 
TB drugs, including pyrazinamide in two different four-month long regimens.  
Pyrazinamide (Z)[20] is a pyrazine analogue of nicotinamide and an approved anti-tuberculosis 
agent which is indicated for the initial treatment of active tuberculosis in adults and children 
when combined with other anti-tuberculosis agents and contributes significantly to the 
sterilization of lesions and thus treatment shortening.[21]   
Control Group: HRZE/HR 
The HRZE/HR combination [HRZE tablets [isoniazid (H), rifampicin (R), pyrazinamide (Z) and 
ethambutol (E)] and HR tablets [isoniazid (H) plus rifampicin (R) combination tablets] is 
approved indicated and commonly used as a 6-month treatment for drug-sensitive TB patients.  
Participants with DS-TB that are randomized to the HRZE/HR control arm in this trial will be 
given standard weight-adjusted doses of HRZE.  Please see the HRZE package insert for 
more information.[22]   
Additional background data supporting the combined use of new novel agents in this 
BPaMZ regimen for the treatment of TB: 
Data from preclinical studies suggest that a regimen consisting of moxifloxacin plus 
pretomanid plus pyrazinamide may not only be appropriate for treating both DS and MDR-TB 
but may also shorten duration of therapy.  Results from an 8-week Phase 2b SSCC trial, 
NC-002-(M-Pa-Z), showed that this combination regimen was effective as measured by time 
dependent decline of viable bacteria in participants with DS pulmonary TB.  The combination 
was also shown to be safe and well tolerated supporting the evaluation of this combination in 
a Phase 3 trial. In this NC-002 trial 71.4% of participants with DS-TB treated with PaMZ at the 
100-mg daily dose of pretomanid converted sputum to negative for MTB growth in liquid 
culture in comparison with only 37.8 % of participants treated with the HRZE control (p<0.05).  
Studies in mice infected with MTB demonstrated reductions in cultured colony counts from 
lungs over an 8-week period when treated with the PaMZ regimen that were substantially, and 
statistically significantly greater, than the reductions in mice treated with an HRZ control.  
Experiments in mice found that mice did not relapse with MTB infection when treated with 
PaMZ for 4 months and followed for 3 months off treatment, in comparison to mice that 
required 6 months of treatment with HRZ to prevent relapse.[14]   
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Drug Resistant TB Background: 
Although some progress has been made in recent years in controlling tuberculosis (TB) 
globally, TB has remained a persistent problem in many countries. TB is the world’s leading 
cause for mortality from infectious disease and is responsible for more deaths than HIV.[23] It 
is the leading cause of death among HIV-infected individuals, and there is more TB in the 
world today than at any other time in history. Because of poor treatment adherence, in addition 
to primary transmission, drug resistance is becoming more common and fears of an epidemic 
with strains of extensively drug-resistant TB (XDR-TB) that is very difficult to treat are growing.  
Novel drugs and regimens for TB are needed for the growing number of patients with drug 
resistant-TB.  
The regulatory approvals of bedaquiline and delamanid have given hope that outcomes for 
patients with drug resistant TB might be improved when added to background regimens. 
Experience recently published from the C209 uncontrolled trial of bedaquiline given on a 
background of multiple drugs notes that the subset of 38 participants with XDR-TB had rates 
of sputum culture conversion to negative of 62.2%.[24] However, in this trial only one participant 
with XDR-TB was co-infected with HIV. All participants were required to have Mycobacterium 
tuberculosis (MTB) isolates susceptible to at least 3 drugs at enrolment and participants had 
a median of only 5.4 months of treatment-free follow-up. This trial added bedaquiline for 6 
months to a background regimen of many drugs given for 18 months or longer. While 
treatment success for MDR-TB is better than for XDR-TB, overall success in treating MDR-
TB is still approximately 50% according to the World Health Organization 2015 Global TB 
Report.[23]  This report presented that overall, the proportion of MDR-TB patients in the 2012 
cohort who successfully completed treatment (i.e. cured or treatment completed) was 50%; 
16% died, 16% were lost to follow-up, 10% failed treatment, and for 8% there was no outcome 
information.   
With such poor historical outcomes for patients with drug resistant-TB and with the complexity, 
expense and toxicity of treatments for all forms of drug resistant TB, novel drug 
combinations are desperately needed to improve treatment outcomes. Linezolid was 
identified in a small trial as a potentially efficacious drug in patients with XDR-TB when added 
to a failing regimen[25] and this drug has increasingly been added to complex regimens to treat 
patients with MDR-TB. 
With the current availability of the following three drugs for which there is little, if any, pre-
existing resistance among strains of MTB (pretomanid [Pa], bedaquiline [B], and linezolid [L]). 
Mice infected with MTB had relapse-free cures with 3 months of treatment with a B-Pa-L 
regimen. While it is not known whether that treatment duration will translate to humans, the 
ongoing Nix-TB clinical trial hypothesizes patients with pulmonary XDR-TB or MDR-TB not 
responsive to or intolerant to therapy may have relapse-free cure after as little as 6 months’ 
treatment with the B-Pa-L regimen.[26]  Moxifloxacin has been added to the B-Pa-Z regimen 
because of the high rate of pyrazinamide resistance seen in MDR-TB participants in the NC-
002 trial. The proposed trial [SimpliciTB] allows the opportunity to assess the efficacy, safety 
and tolerability of BPaMZ, a new 6 months regimen that may be administered orally once daily 
to treat patients with drug resistant -TB (excluding participants with XDR-TB). 
Therefore, the overall purpose of the present proposed trial [SimpliciTB] is to assess the 
efficacy, safety and tolerability of the BPaMZ regime after 4 months of treatment in adult 
participants with drug sensitive TB and after 6 months of treatment in participants with multi 
drug-resistant TB. The trial will also generate data of the potential for a shorted treatment 
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duration with the BPaMZ regime after 4 months compared to a 6-month HRZE/HR (control) 
treatment regime in adult participants with drug sensitive TB. 
This trial will be conducted in accordance with the Protocol, ICH Guidelines for Good Clinical 
Practice (GCP), the ethical principles that have their origin in the Declaration of Helsinki and 
the applicable regulatory requirement(s). 
2.5 
Background of Agents to be Studied in SimpliciTB 
2.5.1 
Bedaquiline (B) 
Bedaquiline (formerly known as TMC-207; SirturoTM package insert[7]) is approved agent for 
TB treatment. As detailed in the Investigator’s Brochure,[8] bedaquiline is a diarylquinoline that 
offers a novel mechanism of anti-tuberculosis action by specifically inhibiting mycobacterial 
adenosine triphosphate  synthase.[11] In vitro, bedaquiline potently inhibits both drug-sensitive 
and drug-resistant MTB isolates,[11, 12] and is also bactericidal against non-replicating MTB[12] 
In the murine model of TB, bedaquiline was as active as the triple combination of isoniazid 
(H), rifampicin (R), and pyrazinamide (Z). Addition of bedaquiline to HRZ results in accelerated 
clearance of MTB.[1, 2]. There appears to be a synergistic interaction with pyrazinamide: 100% 
of mice were culture negative after 8 weeks of treatment with bedaquiline and pyrazinamide 
compared to 0% of mice treated with the standard regimen of rifampicin, isoniazid and 
pyrazinamide.[27].Collectively, these findings in the mouse model have led to the suggestion 
that regimens containing bedaquiline and pyrazinamide could be effective in the treatment of 
both drug sensitive and drug resistant TB and shorten treatment duration in patients. While 
the combination of bedaquiline and pretomanid in the murine model of TB appeared somewhat 
antagonistic relative to bedaquiline alone, it was as active as the triple combination of HRZ[27] 
and in a subsequent trial it was more active in the mouse model than HRZ.[28]. Thus, a novel 
regimen with a bedaquiline plus pretomanid core could be effective in the treatment of MDR-
TB/XDR-TB by providing two novel drugs for which there is no known pre-existing resistance. 
Bedaquiline is currently registered in many countries to be administered to patients with 
pulmonary tuberculosis by the following scheme: 400mg once daily for Days 1-14 followed by 
200mg three times per week for the remainder of treatment. In this trial bedaquiline will be 
administered as 200 mg daily for 8 weeks then 100 mg daily for 9 weeks in participants with 
DS-TB and 200 mg daily for 8 weeks then 100 mg daily for 18 weeks in participants with DR-
TB.  This daily dosing scheme will allow more convenient dosing that should ultimately 
enhance patient adherence and may allow the formulation of fixed dose combinations with 
other drugs.  This daily dosing regimen is supported by safety and efficacy demonstrated in 
the NC-005 trial that administered bedaquiline 200 mg daily over 8 weeks, and by 
pharmacokinetic modelling and simulation of the daily dosing scheme.  This supportive 
information is detailed below. 
2.5.1.1 
Bedaquiline Non-Clinical Studies 
Full details of the preclinical studies are provided in the current bedaquiline Investigator’s 
Brochure,[8] and Sirturo 
TM label.[7] In vitro studies have demonstrated that the range of 
minimum inhibitory concentrations (MICs) for MTB H37Rv, the international reference strain, 
and 6 fully drug-susceptible clinical isolates, was 0.030 to 0.120 μg/ml. The activity of 
bedaquiline appears to be specific for mycobacteria, as the MICs for non- mycobacteria were 
at least 500-fold higher. The activity of the main metabolite of bedaquiline, M2, was determined 
against MTB.  H37Rv in both solid and liquid media and its MIC was found to be 0.1 μg/ml. 
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This MIC shows that M2 is active against MTB but 3-6 times less active than the parent 
compound bedaquiline. Bedaquiline demonstrated similar in vitro efficacy against MTB clinical 
isolates resistant to the known anti-TB drugs (isoniazid, rifampicin, pyrazinamide, 
streptomycin, ethambutol, or fluoroquinolones). As expected, from the lack of cross-resistance 
with currently used anti-tuberculosis agents, bedaquiline retained activity against MDR-TB 
isolates. 
The non-clinical safety evaluation of bedaquiline includes pharmacology, pharmacokinetics, 
toxicology and metabolism studies that were conducted in accordance with current 
International Council for Harmonisation (ICH) guidelines. Repeated dose toxicity studies were 
performed with dosing durations up to 3 months in mice and up to 6 months in rats and in 
dogs. Recovery was studied in rats and dogs. In repeated dose toxicity studies, up to 3 months 
in mice, up to 6 months in the rat and up to 9 months in dogs, bedaquiline was associated with 
target organ changes in the mononuclear phagocytic system (indicative of phospholipidosis), 
stomach, liver, pancreas, and muscle. Toxicity was often associated with an increased 
presence of neutrophils in some tissues such as the female genital tract and this was preceded 
by a peripheral neutrophilia. For more detailed information please refer to the bedaquiline IB.[8] 
Respiratory parameters in rats were unaffected by treatment. There were no effects 
suggestive of neurological impairment or delayed neurotoxicity in rats. In single dose toxicity 
studies, there were no mortalities following oral doses of up to 200 mg/kg in mice and rats. No 
mutagenicity or clastogenic effects were seen in a series of in vitro and in vivo genotoxicity 
tests. Bedaquiline was evaluated for possible developmental toxicity effects in the rat and the 
rabbit. No teratogenic effects were found. In vitro, bedaquiline slightly to moderately inhibited 
the delayed rectifier potassium current (IKr) in the human ether-à-go-go-related gene (hERG) 
model. Bedaquiline and M2 had no notable effects on IKr at 0.01 μM (0.006 and 0.005 μg/mL, 
respectively). However, at higher concentrations (0.03 to 3 μM), both compounds had a slight 
to strong concentration-dependent effect with a 50% inhibitory concentration (IC50) of 0.37 μM 
(0.2 μg/mL) for bedaquiline and up to 0.45 μM (0.24 μg/mL) for M2. However, this effect did 
not manifest as a prolongation of repolarization in subsequent in vivo studies. 
There were no relevant effects on the isolated right atrium of guinea pigs in vitro, or in the 
isolated Langendorff-perfused rabbit heart. In vivo, positive chronotropic effects were seen in 
the anesthetized guinea pig after IV administration, but not in the conscious dog. In conscious, 
telemetered dogs, oral bedaquiline had no relevant effects on cardio-hemodynamic and ECG 
parameters. 
Prior to the use of pretomanid in combination with bedaquiline in clinical trial NC-001, a 
preclinical cardiovascular safety pharmacology trial was conducted in unrestrained beagle 
dogs with both drugs to explore the potential for additive effects on QT prolongation induced 
by the combination. Results indicate that administration of 100 mg/kg bedaquiline daily, for 7 
days, causes a small increase in QTc interval by Day 6 in some animals that is not influenced 
by the addition of 100 mg/kg pretomanid on Day 7.[28] 
 The effect of pretomanid dosing alone 
on QT interval appeared to be due to discomfort related to the SC route of administration and 
not related to the plasma exposure (please see the pretomanid) Investigators Brochure for 
more detail. 
2.5.1.2 
Bedaquiline Clinical Studies 
In the clinical studies conducted to date, a total of approximately 645 participants (including 
265 healthy volunteers) have been exposed to bedaquiline in the Phase 1 and 2 clinical trials 
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conducted as a part of the development program for the treatment of MDR-TB. An additional 
45 participants received bedaquiline, either as monotherapy (B) or in combination with other 
agents (B-Pa or B-Z) in trial NC-001, and 45 more in trial NC-003 (B-Pa-Z, B-Pa-C, B-Pa-Z-
C). Four short-term Phase 2a trials enrolled treatment-naïve participants (C202, TMC207-
CL001, NC-001 and NC-003). One long-term, open-label, Phase 2 trial, in MDR-TB 
participants (bedaquiline- TiDP13-C209) and one long-term, Phase 2b trial, consisting of 2 
different stages in participants infected with newly diagnosed sputum smear-positive 
pulmonary MDR-TB (bedaquiline-TiDP13-C208), have been completed. The principal findings 
of these trials are summarized below. Full details of the completed clinical studies are provided 
in the current bedaquiline IB,[8] and Sirturo
TM label.[7]. 
The Phase 1 trials have provided a basic understanding of bedaquiline’s pharmacokinetic 
characteristics, drug- drug interaction potential, and short-term safety/tolerability profile in 
healthy participants. Bedaquiline was well absorbed with time to reach the maximum plasma 
concentration at approximately 5 hours post-dose. The maximum plasma concentration and 
AUC increased proportionally up to the highest doses studied (up to 700 mg in a single dose-
ranging trial, 800 mg single dose in trial bedaquiline-TBC1003 and 400 mg q.d. multiple 
doses). Accumulation from Days 1 to 14 was approximately 2-fold expressed as increase in 
AUC, while trough concentrations increased up to 3.5-fold. The pharmacokinetics of 
bedaquiline were comparable between healthy participants and participants with pulmonary 
TB. The apparently close to steady-state concentrations in plasma after 14 days of daily 
treatment is ascribed to the important amount of the drug that is eliminated from the circulation 
during the ἀ and β phases of the plasma concentration-time curve. The average terminal 
elimination half-life of bedaquiline and metabolite M2 noted on extended follow-up after repeat 
dosing of participants with TB infection is about 5.5 months. 
Administration of bedaquiline as the tablet formulation with food, increased the relative 
bioavailability (by 95%) compared to administration without food, and drug-drug interaction 
trials confirmed the role of cytochrome P450 3A4 (CYP3A4) in the metabolism of bedaquiline 
to M2. A recently completed trial (DMID 10-0043) demonstrated that when given in 
combination, rifampicin, and to a lesser degree rifabutin, decreased exposure to bedaquiline 
presumptively due to induction of P450 enzymes. The clinical significance of these findings is 
unknown, however the current trial (NC-005) will not permit the concomitant use of bedaquiline 
with any rifamycin. 
The efficacy of bedaquiline was initially demonstrated in two monotherapy EBA studies C202 
and TMC207- CL001. Trial C202 was a 7-day trial of three daily doses of bedaquiline (25, 100 
and 400mg) in treatment-naïve participants with MDR-TB. In this trial, the 400mg dose group 
demonstrated positive EBA and was numerically superior to the 25 and 100mg doses. In trial 
TMC207-CL001, doses of 100, 200, 300 and 400mg daily (following a 2-day loading dose) 
were studied in participants with newly-diagnosed pulmonary TB for 14 days. There were no 
statistically significant differences between the treatment groups, although there was a 
numerical trend suggesting a positive dose-response relationship. Taken together, these 
studies establish that bedaquiline monotherapy has EBA in participants with TB and that 
higher doses appear to have greater efficacy. 
A 14-day EBA regimen trial (TB Alliance Trial NC-001-(B-M-Pa-Z)) evaluated bedaquiline 
administered as monotherapy at 400 mg/d or in combination at that dose with either 
pretomanid administered at 200 mg/d or weight-adjusted pyrazinamide, to participants with 
pulmonary TB at 2 clinical sites in South Africa. The results indicate that over 14 days, the 
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mean logCFU decreased by 1.3 from baseline in the 15 participants given bedaquiline 400 
mg/d after a 2-day loading dose. In the cohort of 15 participants given bedaquiline 400 mg/d 
after a loading dose plus weight-adjusted daily doses of pyrazinamide (Z), the mean logCFU 
decreased by 2.0 logs from baseline, indicating that Z potentiates the early bactericidal effect 
of bedaquiline. In the cohort with 15 participants given bedaquiline 400 mg/d after a loading 
dose plus 200 mg/d pretomanid, the mean logCFU decreased by 1.9. While it appeared that 
the addition of pretomanid potentiated the anti-tuberculosis activity of bedaquiline, the mean 
logCFU decrease of the combination was similar to that of two previous EBA studies using 
pretomanid monotherapy at 200 mg/day. 
The second 14-day EBA combination trial (NC-003) included a number of bedaquiline-
containing arms: bedaquiline, pyrazinamide and clofazimine (B-Z-C), bedaquiline, pretomanid 
and clofazimine (B-Pa-C), bedaquiline, pretomanid, and pyrazinamide (B-Pa-Z) and 
bedaquiline, pretomanid, pyrazinamide and clofazimine (B-Pa-Z-C). Among these, B-Pa-Z had 
the best activity which was at least as good as the HRZE control (Daily Log CFU – 0.167 vs 
0.151, respectively). 
The long-term efficacy of bedaquiline in participants with MDR-TB has been studied in a 
placebo-controlled, randomized Phase 2b trial (C208) and an open-label, uncontrolled, Phase 
2b trial (C209). In the Phase 2b placebo-controlled trial, C208, the addition of bedaquiline to a 
5-drug MDR-TB regimen resulted in significantly faster time to culture conversion compared to 
placebo. During the 8-week treatment in Stage 1, 47.6% of participants in the bedaquiline group 
became MGIT culture negative compared to 8.7% of participants in the placebo group. At Week 
24 in Stage 1, after 8 weeks of investigational treatment and 24 weeks of background 
treatment, 81.0% of participants in the bedaquiline group and 65.2% of participants in the 
placebo group showed treatment success, (i.e., completed week 24 and were liquid culture 
negative, at this time point). 
For C208 Stage 2, in the interim analysis as well as in the primary efficacy analysis, a 
statistically significant difference in time to culture conversion between the treatment groups (p 
< 0.0001) in favour of bedaquiline was shown. In both analyses, an identical number of 
participants with culture conversion at week 24 (i.e., 24-week responders [missing = failure]) 
was observed: 78.8% in the bedaquiline group and 57.6% in the placebo group, which was 
statistically significantly different (p =   0.008) based on a logistic regression model with only 
treatment as covariate. Microbiological response at Week 24 was durable in C208 Stage 2: the 
percentage of responders (missing = failure) at week 72 was 71.2% in the bedaquiline group 
and 56.1% in the placebo group. 
In the Phase 2b uncontrolled trial, C209, treatment with bedaquiline in combination with an 
individualized MDR- TB treatment regimen was effective against pulmonary MDR-TB both in 
newly diagnosed and in non-newly diagnosed participants. Culture conversion rates after 
2 weeks of treatment with bedaquiline as part of an individualized anti-tuberculosis regimen 
were higher in participants with lower extent of resistance of the M. Tb strain and in participants 
with no lung cavitation compared to participants with cavitations (in one or both lungs). 
2.5.1.3 
Bedaquiline Clinical Safety 
In the clinical trials conducted to date, a total of approximately 645 participants (including 
265 healthy volunteers) have been exposed to bedaquiline in the Phase 1 and 2 clinical trials 
conducted as a part of the development program for the treatment of MDR-TB. An additional 
60 participants received bedaquiline in a monotherapy EBA trial of 14 days (trial TMC207-
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CL001) 45 participants received bedaquiline, either as monotherapy (B) or in combination with 
other agents (B-Pa or B-Z) in trial NC-001 and 45 more in trial NC- 003 (B-Pa-Z, B-Pa-C, B-
Pa-Z-C). In these trials, bedaquiline has been shown to be an effective treatment for 
participants with both DS and MDR-TB. Specifically, the regimen B-Pa-Z was demonstrated 
to have efficacy at least as good as the HRZE control in trial NC-003. Furthermore, bedaquiline 
is a novel agent with no pre-existing resistance and, based on mouse model data, may result 
in shortened treatment durations when included in novel regimens to treat both DS- and MDR-
TB. Based on the combined experience in these clinical trials, the following known and 
potential risks have been identified. 
Adverse Drug Reactions for bedaquiline 
During the Investigational Treatment phase in the controlled trials, the most frequently reported 
Adverse Drug Reactions in the any bedaquiline group (> 10.0% of participants) were nausea, 
arthralgia, headache, vomiting, and dizziness. Details of Adverse Events, none of which were 
Serious, that were considered Adverse Drug Reactions are in the table below: 
Table 1.  Bedaquiline Adverse Drug Reactions 
 
 
 
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Mortality 
Overall, there was an imbalance in the number of deaths in the pooled Stage 1 and Stage 2 
C208 trial. In the pooled analysis (Stage 1 and Stage 2), 12 participants in the Any bedaquiline 
group and 5 participants in the Any Placebo group experienced a SAE leading to death; 
causes of death were varied with only death due to TB reported more than once, and none of 
these participants had a treatment-emergent QTcF ≥ 500 ms. The imbalance in deaths is 
primarily driven by the C208 Stage 2 results in which the imbalance was 10 bedaquiline 
participants (12.7%) compared to 3 placebo participants (3.7%). Based on the pooled results 
(Stage 1 and 2) while being followed in the placebo- controlled trial, 7 participants in the Any 
bedaquiline group and 1 Participant in the Any Placebo group died. Of these deaths, 1 
occurred during the Investigational Treatment phase with bedaquiline/placebo, the remaining 
deaths occurred afterwards. In the Any bedaquiline group, causes of death were myocardial 
infarction, TB (2 cases), alcohol poisoning, hepatitis and hepatic cirrhosis (1 case), septic 
shock and peritonitis (1 case), and cerebrovascular accident. In the Any Placebo group, cause 
of death was haemoptysis. The Investigator considered the SAEs leading to death not related 
to bedaquiline intake in the Any bedaquiline group and doubtfully related to investigational 
medication in the Any Placebo group. The analysis of long-term follow-up for survival 
outcomes in participants who prematurely discontinued in trial C208 (Stage 1 and 2), based 
on data collection every 24 weeks (6 months) after withdrawal (up to LSLV in the rollover arm 
[16 Oct 2012] in Stage 2), included 9 deaths. One Participant in the bedaquiline group 
(pulmonary TB) and 2 participants in the Placebo group (TB-related illness and pulmonary TB) 
in Stage 1 died, and 4 participants in the bedaquiline group (3 participants with TB-related 
illness, 1 Participant motor vehicle accident) and 2 participants in the Placebo group (both TB-
related illness) died after they discontinued Stage 2 of the trial. None of these participants had 
a treatment-emergent QTcF ≥ 500 ms. The imbalance in deaths is unexplained.  In addition, 
no discernible pattern between death and  sputum  culture  conversion,  relapse, sensitivity to 
other drugs used to treat TB, human immunodeficiency virus (HIV) status, or severity of disease 
was observed. 
In the uncontrolled Phase 2b trial, C209, the most frequently reported AEs during the 
investigational phase were hyperuricemia, arthralgia, nausea, vomiting, headache, diarrhoea, 
blood uric acid increased, hypokalaemia, pruritus, injection site pain, insomnia, and tinnitus. 
From start of the trial up to the final analysis, 12 participants died during the C209 trial due to 
SAEs that included TB (5 cases), congestive cardiac failure, renal impairment, lung infection, 
cardiac 
arrest 
(underlying 
cause 
pneumonia), 
haemoptysis, 
hypertension, 
and 
pyopneumothorax/respiratory failure. These SAEs leading to death were considered not 
related to bedaquiline by the Investigator, except for renal impairment that was judged 
doubtfully related to bedaquiline. 
The analysis of long-term follow-up for survival outcomes for participants who prematurely 
discontinued in trial C209, based on data collection every 24 weeks (6 months) after 
withdrawal, included 4 deaths (all described as TB-related). In total, since the start of the C209 
trial, 16 participants (6.9%) have died (12 participants during the trial and 4 participants during 
the survival follow-up phase after premature discontinuation). None of the fatal SAEs were 
considered related to bedaquiline by the Investigator and none of these participants has a 
treatment- emergent adverse event. 
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Cardiovascular safety 
During clinical trials with bedaquiline a prolongation of QTc interval was observed. The US 
Product Label for bedaquiline[7] notes that treatment initiation is not recommended in patients 
with: 
• 
Heart failure; 
• 
QTcF interval > 500 ms (confirmed by repeat electrocardiogram); 
• 
A personal or family history of congenital QT prolongation; 
• 
Concomitant administration of fluoroquinolone antibiotics that have a greater 
potential for significant QT prolongation (i.e., gatifloxacin, moxifloxacin and 
sparfloxacin). 
• 
Hypokalaemia 
The US Product Label recommends that bedaquiline treatment must be discontinued if the 
patient develops clinically significant ventricular arrhythmia. An additive or synergistic effect 
on QT prolongation of bedaquiline when co-administered with other medicinal products that 
prolong the QT interval cannot be excluded. Caution is recommended when using bedaquiline 
concomitantly with medicinal products with a known risk of QT prolongation. If co-
administration of such medicinal products with bedaquiline is necessary, clinical monitoring 
including frequent ECG assessment is recommended. 
Hepatic safety 
The US product label notes increases in transaminases were seen in clinical trials during 
administration of bedaquiline with the background regimen. participants should be monitored 
during treatment. Other hepatotoxic medicinal products and alcohol should be avoided while 
taking bedaquiline, especially in those participants with diminished hepatic reserve.[7]  
Additional safety information from a recently completed trial 
In a recently completed phase I trial not yet included in the bedaquiline Investigators Brochure 
that evaluated drug-drug interactions between bedaquiline and either rifampin or rifabutin, 7 
participants experienced SAEs. Of those participants, 5 experienced SAEs of 
lymphocytopenia (all received rifabutin), which did not appear to be related to the AUC or 
Cmax of TMC207 or rifabutin. One participant experienced an SAE of elevated Creatine 
Kinase (rifampicin arm) and one experienced a grade 4 Total Bilirubin SAE (rifampicin arm). 
Lymphopenia was previously noted to be an infrequent toxicity associated with rifabutin, but 
not previously seen with bedaquiline. 
The bedaquiline/rifabutin regimen demonstrated significant reversible lymphopenia, which did 
not appear to be related to the AUC or Cmax of TMC-207 or rifabutin. 
2.5.2 
Pretomanid (P) 
As detailed in the Investigator’s Brochure,[15] pretomanid is a new chemical entity and a 
member of a class of compounds known as nitroimidazo-oxazines, which possess significant 
anti-tuberculosis activity and a unique mechanism of action.[16] Pretomanid demonstrated in 
vitro activity against both DS- and MDR-TB,[17] and in vivo activity in a mouse model of 
tuberculosis.[16, 17]  
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2.5.2.1 
Pharmacology 
Key in Vitro Evaluation of Pretomanid Bactericidal Activity 
Non-clinical in vitro trials demonstrated that pretomanid was active against actively growing 
drug- sensitive and drug-resistant MTB strains as well as against non-replicating MTB. The 
minimum inhibitory concentration (MIC) of pretomanid against a variety of drug-sensitive MTB 
isolates in vitro was shown to be like the MIC of isoniazid (MIC of pretomanid, ≤0.015 to 0.25 
µg/mL; MIC of isoniazid, 0.03 to 0.06 µg/mL). Pretomanid was efficacious in vitro against drug-
resistant clinical isolates of MTB with MIC values ranging from 0.03 to 0.53 µg/mL. The 
Investigator’s Brochure contains further information on in vitro bactericidal activity.[16] 
Although not thoroughly elucidated at this time, pretomanid has a novel mechanism of action 
that appears to involve inhibition of the synthesis of cell wall lipids under aerobic conditions 
and generation of reactive nitrogen species under anaerobic conditions. Reduction of 
pretomanid by a deazaflavin (F420)-dependent nitroreductase has been shown to be 
associated with generation of reactive nitrogen species, including nitric oxide (NO),[29] although 
the exact target(s) of the reactive nitrogen species are not known. Transcriptional profiling 
trials also suggest that pretomanid affects both cell wall biosynthesis and the respiratory 
complex of MTB.[30, 31] 
2.5.2.2 
Key Non-Clinical Trials of Pretomanid 
The activity of pretomanid as a single agent or as part of a multi-drug combination regimen 
has been examined in a number of mouse trials.[13, 14, 18, 32, 33] In a mouse model of established 
TB, the activity of various doses of pretomanid (given once daily, 5 days/week, for 1 month), 
initiated 22 days after inhalation infection with H37Rv MTB is shown in Figure 2. In this model, 
the minimum effective dose (MED) for pretomanid, defined as the lowest dose able to prevent 
the development of gross lung lesions and splenomegaly, was 12.5 mg/kg/day, while the 
minimum bactericidal dose (MBD), defined as the lowest dose able to reduce lung colony 
forming units (CFU) by 99%, was 100 mg/kg/day. Moreover, in these experiments, the activity 
of pretomanid at 100 mg/kg was comparable to the activity of isoniazid at 25 mg/kg. 
Figure 2.  Log10 CFU Counts in Lungs  
After One Month of Daily Treatment with the Indicated Dose (in mg/kg) of Pretomanid 
 
Arrows denote the minimum effective dose (MED) and minimum bactericidal dose (MBD). 
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2.5.2.3 
Non-Clinical Toxicology and Safety 
Pretomanid has been evaluated in an ICH recommended battery of safety pharmacology trials, 
in repeat-dose toxicity trials in rats (2 to 26 weeks) and cynomolgus monkeys (7 days to 
9 months), in 8 genotoxicity trials, and in fertility and teratology trials in rats and rabbits.  
In the repeat-dose toxicity trials, the lowest no-observed adverse effect level (NOAELs) was 
10 mg/kg/day in a 26-week trial in rats, 50 mg/kg/day in a 13-week trial in monkeys and 
<25 mg/kg/day (based on findings of thickening of the gastrointestinal tract at all doses) in a 
9-month trial in monkeys. The major findings in safety and toxicity trials are listed below in 
Table 2 and are detailed in the Investigator’s Brochure.[15] 
Table 2.  Key findings of Pretomanid in Safety and Toxicity Trials 
Nervous system-related effects.  
Rats given single oral pretomanid doses had decreased body tone, touch responses and 
decreased grooming behaviour at ≥150 mg/kg, which resolved within 24 hours. Rats given 
repeated daily doses of pretomanid had convulsions, ataxia, hypoactivity, recumbency, 
hyperactivity and sensitivity to touch, and squinting at ≥100 mg/kg/day, and early deaths 
occurred at doses ≥500 mg/kg/day. Monkeys given repeated daily doses of pretomanid had 
hypoactivity, ataxia, tremors, and convulsions at ≥450/300 mg/kg/day. These effects were 
reversible when dosing stopped and were absent at ≤30 mg/kg/day in rats and 
≤150 mg/kg/day in monkeys. 
Testicular toxicity 
Although rat and rabbit embryonic development trials indicate no effects of pretomanid on 
foetal development, testicular atrophy in rats was observed in 3-month and 6-month repeat-
dose toxicology trials and a Segment I fertility trial. In this fertility trial, testicular atrophy was 
associated with infertility; an approximate 30% reduction in fertility was also observed at a 
lower dose not associated with testicular atrophy. A detailed trial in sexually mature male 
monkeys demonstrated no effects on testicular histology or function in adult cynomolgus 
monkeys after 3 months’ dosing.  
Cataracts 
Cataracts developed in rats with prolonged daily administration of pretomanid at doses 
≥100 mg/kg/day. In one 13-week trial in monkeys, cataracts did develop at 
450/300 mg/kg/day, but only by the end of a 13-week recovery period. In a second 13-week 
trial in monkeys that included extensive ophthalmic examinations, cataracts did not develop 
at the high-dose level of 300 mg/kg/day. 
hERG inhibition and QT prolongation 
Altered ventricular repolarisation due to inhibition of hERG-mediated potassium current and 
manifested on the ECG as a prolonged QT interval corrected for heart rate (QTc). 
Pretomanid inhibited hERG current with IC50 values of approximately 6.2 µg/mL. Following 
a single pretomanid dose of 450 mg/kg in monkeys, QTc interval prolongation ranged from 
21 to 36 msec using Fridericia’s formula (QTcF) to correct for heart rate. Co-administration 
of pretomanid with moxifloxacin in the monkey or with bedaquiline in the dog did not result 
in any greater effect on the QT interval than with either agent alone. After repeated daily 
doses, the QTc interval in the monkey was prolonged at pretomanid doses of 
≥150 mg/kg/day. 
 
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2.5.2.4 
Clinical Background Information 
Pretomanid has been evaluated in 8 single- and multi-dose Phase 1 trials with healthy adult 
male and female participants, with 163 participants receiving single oral doses ranging from 
50 to 1500 mg and multiple oral doses ranging from 50 to 1000 mg/day given for up to 7 days. 
These Phase 1 trials have evaluated the safety, tolerability, and pharmacokinetics (PK) of 
pretomanid. Two additional Phase 1 trials Sponsored by the NIH included a Thorough QT trial 
and a trial of drug interactions among pretomanid, efavirenz and ritonavir/lopinavir.  Further 
details of the trials are in the Investigator’s Brochure.[15] 
2.5.2.5 
Pharmacokinetics 
Several Phase 1 trials have evaluated the safety, tolerability, and pharmacokinetics (PK) of 
pretomanid and have demonstrated that pretomanid has a half-life of approximately 18 hours, 
which supports daily dosing, and an effect of food with the 200-mg dose that increases total 
exposure by 88%. Interaction trials with midazolam, efavirenz and ritonavir/lopinavir 
demonstrate effects that are not likely to be clinically significant. 
Drug interaction with midazolam: Trial CL-006 was an open-label, fixed-sequence drug-drug 
interaction trial to evaluate the effects of multiple-dose administration of pretomanid on the PK 
of midazolam, a sensitive probe substrate and representative compound for drugs 
metabolised by CYP3A enzymes. Dosing with pretomanid at 400 mg/day for 14 days (to 
steady state) had minimal effect on the PK of midazolam and its 1-hydroxy metabolite as 
assessed by measurement of the Day 17: Day 1 ratios of maximum concentration (Cmax, AUC0-
t, and AUC0-inf. The Cmax and AUC values for midazolam after co-administration with 
pretomanid were approximately 85% of those observed after treatment with midazolam alone. 
Furthermore, midazolam and 1-hydroxy midazolam time to maximum concentration (Tmax) and 
half-life (t1/2) values were not different in the presence or absence of pretomanid. Therefore, 
14 days’ dosing with 400 mg/day pretomanid does not appear to significantly inhibit CYP3A4 
in humans. 
Drug interaction with efavirenz, ritonavir/lopinavir, and rifampicin: The US NIH Sponsored this 
drug interaction trial with rifampicin, a known hepatic enzyme inducer, and with the 
antiretroviral drugs efavirenz and ritonavir/lopinavir (LPV/r) in healthy participants. Participants 
in Arm 1 were randomised to Sequence 1 (pretomanid 200 mg once daily for 7 days, two-
week washout period, efavirenz (EFV) 600 mg once daily for 14 days, then both drugs for 7 
days) or Sequence 2 (Treatment 1B: EFV, then EFV + pretomanid, washout, and pretomanid). 
Results indicate that comparing pretomanid given with EFV versus pretomanid alone in 16 
participants, the geometric mean ratio (GMR) for Cmax was 0.71, the GMR for AUC0-24h was 
0.65, and the GMR for Cmin was 0.54. Concentrations of EFV when given with pretomanid 
versus given alone were similar. Participants in Arm 2 were randomised to Sequence 1 
(pretomanid 200 mg once daily for 7 days, then a 2-week washout period, then LPV/r 400/100 
mg twice daily for 14 days, then LPV/r + pretomanid together for 7 days) or Sequence 2 (LPV/r, 
then LPV/r + pretomanid, washout, then pretomanid alone). Comparing pretomanid + LPV/r 
versus pretomanid- alone from 16 PK-evaluable participants, the GMR for Cmax was 0.87, for 
AUC0-24h was 0.83, and for Cmin was 0.78. In Arm 3, participants received pretomanid for 7 
days, then rifampicin 600 mg for 7 days, then pretomanid + rifampicin together for 7 days. 
Comparing pretomanid + rifampicin versus pretomanid alone from 16 PK-evaluable 
participants, the GMR for Cmax, AUC0-24h, and Cmin were 0.47, 0.34, and 0.15, respectively.  
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In conclusion, compared to pretomanid alone, plasma pretomanid values (based on geometric 
mean ratios) for Cmax, AUC0-24h, and Cmin were reduced 28%, 35%, and 46% with efavirenz; 
13%, 17%, and 21% with LPV/r; and 53%, 66%, and 85% with rifampicin, respectively. 
2.5.2.6 
Pretomanid Clinical Efficacy 
The first two Phase 2 trials to evaluate the early bactericidal effect (EBA) of pretomanid oral 
monotherapy (50 to 1200 mg/day for 14 days) examined the dose-response for pretomanid in 
participants with newly diagnosed pulmonary TB infection. The first trial (CL-007) 
demonstrated good EBA, but all doses in this trial (200 to 1200 mg/day) had the same activity. 
The second trial (CL-010) evaluated a lower dose range (50 to 200 mg/day) and the maximum 
effect on EBA was seen at a dose of 100 mg/day over 14 days (Figure 3).[34] 
Figure 3.  Mean log Colony Forming Unit Values over Time Trial CL-010 
 
CFU = colony-forming unit; PRETOMANID = pretomanid 
* Day 0 = (Day -2 + Day -1)/2 = baseline measurement 
Pretomanid has been evaluated in patients with TB as monotherapy for a maximum duration 
of 14 days, the longest considered acceptable for a TB patient to be treated in a clinical trial 
with a single drug.  Trials of pretomanid for both 14 days and for up to 6 months, in combination 
with either bedaquiline and/or linezolid, are described below.  
2.5.2.7 
Pretomanid Clinical Safety 
The pretomanid Investigator’s Brochure[15] provides detailed safety information. 
Across the 16 clinical trials with pretomanid completed to date, a total of 649 participants have 
been exposed to pretomanid, including 289 healthy participants across the 10 Phase 1 trials 
4
4.5
5
5.5
6
logCFU
0
2
4
6
8
10
12
14
Day
 PA-824 50mg
 PA-824 100mg
 PA-824 150mg
 PA-824 200mg
 Rifafour e275 
Bi-linear regression of logCFU vs day over treatment
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and 360 participants with newly diagnosed smear positive pulmonary TB across 5 Phase 2 
trials.  Among the 289 healthy participants, 174 received exposure to a single dose of 
pretomanid ranging from 50 to 1500 mg and 115 received exposures to repeated daily doses 
of pretomanid (50 to 1000 mg) for up to 14 days. The 360 participants with newly diagnosed 
smear positive pulmonary TB were exposed to pretomanid either as a single agent at daily 
doses of 50 to 1200 mg for 14 days or in combination with other anti-TB agents (bedaquiline, 
moxifloxacin, pyrazinamide, linezolid and/or clofazimine) at a dose of 100 mg or 200 mg for 
up to 26 weeks.  The overall safety profile determined from the clinical trials completed to date 
indicates pretomanid is well tolerated in healthy adults and in TB patients when administered 
alone and in combination with moxifloxacin, pyrazinamide, bedaquiline and clofazimine.   
Pretomanid is an investigational drug and there is limited experience in humans; the safety 
database is being developed and Investigators should be vigilant to any adverse events noted 
in clinical trials.  Across these trials, the most common side effects or AEs associated with 
pretomanid exposure include: 
• 
Headache 
• 
Stomach discomfort (nausea, vomiting, flatulence, and/or diarrhoea) 
• 
Skin and subcutaneous tissue disorders 
The only adverse drug reaction identified in clinical trials completed to date as likely caused 
by pretomanid is blood creatinine increased.  A trial of the effects of repeat doses of 
pretomanid in healthy volunteers determined that the drug does not adversely affect 
glomerular filtration rate, effective renal plasma flow or filtration fraction and the elevations in 
serum creatinine reverse.  
The following parameters will be followed with particular care in the Phase 3 development 
program: 
• 
Hepatic Safety – Specific guidelines are included in the protocol to assure close 
surveillance and careful management of participants who have elevations in 
aminotransferases and/or bilirubin. Serious liver injury, including death in 3 participants 
taking a combination of pretomanid, pyrazinamide and moxifloxacin, has occurred during 
clinical trials and the risk of liver injury may be higher for participants taking a combination 
of pretomanid and pyrazinamide than it is for the standard HRZE treatment. Therefore, 
close monitoring of liver function is required for participants who are administered 
pretomanid, especially when combined with pyrazinamide.  Administration of the regimen 
of PaMZ has been associated with death in 3 participants associated with hepatic injury. 
Furthermore, the HRZE control regimen, and both pyrazinamide and moxifloxacin, has 
been associated with drug induced liver injury and in rare cases hepatic necrosis.  
Consequently, hepatic safety will be under close surveillance in all clinical trials. 
• 
Ophthalmologic Evaluations – while the detailed examinations in Phase 2 have not raised 
concern for humans, ophthalmologic examinations, with slit lamp exam and grading of lens 
opacities, will continue in all human trials that involve exposure to pretomanid longer than 
14 days.  These examinations will be conducted at baseline, near the end of the dosing 
period and 3 months after the end of trial drug exposure.  These examinations are to follow 
up on the finding of cataracts in rats exposed to pretomanid in clinical trials. 
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• 
Cardiovascular Safety – All participants will have ECGs taken at baseline and at multiple 
time points during the trial.  Although the Thorough QT Trial in healthy participants found 
that pretomanid did not increase corrected QT intervals in a clinically meaningful way and 
did not add to the known effect of moxifloxacin, the ECGs will be carefully monitored during 
Phase 3.  All ECGs will be interpreted and conduction intervals will be confirmed by a 
central cardiology service. 
• 
Central Nervous System Safety –While pretomanid alone or combined in various regimens 
has been well tolerated overall, one participant in Trial NC-002 of the Pa-M-Z regimen had 
a seizure without any prior seizure history, and some animals in toxicology trials have had 
seizures at high drug exposures.  Consequently, close surveillance will be made of 
participants in the Phase 3 trial for seizures or any central nervous system adverse events 
of potential concern. 
Of note, preclinical toxicology trials found that rats, but not primates, had testicular toxicity 
when treated with pretomanid. Clinical evaluations of potential testicular toxicity in Phase 2 
trials have evaluated over 300 participants exposed to pretomanid over 2-6 months with 
evaluations of testosterone, LH, or Inhibin B (2 trials) or FSH values (3 trials) at baseline and 
after daily dosing of regimens containing pretomanid in various combinations with 
moxifloxacin, pyrazinamide and bedaquiline.  A review of data from the 3 trials by an 
independent reproductive endocrine expert concluded that, based on the hormone evaluations 
to date, there is no evidence that pretomanid is a testicular toxicant in men at the doses and 
exposure times evaluated. 
2.5.3 
Moxifloxacin (M) 
Moxifloxacin (M)[19]  is an 8-methoxyquinolone whose oral formulation (which will be used 
in this trial) has enhanced activity against Gram-positive pathogens, and anaerobes while 
retaining useful activity against Gram-negative organisms. Moxifloxacin is not metabolized by 
nor induces the cytochrome P450 system, thus the risk of clinically relevant drug interactions 
is reduced. It has a positive safety profile within the fluoroquinolone class at the approved daily 
dose of 400 mg. Moxifloxacin while not approved for TB by most regulatory authorities, it is 
regularly used in second line MDR-TB treatment. The WHO TB Treatment Guidelines place 
moxifloxacin in the category of Group 3 drugs and notes that “all patients [with MDR-TB] 
should receive a Group 3 medication if the strain of MTB is susceptible or if the agent is thought 
to have efficacy. One of the higher generation fluoroquinolones, such as levofloxacin or 
moxifloxacin, is the fluoroquinolone of choice.[5]” It is currently in late stage clinical 
development for first-line TB treatment in combination with other TB drugs, including 
pyrazinamide in two different four-month long regimens.  
2.2.3.1. 
Moxifloxacin Clinical Trials 
Moxifloxacin is commonly used as second line therapy for TB (e.g. MDR- TB), and has also 
been evaluated in several clinical studies of participants with TB, including four 8-week 
treatment period Phase 2b studies (see Table 3 below).  
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Table 3.  Summary of Phase 2b trials in which moxifloxacin were administered 
as part of a four-drug regimen during the intensive phase of treatment (total 
treatment duration: 2 months) 
Trial 
Design 
Objective 
Participants 
(N) 
Status 
Trial 27 
Randomized, 
double-blind, 
controlled 
To compare the sputum culture-
conversion rate at the end of the 4-
drug (intensive) phase of therapy 
using the standard 4-drug regimen 
HRZE with a standard regimen with M 
replacing E.  
336 
Completed 
OFLOTUB 
Trial 
Randomized, 
Open label, 
Controlled 
To compare the bactericidal activities 
of regimens where gatifloxacin, M, 
and ofloxacin were substituted for E in 
the 2-month initial phase of standard 
TB treatment with HRZE.  
 
217 
Completed 
Johns 
Hopkins 
(FDA 
orphan 
drug) Trial 
Randomized, 
double-blind, 
Controlled 
To compare the sputum culture 
conversion rate at the end of the 4-
drug (intensive) phase of therapy 
using a standard 4-drug regimen 
(HRZE) with a regimen with M 
replacing E (HRZM). 
170 
Completed 
Trial 28 
Randomized, 
double-blind, 
Controlled 
To compare the culture-conversion 
rate at the end of the 4-drug 
(intensive) phase of therapy using a 
standard 4-drug regimen (HRZE 5 
days per week) with a regimen with M 
replacing H (MRZE 5 days per week). 
 
433 
Completed 
 
2.5.3.1 
Moxifloxacin Clinical Safety 
In Trial 27,[35] the moxifloxacin-containing TB regimens (HRZM) were shown to be safe and 
well tolerated. There was no difference in SAEs between the HRZM and HRZE treatment 
arms, and most SAEs were hospitalizations thought to be unrelated to the trial treatment.  
Participants treated with the moxifloxacin-containing regimen were more likely to report 
nausea (22% vs. 9%, p = 0.002), but this was generally mild and did not lead to treatment 
discontinuation as similar proportions of participants in both groups completed trial drug 
treatment (88% HRZM-treated vs. 89% HRZE-treated).  The one death during the first 2 
months of treatment was thought to be caused by a pulmonary embolism unrelated to 
tuberculosis therapy.   
In the OFLOTUB trial,[36] AEs and SAEs occurred with equal frequency in the four treatment 
arms.  The most frequent AEs were raised amylase (in 41% of participants due to HIV 
infection), raised transaminase (10%), arthralgia (9%), anaemia (7%), hypokalaemia (6%) and 
vomiting (5%).  No Participant was withdrawn from the trial due to an adverse event.  There 
were 4 deaths in the trial: 2 in the control group, 1 each in the moxifloxacin and ofloxacin arms.  
Importantly, participants in this trial who received moxifloxacin and pyrazinamide in addition 
to isoniazid and rifampin had more rapid sputum clearance than participants on the four 
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standard first line drugs (isoniazid, rifampin, pyrazinamide and ethambutol). This difference 
was evident 14 days after initiation of treatment. 
In the JHU trial,[37] AEs did not differ by treatment group. There were 16 SAEs (8 in each 
group) in 12 participants. Only 1 event was judged related to trial drug (grade 3 cutaneous 
reaction in the ethambutol group). Eight participants died during the trial, including 1 in each 
group still receiving trial phase treatment. No death was attributed to trial treatment. Only 5 
participants discontinued treatment because of toxic effects; 2 participants in the moxifloxacin 
group stopped because of grade 2 nausea and vomiting and 1 because of grade 2 
paraesthesia’s and ataxia. Two participants in the E group stopped because of grade 2 rash 
and pruritus and 1 because of grade 3 peripheral neuropathy.  There was no change in the 
QTc interval on serial electrocardiograms taken during the trial. 
In Trial 28,[38] the proportions of participants with SAEs during the intensive phase treatment 
were similar between arms (isoniazid 3.9% vs. moxifloxacin 4.2%; P = 0.88). Three SAEs 
attributed to trial treatment during the first 2 months occurred among the moxifloxacin group 
and two in the isoniazid group.  Seven participants died during the trial including 3 participants 
receiving the moxifloxacin treatment regimen and 4 participants receiving the isoniazid 
treatment regimen. The 3 moxifloxacin participants died during the intensive phase of TB 
treatment. Two participants died from advanced pulmonary TB judged not related to trial 
treatment and 1 Participant (who developed diabetic ketoacidosis considered possibly related 
to trial treatment) died from possible acute pulmonary embolus unrelated to trial treatment. 
The 4 isoniazid deaths occurred during the continuation phase, and all 4 were considered 
unrelated to trial treatment.  Nausea was more common among participants in the moxifloxacin 
arm than in the isoniazid arm (19.6% vs. 11.7%, respectively; P = 0.03) although similar 
proportions reported vomiting.  However, the proportions of participants with hepatitis, defined 
as serum AST 3 times or greater than the upper limit of normal, were similar between treatment 
arms during intensive phase (isoniazid 3.4% vs. moxifloxacin 3.3%; P = 0.93).  Moxifloxacin 
has also been evaluated in combination with pretomanid for two weeks in participants with TB 
(Trial NC-001) and for 8 weeks in NC002 as reviewed above in Section 2.2.3 (Trial NC-001). 
For additional information on moxifloxacin, refer to the IB[39] and the manufacturer’s package 
insert.[19] 
2.5.4 
Pyrazinamide (Z) 
Pyrazinamide (Z) is a standard drug used as part of the four drug HRZE regimen used for the 
first two months of intensive therapy for drug-sensitive TB as recommended by the WHO and 
many National TB programs.  Please see the Package Insert[20] for more detail.  Z is active 
against TB in vitro and it potentiates the bactericidal and sterilizing activity of both bedaquiline 
and  pretomanid in mouse models of TB infection.[8, 15]  Pyrazinamide enhanced the 
bactericidal activity of both bedaquiline and  pretomanid in Trial NC-001-(J-M-Pa-Z) as noted 
by decreases over 14 days in the CFU counts in sputum among participants. 
The pyrazinamide product label notes that pyrazinamide is contraindicated in persons with 
severe hepatic damage, who have shown hypersensitivity to it, and with acute gout.  The most 
serious side effect is hepatotoxicity. Its frequency appears to be dose-related and thus liver 
function should be assessed before and regularly during treatment with pyrazinamide.  
Hyperuricemia commonly occurs and is occasionally accompanied by arthralgia and may lead 
to attacks of gout. Photosensitivity and skin rash have been reported less frequently. Other 
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side effects that have been reported are anorexia, nausea and vomiting, malaise, fever, 
sideroblastic anaemia and dysuria.  
Pyrazinamide may decrease the efficacy of gout therapy (e.g. allopurinol, colchicine, 
probenecid or sulphinpyrazone) and dosage adjustments of these medications may be 
necessary.  For additional information on pyrazinamide, refer to the manufacturer’s package 
insert. [20] 
2.6 
Overall Benefit/Risk Assessment 
Some participants with pulmonary TB in this trial will be given a regimen of BPaMZ. These 
drugs individually and in combination are known to have anti-tuberculosis activity and is not 
expected to have an adverse impact on the ultimate cure of TB in these participants. Based 
on NC-005 and other regimens using each of the regimen drugs in different combinations 
there is good evidence that this may be a highly effective therapy for both DS-TB and DR-TB.  
For DS-TB the potential for a shorter regimen than 6 months is expected to be successful 
based on preclinical and clinical information as listed before.  Participants in this trial will have 
their TB infection carefully characterized, with drug sensitivity profiles established, and they 
will receive treatment with trial drugs that have demonstrated activity against MTB.   
Participants will receive individualized medical attention; this will allow a continuous monitoring 
of the health conditions of each participant, any of whom can be withdrawn at any stage of the 
trial and removed from trial treatment should his/her condition suggest to the Investigator that 
this would be in his/her best interest.  Multiple blood samples will be taken for safety laboratory 
studies, and ECGs will be taken at multiple time points.  
One concern in particular, the combination of two agents with known QT-prolonging effects 
(bedaquiline and moxifloxacin), has been addressed specifically by carefully identifying and 
excluding participants with risk factors that might predispose them to cardiac arrhythmias, 
screening all participants for evidence of existing cardiac disease and monitoring all 
participants with ECGs throughout the trial.  
The trial drugs in the proposed regimens to be tested in this trial have all demonstrated safety 
and efficacy in the treatment of pulmonary tuberculosis in non-clinical and clinical studies. 
Specifically, the regimen B-Pa-Z was generally well-tolerated and demonstrated bactericidal 
activity in a 14-day EBA trial. The potential risks associated with the trial drugs and regimens 
has been identified as outlined below and will be monitored carefully throughout the conduct 
of the trial. 
The BPaMZ regimen is a novel regimen treatment expected to be effective, safe and well-
tolerated and might even shorten the current treatment duration for patients with TB. Based 
on data from previous trial evaluations of key monitoring and safety information as outlined 
before suggests a favourable benefit-to-risk ratio trials.  
Key Monitoring and Safety Information Regarding Regimen Agents 
2.6.1 
Bedaquiline (B) 
2.6.1.1 
Adverse Drug Reactions for bedaquiline  
Participants in the Any bedaquiline group compared to the Any Placebo group (difference > 
5.0%) had headache (23.5% versus 11.4%, respectively), nausea (35.3% versus 25.7%, 
respectively), arthralgia (29.4% versus 20.0%, respectively), and transaminases increased 
(6.9% versus 1.0%, respectively).and diarrhoea (11.4% versus 5.9%, respectively). 
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2.6.1.2 
Cardiovascular safety 
During clinical studies with bedaquiline a prolongation of QTc interval was observed. An ECG 
should be obtained prior to and after initiation of therapy with bedaquiline to monitor the QTc 
interval. 
Bedaquiline treatment initiation is not recommended in patients with: 
• 
Heart failure 
• 
QTcF interval > 450 ms (confirmed by repeat electrocardiogram) 
• 
A personal or family history of congenital QT prolongation 
• 
Concomitant administration of fluoroquinolone antibiotics that have a greater potential 
for significant QT prolongation (i.e., gatifloxacin, moxifloxacin and sparfloxacin) 
• 
Hypokalemia 
 
Bedaquiline treatment must be discontinued if the patient develops clinically significant 
ventricular arrhythmia. An additive or synergistic effect on QT prolongation of bedaquiline 
when co-administered with other medicinal products that prolong the QT interval cannot be 
excluded. Caution is recommended when using bedaquiline concomitantly with medicinal 
products with a known risk of QT prolongation. If co-administration of such medicinal products 
with bedaquiline is necessary, clinical monitoring including frequent ECG assessment is 
recommended. 
In the DR-TB treatment arm of the present trial, moxifloxacin will be co-administered with 
bedaquiline. This is to prevent the development of resistance to the other drugs in the regimen 
in case the participant’s strain of MTB is resistant to pyrazinamide. ECG assessments will be 
performed on all participants at screening, baseline, and at treatment visits specified in the 
flow chart.   
2.6.1.3 
Hepatic safety 
Increases in transaminases were seen in clinical studies during administration of bedaquiline 
with the background regimen. Participants should be monitored during treatment. 
Other hepatotoxic medicinal products and alcohol should be avoided while taking bedaquiline, 
especially in participants with diminished hepatic reserve. 
2.6.2 
Pretomanid (P) 
The most common side effects or AEs associated with pretomanid exposure include: 
• 
Headache 
• 
Benign, isolated and reversible elevations of serum creatinine 
• 
Stomach discomfort (nausea, vomiting, flatulence, and/or diarrhoea) 
• 
Skin and subcutaneous tissue disorders 
2.6.2.1 
Hepatic Safety 
Hepatic enzyme increases have been seen in participants treated with pretomanid in 
combinations with various other medications during the clinical development program. It is 
difficult to assign specific causality to any one drug within a regimen; nonetheless, the NC-008 
trial will include specific monitoring of hepatic enzymes. 
For additional information refer to  pretomanid IB.[15] 
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2.6.3 
Moxifloxacin (M) 
In the usual daily doses of 400 mg/day, moxifloxacin is well tolerated.  As stated in the Package 
Insert[19]  the most frequent individual drug related AEs observed in clinical trials with 400 mg 
oral moxifloxacin therapy were nausea (7.5%) and diarrhoea (5.8%).  Fluoroquinolones, 
including moxifloxacin, are associated with an increased risk of tendinitis and tendon rupture 
in all ages.   
A known but rare side effect of fluoroquinolones, including moxifloxacin is exacerbation of 
myasthenia gravis. In addition, moxifloxacin has been shown to prolong the QT interval of the 
electrocardiogram in some participants.  It should be used with caution in participants being 
treated concomitantly with other drugs where an additive effect on the QT interval cannot be 
excluded.  
Serious and sometimes fatal hypersensitivity reactions, including anaphylactic reactions, as 
well as peripheral neuropathy may occur after the first or subsequent doses of moxifloxacin. 
For additional information, refer to the moxifloxacin package insert.[19] 
2.6.4 
Pyrazinamide (Z) 
The dose of pyrazinamide that will be used in this trial is an approved dosage for the treatment 
of TB. The most serious side-effect of pyrazinamide is hepatotoxicity and its frequency 
appears to be dose-related. Hyperuricemia commonly occurs, occasionally accompanied by 
arthralgia and may lead to attacks of gout.  Photosensitivity and skin rash have been reported 
less frequently.  Other side-effects that have been reported are anorexia, nausea and 
vomiting, malaise, fever, sideroblastic anaemia and dysuria.  Pyrazinamide may decrease the 
efficacy of gout therapy (e.g. allopurinol, colchicine, probenecid or sulphinpyrazone) and 
dosage adjustments of these medications may be necessary.  For additional information on 
pyrazinamide, refer to the manufacturer’s package insert.[20] 
2.6.5 
HRZE/HR Control 
The HRZE (isoniazid 75 mg plus rifampicin 150 mg plus pyrazinamide 400 mg plus ethambutol 
275 mg combination tablets) combination will be given the first 8 weeks and the HR (isoniazid 
75 mg plus rifampicin 150 mg combination tablets) combination will be given from Weeks 9 to 
26. 
Participants with DS-TB that are randomized to the HRZE/HR control arm in this trial will be 
given standard weight-adjusted doses of HRZE.   
Please see the HRZE and HR Package Inserts[22, 40] for known and potential risks and benefits. 
3.0 
Trial Objectives 
3.1 
Primary Objectives 
To evaluate the efficacy, safety and tolerability at 8 weeks (2-months), 52 weeks (12-months), 
and 104 Weeks (24-months) post the start of the following treatment regimens in participants 
with: 
Drug Sensitive TB (DS-TB) 
–  BPaMZ given for 17 Weeks (4 months) 
– Standard HRZE/HR treatment given for 26 weeks (6 months) 
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Drug Resistant TB (DR-TB)  
– BPaMZ given for 26 Weeks (6 months) 
 
DR-TB are defined as participants with: 
1. mono-resistance to rifampicin or isoniazid, OR 
2. resistance to both rifampicin and isoniazid (DR-TB) 
3.2 
Secondary Objectives 
Efficacy: 
 
• 
Incidence of bacteriologic failure or relapse or clinical failure at 52 weeks (or 12 months) 
and 104 weeks (or 24 months) weeks from the start of therapy.  
• 
Proportion of participants with sputum culture conversion to negative status in liquid culture 
(MGIT) at 4, 6, 12 and 17 weeks to be explored as a potential biomarker of outcome at 52 
weeks from start of therapy. 
• 
Change from baseline in weight. 
• 
Change from baseline in TB symptoms. 
• 
Change from baseline in Participant Reported Health Status. 
 
Safety and Tolerability: 
 
• 
Incidence of Treatment Emergent Adverse Events (TEAEs) presented by incidence, 
severity, drug relatedness, seriousness, leading to early withdrawal, and leading to death.  
 
Quantitative and qualitative clinical safety laboratory measurements, including 
observed and change from baseline. 
 
Quantitative and qualitative ECG results (heart rate, RR interval, PR interval, QRS 
interval, QT interval and QTc interval), including observed. QT/QTc intervals, change 
from baseline, will be categorized as these will be centrally read. 
• 
Changes in male reproductive hormones and lens opacities. 
 
These data will be presented as descriptive analyses, and no inferential tests will be carried 
out. 
Pharmacokinetics (PK) and Pharmacokinetics/Pharmacodynamics (PK/PD): 
 
Plasma concentrations from sparse sampling will be used to update existing population PK 
models and derive exposure metrics (e.g., Cmin, Cmax, AUC) for bedaquiline and its M2 
metabolite, pretomanid, moxifloxacin, and pyrazinamide. Effects of baseline covariates on 
exposure will be assessed; so too, will the effects of con-medications including antiretroviral 
therapy (ART), as feasible.  
Data from other trials may be included to enhance the model-based analysis. Relationships 
will be explored between drug exposure and efficacy and safety endpoints. These exploratory 
PK/PD analyses may include HIV status as a covariate. 
3.3 
Exploratory Objectives 
• 
Evaluate whether any of the secondary endpoints predicts relapse free cure. 
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• 
Subgroup analysis of populations by HIV status.  
No formal statistical comparisons will be made for the participants enrolled with DR-TB. 
 
4.0 
Trial Design 
4.1 
Summary of Trial Design 
This is a Phase 2c, multi-centre, open-label, partially randomized clinical trial conducted in 3 
treatment groups.  Participants, trial Investigators and staff, including laboratory staff, will not 
be blinded to treatment allocation during the treatment phase of the trial. 
The trial will be performed globally at multiple centres located throughout all regions of the 
world.    
A total of 300 DS-TB participants (150 per treatment arm) will be randomized and stratified for 
co-infection with HIV and cavitation.  Up to 150 DR-TB participants will be enrolled and 
assigned to the treatment arm described in Table 4 below.   
Participants with Drug Sensitive TB (DS-TB): 
 
Participants with DS-TB will be randomized to one of two treatment arms. These participants 
will receive either BPaMZ daily for 17 weeks (4 months), or HRZE/HR combination tablets 
daily for 26 weeks (6 months).  Participants will be stratified for co-infection with human 
immunodeficiency virus (HIV) and cavitation. 
 
Participants with Drug Resistant TB (DR-TB): 
 
Participants with DR-TB will be assigned to receive BPaMZ daily for 26 weeks (6 months). 
Eligible participants who meet all the inclusion criteria and none of the exclusion criteria, aged 
18 and over, male or female will be assigned to one of the 3 treatment groups with a target of 
50% of the participants being HIV positive. An interactive web response system (IWRS) will 
be used which will utilize a dynamic randomization system using cavitation with a random 
element to allocate participants evenly across the arms by HIV status and type of TB (DS 
versus DR) after they have given written, informed consent during the Screening Visit (Days -
9 to -1) and met all eligibility criteria. 
4.2 
Treatment Plan: Schedule of Assessments 
• 
Screening Period (Day -9 to Day -1) 
• 
Treatment Period (Day 1 to Week 17 (4-month treatment); or Week 26 (6-month 
treatment))  
• 
Follow-Up Period (Week 39 to Week 104) 
 
Refer to: 
• 
Synopsis Flow Chart and Procedures (Section 1.2; flow chart) for the timing of all 
procedures and laboratory samples to done at each visit.   
• 
Trial Procedures (Section 7.0, Trial Variables and Procedures) for details regarding 
specific procedures or laboratory tests. 
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Each participant will receive up to 26 weeks of treatment.  The trial treatment regimens may 
require interruptions/pauses due to toxicities. All dose interruptions/pauses should be 
discussed with the Sponsor’s Medical Monitor prior to implementation unless an 
interruption/pause is required urgently for a safety concern.  
 
All participants will enter post-treatment follow-up which continues until Week 104 (24 months) 
after start of treatment / randomisation. 
 
Participants will receive daily dosing, orally. They will be randomized to one of the following 
arms: 
Table 4: Treatment Groups 
 
Treatment Group 
Treatment 
Duration 
No of 
Participants 
1 Bedaquiline 200 mg daily for 8 weeks  
then 100 mg daily for 9 weeks, together with pretomanid 
200 mg + moxifloxacin 400 mg + pyrazinamide 1500 mg 
daily 
17 weeks 
(4 months) 
150 DS-TB 
2 HRZE Tablets (Weeks 1-8): (isoniazid 75 mg plus 
rifampicin 150 mg plus pyrazinamide 400 mg plus 
ethambutol 275 mg combination tablets).  
 
Followed by 
 
HR Tablets (Weeks 9-26): (isoniazid 75 mg plus 
rifampicin 150 mg combination tablets).   
First 8 weeks  
(2 months) 
 
 
then 
 
17 weeks  
(4 months) 
 
Total 6 months 
150 DS-TB 
3 Bedaquiline 200 mg daily for 8 weeks  
then 100 mg daily for 18 weeks, together with pretomanid 
200 mg + moxifloxacin 400 mg + pyrazinamide 1500 mg 
daily. 
26 weeks 
(6 months) 
Up to 150 
DR-TB 
5.0 
Trial Population 
The participant must meet all inclusion and no exclusion criteria within the screening period.  
Retesting for any laboratory or ECG parameters is allowed within the screening period.  
Sponsor may consider replacement of late exclusions. It is the intent of the protocol that the 
participants are hospitalized according to local practices and at the judgment of the treating 
physician / investigator. 
5.1 
Inclusion Criteria 
Participants are required to meet all the following inclusion criteria during the screening period 
to be randomized. 
1. Signed written consent prior to undertaking any trial-related procedures. 
2. Male or female, aged 18 years or over. 
3. Body weight (in light clothing and no shoes) ≥ 30 kg. 
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4. Sputum positive for tubercule bacilli (at least 1+ on the International Union Against 
Tuberculosis and Lung Disease [IUATLD]/WHO scale (Appendix 1) on smear microscopy) 
at the trial laboratory. 
5. Disease Characteristics: 
• 
Participants with one of the following pulmonary TB conditions: 
DS-TB treatment arm participants should be: 
a. sensitive to rifampicin and isoniazid by rapid sputum based test AND 
b. either newly diagnosed for TB or have a history of being untreated for at least 
3 years after cure from a previous episode of TB. 
If they are randomised into the trial due to being sensitive to rifampicin and 
isoniazid by rapid molecular sputum based test, however on receipt of the 
rifampicin and/or isoniazid phenotypic resistance testing in liquid culture this shows 
they are rifampicin or isoniazid resistant, they will be: 
a. Excluded as late exclusions; 
b. Possibly replaced as determined by the Sponsor.  
DR-TB treatment arm participants should be: 
a. Resistant to rifampicin and/or isoniazid.  
b. Should not have had previous treatment for DR-TB/MDR-TB, although may 
have been on a DR-TB/MDR-TB treatment regimen for no longer than 7 days 
at start of screening. 
6. A chest x-ray, within 6 months prior to or during the Screening visit, which in the opinion 
of the Investigator is compatible with pulmonary TB.  
7. Contraception: 
 
Be of non-childbearing potential or using effective methods of birth control, as defined 
 
below: 
Non-childbearing potential: 
a. Participant - not heterosexually active or practice sexual abstinence; or  
b. Female participant or male participants female sexual partner - bilateral 
oophorectomy, bilateral tubal ligation and/or hysterectomy or has been 
postmenopausal with a history of no menses for at least 12 consecutive months; 
or  
c. Male participant or female participants male sexual partner - vasectomised or has 
had a bilateral orchidectomy at least three months prior to screening; 
 
Effective birth control methods: 
a. Double barrier method which can include a male condom, diaphragm, cervical cap, 
or female condom; or  
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b. Female participant: Barrier method combined with hormone-based contraceptives 
or an intra-uterine device for the female participant.  
c. Male participants’ female sexual partner: Double barrier method or hormone-based 
contraceptives or an intra-uterine device for the female partner.  
Both male and female participants must be willing to continue practicing birth control 
methods and are not planning to conceive throughout treatment and for 12 weeks after 
the last dose of trial medication or discontinuation from trial medication in case of 
premature discontinuation.  
Note: Hormone-based contraception alone may not be reliable when taking IMP; therefore, 
hormone-based contraceptives alone cannot be used by female participants to prevent 
pregnancy. 
 
5.2 
Exclusion Criteria 
Participants will be excluded from participation if they meet any of the following criteria: 
Medical History and Concurrent Conditions: 
1. Any non-TB related condition where participation in the trial, as judged by the 
Investigator, could compromise the well-being of the participant or prevent, limit or 
confound protocol specified assessments. 
2. Abuse of alcohol or illegal drugs that in the opinion of the Investigator would 
compromise the participants’ safety or ability to follow through with all protocol-
specified restrictions, visits and evaluations. 
3. Being, or about to be, treated for malaria. 
4. Is critically ill and, in the judgment of the Investigator, has a diagnosis likely to result in 
death during the trial or the follow-up period. 
5. TB meningitis or other forms of extrapulmonary tuberculosis with high risk of a poor 
outcome, or likely to require a longer course of therapy (such as TB of the bone or 
joint), as judged by the Investigator. 
6. History of allergy or hypersensitivity to any of the trial IMP or related substances, 
including known allergy to any fluoroquinolone antibiotic, history of tendinopathy 
associated with quinolones or suspected hypersensitivity to any rifampicin antibiotics. 
7. For HIV infected participants any of the following: 
 
a. CD4+ count <100 cells/µL  
b. Karnofsky score <60% (Appendix 5)   
c. Received intravenous antifungal medication within the last 90 days 
d. WHO Clinical Stage 4 HIV disease (Appendix 3) 
 
8. Participants who recently started or expected to need to start ART within 1 month after 
randomization. Participants who have been on ARTs for more than 30 days prior to 
start of the Screening visit, or expected to start ART greater than 30 days after 
randomization may be included.  
9. Resistant to fluoroquinolones (rapid, sputum-based molecular screening tests)  
 
a. If they are randomised into the trial due to being sensitive to fluoroquinolones 
by rapid sputum based test, however on receipt of the moxifloxacin phenotypic 
resistance testing in liquid culture they are found to be fluoroquinolones 
resistant, they will be excluded as late exclusions. 
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10. Having participated in other clinical trials with investigational agents within 8 weeks 
prior to start of trial medication or currently enrolled in an investigational trial. 
11. Participants with any of the following at the Screening visit (per measurements and 
reading done by ECG): 
 
a. QTcF interval on ECG >500 msec.  Participants with QTcF > 450 must be 
discussed with the Sponsor Medical Monitor before enrolment. 
b. Heart failure 
c. A personal or family history of congenital QT prolongation 
d. A history of or known, untreated, ongoing hypothyroidism 
e. A history of or ongoing bradyarrhythmia 
f. 
A history of Torsade de Pointe 
 
12. Unstable Diabetes Mellitus which required hospitalization for hyper- or hypo-glycaemia 
within the past year prior to start of screening. 
13. Females who have a positive pregnancy test at the Screening visit or already known 
to be pregnant, breast-feeding, or planning to conceive a child during the trial or within 
6 months of stopping treatment.  Males planning to conceive a child during the trial or 
within 6 months of stopping treatment.  
14. Participants with lactose intolerance, lactase deficiency and/or glucose-galactose 
malabsorption. 
 
Previous and Concomitant Therapy 
15. Previous treatment with pretomanid or bedaquiline. 
16. Previous treatment for TB which includes, but is not limited to, gatifloxacin, amikacin, 
cycloserine, rifabutin, kanamycin, para-aminosalicylic acid, rifapentine, thioacetazone, 
capreomycin, quinolones, thioamides, and metronidazole. 
17. For DS-TB participants: Previous treatment for tuberculosis within 3 years prior to the 
Screening visit. Participants who have previously received isoniazid prophylactically 
may be included in the trial if that treatment is/was discontinued at least 7 days prior 
to randomization. 
18. For the DR-TB participants: Previous treatment for DR-TB/MDR-TB, although may 
have been on a DR/MDR-TB treatment regimen for no longer than 7 days at start of 
screening. 
19. Any diseases or conditions in which the use of the standard TB drugs or any of their 
components is contra-indicated, including but not limited to drug allergy. 
20. Use of any drug within 30 days prior to randomisation known to prolong QTc interval 
(including, but not limited to, amiodarone, amitriptyline, bepridil, chloroquine, 
chlorpromazine, cisapride, clarithromycin, disopyramide dofetilide, domperidone, 
droperidol, 
erythromycin, 
halofantrine, 
haloperidol, 
ibutilide, 
levomethadyl, 
mesoridazine, methadone, pentamidine, pimozide, procainamide, quinacrine, 
quinidine, sotalol, sparfloxacin, thioridazine). 
21. Use of systemic glucocorticoids within one year of start of screening (topical, inhaled 
or intranasal glucocorticoids are allowed) due to visual opacities or cataracts. 
22. For HIV infected participants, only the following types of ART are permissible:  
 
a. Lopinavir/ritonavir 
based 
regimen 
consisting 
of 
lopinavir/ritonavir 
in 
combination with any two NRTI. TDF/ABC and FTC/3TC. 
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b. Integrase inhibitor (e.g., dolutegravir) in combination with TDF/ABC and 
FTC/3TC. 
c. In participants who have viral load suppressed on efavirenz at the time of 
screening, their ART can be changed to rilpivirine in combination with TDF/ABC 
and FTC/3TC. If possible, the same nucleoside backbone should be used. 
d. Nevirapine (NVP) based regimen consisting of NVP in combination with any 
two 
nucleosidase 
reverse 
transcriptase 
inhibitors 
(NRTIs) 
tenofovir 
(TDF)/abacavir (ABC) and emtricitabine (FTC)/lamivudine (3TC). 
 
23. In the case where participants are randomized to a rifampicin containing regime: 
 
a. EFV can be used with rifampicin.  
b. LPV needs to be double dosed.  
c. Rilpivirine cannot be given with rifampicin  
 
Diagnostic and Laboratory Abnormalities 
24. Participants with the following toxicities at screening as defined by the enhanced 
Division of Microbiology and Infectious Disease (DMID) adult toxicity table (Draft 
November 2007) (Appendix 2) where applicable: 
 
a. platelets grade 2 or greater (<100,000/mm3) 
b. creatinine grade 2 or greater (>1.5 times upper limit of normal [ULN])  
c. eGFR ≤ 60 mL/min/m2 
d. haemoglobin grade 2 or greater (≤8.0 g/dL) 
e. serum potassium less than the lower limit of normal for the laboratory. This may 
be repeated once 
f. GGT: greater than 3 x ULN 
g. AST: 
• 
grade 3 or greater (≥3.0 x ULN) to be excluded; 
• 
results between 1.5 x ULN and 3 x ULN must be discussed with and 
approved by the Sponsor Medical Monitor 
h. ALT: 
• 
grade 3 or greater (≥3.0 x ULN) to be excluded 
• 
greater than ULN must be discussed with and approved by the Sponsor 
Medical Monitor 
i. 
 ALP: 
• 
grade 3 or greater (≥3.0 x ULN) to be excluded 
• 
grade 2 (2.0 – <3.0 x ULN) must be discussed with and approved by 
the Sponsor Medical Monitor 
j. 
Total bilirubin: 
• 
>1.5 x ULN to be excluded; 
• 
1 – 1.5 x ULN must be discussed with and approved by the Sponsor 
Medical Monitor 
k. Direct bilirubin: 
• 
greater than 1x ULN to be excluded 
All the inclusion and none of the exclusion criteria must be met. If no single variable/value is 
outside of the ranges of acceptability, but when multiple values are close to the limits and/or 
whenever the Investigator has reason to suspect that there might be a health problem (other 
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than TB), enrolment should only be considered after discussing the case with the Sponsor 
Medical monitor. 
 No protocol waivers will be granted by the TB Alliance. 
 
5.3 
Restrictions 
Concomitant medications should be kept to a minimum during the trial. However, if 
concomitant medications are necessary for the participant’s welfare and are unlikely to 
interfere with the IMP, they may be given at the discretion of the Investigator. For any 
concomitant medications given as a treatment for a new condition or a worsening of an existing 
condition occurring after signing of the informed consent form, the condition must be 
documented on the Adverse Event pages of the electronic Case Report Form (eCRF). 
The prescribing information for all concomitant medication should be reviewed carefully. The 
determinations listed in the respective contraindicated, warning, and precaution sections must 
be respected to prevent any potentially serious and/or life-threatening drug interactions. 
The following recommendations should be followed with regards to concomitant medication to 
avoid possible drug interaction with the IMP: 
Participants on a moxifloxacin containing treatment arm: The IMP should be taken either 
4 hours before or 8 hours after taking the following products: 
• 
An antacid, multivitamin, or other product that has magnesium, aluminium, iron 
or zinc 
• 
Sucralfate 
• 
Didanosine 
Participants on the HRZE/HR treatment arm: 
• 
Any aluminium-containing antacids should be taken at least one hour after the IMP 
dose. 
The following medicinal products are prohibited from Day -9 to Day -1 (Screening) and during 
the treatment period: 
• 
Quinolone antimalarial (e.g., chloroquine and quinacrine). Participants who have 
malaria at screening are to be excluded. However, if a participant develops malaria 
during the trial, the Investigator is advised to consult the Malaria Treatment 
Guidance document regarding the interaction between moxifloxacin and 
bedaquiline with anti-malarial drugs. Investigators may also contact the Sponsor 
Medical Monitor for further guidance. 
• 
Chronic systemic glucocorticoids (topical, inhaled or intranasal glucocorticoids are 
allowed) due to their potential to cause visual opacities. Short term systemic 
glucocorticoids are allowed for emergency situations (e.g. for treatment of 
pulmonary exacerbation when Inhaled glucocorticoids is inadequate). 
• 
Medicinal products used to treat pulmonary TB: including but not limited to 
gatifloxacin, amikacin, cycloserine, rifabutin, kanamycin, para-aminosalicylic acid, 
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rifapentine, thioacetazone, capreomycin, other quinolones, thioamides, and 
metronidazole. 
The following medicinal products should be avoided from Day 1 (Baseline visit) and during the 
treatment period as much as possible unless discussed with the Sponsor Medical Monitor: 
• 
Any drug known to prolong QTc interval (including but not limited to amiodarone, 
bepridil, chloroquine, chlorpromazine, cisapride, clarithromycin, disopyramide 
dofetilide, domperidone, droperidol, erythromycin, halofantrine, haloperidol, 
ibutilide, levomethadyl, mesoridazine, methadone, pentamidine, pimozide, 
procainamide, quinidine, sotalol, sparfloxacin, thioridazine). The exception is 
moxifloxacin and bedaquiline administered as part of the trial IMP, with ECG 
monitoring, to help ensure participant safety. 
• 
Any 
drug 
known 
to 
be 
hepatotoxic 
(including 
but 
not 
limited 
to 
acetaminophen/paracetamol, 
acetazolamide, 
allopurinol, 
amiodarone, 
amitriptyline, amoxicillin, amprenavir, atorvastatin, augmentin/co-amoxiclav, 
azathioprine, baclofen, bumetanide, captopril, carbamazepine, celecoxib, 
chlorpromazine, chlorpromazine, clindamycin, clopidogrel, contraceptive pill, co-
trimoxazole, darunavir, delavirdine, diclofenac, doxycycline, enalapril, fluconazole, 
fluoxetine, fosamprenavir, furosemide, gliclazide, glimeperide, glipizide, ibuprofen, 
irbesartan, 
ketoconazole, 
lisinopril, 
loperamide, 
losartan, 
methotrexate, 
metolazone, mirtazepine, nitrofurantoin, omeprazole, other non-steroidal anti-
inflammatory drugs, paroxetine, phenobarbital, phenothiazines, phenytoin, 
pravastatin, probenecid, prochlorperazine, risperidone, rosuvastatin, sertraline, 
simeprevir, simvastatin, sodium valproate, sotalol, sulfasalazine, sumatriptan, 
tamsulosin, terbinafine, tetracycline, theophyllin/uniphyllin, tipranavir, tolazamide, 
tolbutamide, topiramate, trazodone, tricyclic antidepressants, trimethoprim, 
verapamil).  
 
5.4 
Treatment Discontinuation and/or Early Withdrawal  
Any participant for whom the Investigator decides to temporarily discontinue their IMP is to be 
discussed with the Sponsor Medical Monitor and, if applicable, be restarted on IMP as soon 
as possible.  
A participant must be prematurely withdrawn from the trial (during the trial treatment or follow-
up periods) because of the following: 
• 
Withdrawal of informed consent 
• 
Investigator considers that for safety reasons it is in the best interest of the participant 
that he/she be withdrawn, including a concern that the participant has symptomatic TB 
and/or bacteriological failure/relapse and requires a change in TB treatment. 
• 
Pregnancy 
• 
At the specific request of the Sponsor or termination of the trial by the Sponsor. 
• 
Lost to follow-up 
• 
Drug-Sensitive TB treatment arms: participants, who have been randomised onto the trial 
as a rifampicin sensitive participant on the rapid sputum based test result, who on receipt 
of the rifampicin resistance testing using an indirect susceptibility test in liquid culture, 
shows a rifampicin resistant result. 
• 
Participants, who have been randomised onto the trial as fluoroquinolone sensitive on the 
rapid sputum based test result, who on receipt of the fluoroquinolone resistance testing 
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using an indirect susceptibility test in liquid culture; this shows a fluoroquinolone resistant 
result. 
• 
Early withdrawal due to TB (see Section 5.4.4) 
A participant may withdraw from the trial at any time at his/her request (withdrawal of consent), 
or may be withdrawn at any time at the discretion of the Investigator for safety, behavioural, 
compliance or administrative issues. When a participant withdraws consent from the trial, no 
additional follow-up visits will be performed. 
Participants who withdraw from the trial after having received IMP will not be replaced.  
All participants withdrawn from trial and who received at least one dose of IMP will be 
requested to return for an Early Withdrawal visit and the applicable safety Follow-Up visits, as 
per the Synopsis Flow Chart and Procedures (Section 1.2 footnote c), as well as Table 5. 
5.4.1 
Early Withdrawal 
In case of early withdrawal during the treatment or follow-up period, all efforts shall be made 
to complete the Early Withdrawal assessments.  At the Early Withdrawal visit the following 
information will be collected and procedures performed: 
• 
Sputum sample collection x 2 (one early morning brought from home and one spot at the 
research site under the coaching and observation of the trial staff).  If no early morning 
sputum sample was provided by the participant, 2 samples may be collected at the site, 
at least 30 minutes apart. 
• 
Urine pregnancy test (women of child bearing potential, whether they are sexually active 
or not) 
• 
Laboratory safety sampling (including male reproductive hormone tests); 
• 
Single 12-lead ECG 
• 
TB Symptoms Profile 
• 
Patient Reported Health Status Questionnaire 
• 
Vital signs 
• 
Full physical examination, including weight 
• 
Ophthalmology examination, if required as described in Table 5 
• 
IMP compliance check (if participant on IMP) 
• 
Concomitant medications 
• 
Adverse events 
Once a participant has been withdrawn early from the trial, they will be requested to attend 
follow-up visits as described in Table 5: 
Table 5: Follow-up Visits Required for Early Withdrawal Participants 
Treatment 
Duration at 
EWD visit 
Ophthalmology 
Examination at 
EWDa 
Ophthalmology 
Examination  
 
Visit 3 months 
after EWD Visita 
Week 52  
(Month12) 
Follow-up 
Visit 
Week 104 
(Month 24) 
Follow-up 
Visit 
≤ 14 days 
Not required 
Not required 
Required 
Required 
15 days to      
≤ 12 weeks 
Not required 
Required 
Required 
Required 
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> 12 weeks  
Required 
Required 
Required, if 
not already 
performed 
Required 
a. If an additional visit is required for an ophthalmology examination after EWD, only the 
ophthalmology examination will be performed at this visit, and it will occur 3 months after 
the EWD visit date. 
The Weeks 52 and 104 (Month 12 and 24) visits will be performed to collect SAE information 
(including verification of survival) and participant reported TB outcome information.  This visit 
may be telephonic, a home or a site visit at Weeks 52 (Month 12) and/or Week 104 (Month 
24) after the participants’ start of treatment date. 
5.4.2 
Unscheduled Visits 
Any visit which is conducted in addition to those required by the Synopsis Flow Chart and 
Procedures, should be considered unscheduled regardless of the reason for the visit. The 
assessments which are undertaken as part of a Unscheduled visit should be as clinically 
indicated.  
The following situation/s would require an unscheduled visit/s: 
• 
If both sputum samples (Early Morning and Spot) at Week 8 or later are contaminated, 
the participant should return for an unscheduled visit(s) to give additional sputum 
samples x 2 (one early morning and one spot at the research site under the coaching 
and observation of the trial staff) or to document that the participant is not able to 
produce sputum. 
• 
If there is a MTB confirmed positive culture at or after the end of treatment at Week 17 
(4-month treatment) or Week 26 (6-month treatment), the participant should return for 
an Unscheduled visit(s) to give additional sputum samples x 2 (one early morning and 
one spot at the research site under the coaching and observation of the trial staff) or 
to document that the participant is not able to produce sputum. If no early morning 
sputum sample was provided by the participant, 2 samples may be collected at the 
site, at least 30 minutes apart. 
To be able to define a participant’s primary outcome status it may be necessary in certain 
situations to contact a participant and request they visit the site to collect additional sputum 
samples at unscheduled visits, as follows: 
• 
To be assessed on sputum culture results from: 
o End of Treatment Period (Week 17 or 26) 
o End of Follow-up Period (Month 12 and 24) 
o Early Withdrawal, if applicable 
• 
To confirm whether the participant has: 
o two sequential negative sputum culture results; or  
o two sequential positive sputum culture results; or  
o has been unable to produce sputum after documentation of two negative 
sputum cultures with no intervening positive and are clinically asymptomatic 
If they do not fall into one of these categories, two sputum samples x 2 (one early morning 
and one spot at the research site under the coaching and observation of the trial staff) should 
be taken at least 7 days apart until they fall into one of the above categories.  If no early 
morning sputum sample was provided by the participant, 2 samples may be collected on site 
at least 30 minutes apart. 
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If the Investigator is unsure of the outcome in any of the above scenarios the Investigator is to 
contact the Sponsor Medical Monitor and discuss and agree on how the participant is to be 
managed. 
5.4.3 
Lost-to-Follow-up 
Every reasonable attempt must be made to minimise Lost-to-Follow-up (LTFU) participants.  
A minimum of three contact attempts (telephonic/home visit) will be made for participants who 
do not arrive for their scheduled trial visits. If these attempts are unsuccessful the participant 
will be considered LTFU.  All attempts to contact the participant must be clearly documented 
in the participant’s source documents. 
5.4.4 
Early Withdrawal due to TB 
Ultimately it is the Investigator’s decision whether a participant requires early withdrawal from 
the trial due to a concern that the participant has symptomatic worsening of TB and/or 
bacteriological failure/relapse.  
Early withdrawal is usually not indicated for a single positive culture.  Should a participant have 
a single positive culture result after being negative, the Investigator is to evaluate whether the 
participant has signs and symptoms suggestive of active inadequately treated TB and whether 
it is in the participants best interest that he/she be withdrawn. Prior to early withdrawal of a 
participant due to TB, the Investigator must discuss the participant with the Sponsor Medical 
Monitor, unless the Investigator cannot contact the Sponsor Medical Monitor and considers 
that early withdrawal must occur immediately due to immediate safety concerns with respect 
to the participant. 
If the Investigator decides to withdraw a participant due to TB, additional sputum samples may 
need to be collected to ensure the participant’s outcome status as determined in Section 5.5. 
All early withdrawn participants who are confirmed sputum positive (two sequential sputum 
positive cultures) and/or have symptomatic TB will require further TB treatment. These 
participants will be referred to their applicable DS/DR local community TB clinics for standard 
anti-tuberculosis chemotherapy according to National TB Treatment Guidelines. The 
participants will be provided with a referral letter from the Investigator to take with them to the 
TB clinic.  A follow-up call will be made by the trial site staff to the clinic to ensure the 
participant attended the clinic.  
5.5 
Participant Progress Definitions 
Status 
Treatment 
Follow-Up 
Screen Failure 
Participants from whom informed consent is obtained and is 
documented in writing (i.e., participant signs an informed consent form) 
but who are not randomized 
Completed 
Treatment / 
Completed 
Follow-Up* 
Participants who complete 
the full course of IMP 
Participants who complete all follow-up 
visits 
Completed 
Treatment / 
Discontinued 
Follow-Up 
Participants who complete 
the full course of IMP 
Participants who do not complete all 
applicable follow-up visits, regardless of 
the reason (excluding LTFU) 
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Completed 
Treatment / Lost 
to Follow-Up 
Participants who complete 
the full course of IMP 
Participants who are unable to be 
contacted on or before their final visit 
Discontinued 
Treatment / 
Completed FU 
Participants who discontinue 
treatment prior to completion 
of the protocol-defined 
treatment course 
Participants who complete all applicable 
follow-up visits 
Discontinued 
Treatment / 
Discontinued 
Follow-Up** 
Participants who discontinue 
treatment prior to completion 
of the protocol-defined 
treatment course 
Participants who do not complete all 
applicable follow-up visits, regardless of 
the reason (excluding LTFU) 
Lost to Follow-Up 
Participants who are unable to be contacted on or before their final 
treatment visit and it cannot be confirmed whether treatment was 
completed 
* 
Note that this includes treatment failures who complete all applicable follow-up visits 
** 
Early Withdrawal 
5.6 
Trial Stopping Rules 
There are no trial specific stopping rules.  
The trial or parts of the trial can be stopped by the Sponsor on advice from the Data Safety 
and Monitoring Committee (DSMC) after their review of applicable trial data.  In addition, the 
Sponsor has the right to stop the trial or a specific trial site at any time, although this should 
only occur after consultation between the involved parties.  Should this occur, the local and 
central Ethics Committee/Institutional Review Board (EC/IRB) and Regulatory Authorities will 
be informed.   
Should a trial site be closed prematurely, all trial materials (except documentation that must 
remain at the site) will be returned to the Sponsor or vendor.   The Investigator will retain all 
other documents until notification given by the Sponsor for destruction.  Participants currently 
on treatment will receive an appropriate regimen and all participants will be referred to their 
applicable DS-TB/DR-TB National Treatment Program. 
6.0 
Treatment 
6.1 
IMP Administration  
6.1.1 
Instructions for Dosing of Test Regimen (BPaMZ):  
• 
Treatment will be orally administered once daily, to be taken during breakfast, with a 
full glass of water (approximately 240 ml), for 17 weeks (4 months) or 26 weeks (6 
months). 
 
6.1.2 
Instructions for Dosing Control Treatment Regimen (HRZE/HR): 
• 
To be taken with a glass of water (approximately 240 ml). 
• 
HRZE or HR should not be taken with a meal (generally, no closer to meals than 1 
hour before or 2 hours after a meal) in the following dosing schemes. 
HRZE/HR treatment will be administered orally once daily to DS-TB participants as follows: 
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Weight Band 
Weight Range 
Number of tablets 
per weight band 
1 
30-39 kg 
2 
2 
40-54 kg 
3 
3 
55-70 kg 
4 
4 
≥ 71 kg 
5 
 
A daily supplement of Vitamin B6 will be provided by the trial site to participants randomised 
to the HRZE/HR treatment arm, per each country’s National TB Treatment Guideline.   
6.2 
Participant Compliance 
During site clinic visits, the IMP will be administered by the Investigator(s)/designated site 
personnel and when possible, the check for IMP compliance via the hand-and-mouth 
procedure (both the hand and the mouth of the participant will be checked to ensure that the 
participant has swallowed the IMP). During the trial, sites will be responsible for ensuring 
participants are taking IMP correctly and are fully trained on how the IMP is to be taken as 
well as check cards for unused tablets in the containers at each visit during the treatment 
phase.  
6.3 
Treatment Modification(s) 
The importance of adherence to the treatment schedule will be reinforced at each visit.  Non-
adherence should prompt the Investigator to identify and address the cause(s) (e.g. side 
effects).  
 
Participants that do not take: 
 
• 
Up to 7 consecutive doses of IMP doses: restart IMP, no extension of IMP required. 
• 
Greater than 7 to ≤ 35 consecutive doses of IMP: restart IMP and extend the IMP 
treatment by the number of consecutive doses missed. The final treatment visit 
should also be pushed out to the date of last dose. It is not necessary to have an 
unscheduled visit at the time when the end of treatment visit would have been.   
• 
Greater than 35 consecutive doses of IMP, discontinue IMP and withdraw participant 
from the trial. 
• 
If the participant misses a total (sum) of 56 cumulative missed doses, discontinue 
IMP and withdraw participant from the trial. 
Any participant for whom the trial medication is discontinued (including for non-adherence) will 
be discussed with the Sponsor Medical Monitor and, if applicable, the participant will be 
restarted on trial medication as soon as possible.  
6.4 
IMP Packaging and Labelling 
The complete formulations of the IMP, bedaquiline and pretomanid, are found in the respective 
Investigator Brochures.[8, 15] The complete formulations of moxifloxacin, pyrazinamide, 
HRZE/HR are found in the Package Inserts.[19, 20, 22, 40]  
The IMP will be packaged in weekly or bi-weekly cards as follows: 
Week 1 to 8 Cards: Dispensed Weekly 
IMP 
Strength 
Number of tablets 
Abbreviation 
Bedaquiline 
100 mg 
14 
B 
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Pretomanid 
200 mg 
7 
Pa 
Moxifloxacin 
400 mg 
7 
M 
Pyrazinamide 
500 mg 
21 
Z 
 
Week 9 to 17/26 Cards: Dispensed Weekly 
IMP 
Strength 
Number of tablets 
Abbreviation 
Bedaquiline 
100 mg 
7 
B 
Pretomanid 
200 mg 
7 
Pa 
Moxifloxacin 
400 mg 
7 
M 
Pyrazinamide 
500 mg 
21 
Z 
 
Control (HRZE/HR) Group: Dispensed Bi-weekly 
Weight Band 
Weight Range 
Number of tablets 
per weight band 
Number of tablets 
in each card 
1 
30-39 kg 
2 
28 
2 
40-54 kg 
3 
42 
3 
55-70 kg 
4 
56 
4 
≥71 kg 
5 
70 
 
A daily supplement of Vitamin B6 will be provided by the trial site to participants randomised 
to the HRZE/HR treatment arm, per each country’s National TB Treatment Guideline. 
The packaging of each weekly and biweekly cards will be labelled with, at a minimum, the 
following information: 
• 
Name of Sponsor 
• 
Name of medication 
• 
Dosage, quantity and method of administration  
• 
Reference/lot number 
• 
The statement “For Clinical Trial Use Only” 
• 
Space for completion of name of Investigator and site number 
• 
MedID: medication identification number 
• 
Storage conditions 
• 
Period of use 
• 
The statement “Keep out of reach of children” 
• 
Expiry date 
• 
Directions for use 
• 
Space for completion of participant number and visit/date dispensed 
6.5 
Blinding and Procedures for Breaking the Blind 
As this is an open label trial there is no need for blinding or procedures to break the blind. The 
trial participants, the site staff, Sponsor, and CROs will not be blinded to treatment assignment.  
6.6 
Handling, Storage and Accountability  
The Investigator or designee must confirm that the appropriate temperature conditions as per 
details on IMP labelling, have been maintained during transit for all trial treatment received 
and any discrepancies are reported and resolved before use of the trial treatment. 
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Only participants randomised in the trial may receive trial treatment and only authorized site 
staff may supply or administer trial treatment. All trial treatments must be stored in a secure, 
environmentally controlled, and monitored (manual or automated) area in accordance with the 
labelled storage conditions with access limited to the Investigator and authorized site staff. 
The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for trial treatment accountability, reconciliation, and record maintenance (i.e., 
receipt, reconciliation, and final disposition records).  Upon completion or termination of the 
trial, all unused and/or partially used IMPs must either be returned to Sponsor (or designated 
vendor: who will arrange for destruction) or destroyed at site as agreed by Sponsor, after final 
accountability has been confirmed. 
The Investigator/designee will immediately inform the Sponsor of any quality issues arising 
with respect to the trial medication. The Sponsor will take whatever action is required should 
such a situation arise. 
Further guidance and information for the handling, storage, accountability and final disposition 
of unused trial treatment are provided in the pharmacy manual. 
7.0 
Trial Variables and Procedures 
The Synopsis Flowchart and Procedures in Section 1.2  should be referenced for timing, 
sequence of assessments, and specific procedures. 
7.1 
Demographic and Background Variables and Procedures 
The following demographic and background variables will be collected: 
• 
Written Informed Consent 
• 
Visit dates 
• 
Participant disposition 
• 
Demography (date of birth, race and gender) 
• 
Inclusion and exclusion criteria 
• 
Clinically significant medical and TB treatment history (including past and current TB 
diagnosis, smoking and alcohol use) 
• 
Screening coached spot sputum samples: 
o Smear microscopy for acid-fast bacilli 
o Gene Xpert, Hain Assay MTBDRplus or equivalent to determine MTB complex and 
rifamycin resistance 
• 
Urine pregnancy test: women of childbearing potential only, whether they are sexually 
active or not (Non-childbearing potential for a female participant is defined as having 
bilateral oophorectomy, bilateral tubal ligation and/or hysterectomy or has been 
postmenopausal with a history of no menses for at least 12 consecutive months). 
• 
Serology: HIV and CD4 count.  Where required by regulatory authorities or ethics 
committees, a separate (EC/IRB approved) HIV informed consent form will be obtained 
from participants: 
o Prior to HIV testing and on receipt of the results, participants will be counselled on 
HIV by trained counsellors if they have indicated as such on the HIV consent form. If 
requested by the participant, HIV counselling that is provided to the participant by 
the trial site should be clearly documented in the participant’s medical 
records/source.  Participants have the right to decline to know or receive their HIV 
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test results. This decision should be clearly documented in the participant’s medical 
records/source.   
• 
Karnofsky Score (Appendix 4) 
• 
Chest X-Ray: A chest X-ray digital image within 6 months prior to or during the 
Screening visit, will be obtained and read locally by the Investigator or designee.  Digital 
images will be provided to the Sponsor; this process will be documented in the 
Radiology Manual.  The investigator is responsible for review and analysis of the chest 
X-ray for participant’s inclusion. 
• 
Method of birth control: male and female participants and their partners 
• 
IMP details: randomization 
• 
IMP compliance and actual dosing 
• 
Concomitant medications 
7.2 
Efficacy Variables and Procedures 
Two spot sputum samples are collected, one early morning brought from home or collected in 
the hospital ward (only if the participant is hospitalised) and one spot sputum sample collected 
at the research site under the coaching and observation of the trial staff or, if no early morning 
sputum sample was provided by the participant, 2 samples may be collected on site at least 
30 minutes apart. The mycobacteriology sampling methodology and requirements will be 
described in a separate document, the Mycobacteriology Laboratory Manual, which will be 
provided prior to the trial start. Sputum samples may not be obtained by induction. 
The following analyses will be performed: 
• 
Liquid culture (MGIT), to detect presence or absence of MTB and obtain the TTP 
followed by a speciation test when applicable, to confirm MTB. 
 
Using these observed variables, the following derived variables will be assessed for evaluation 
of the efficacy endpoints: 
• 
Bacteriologic failure/relapse 
• 
Time to sputum culture conversion 
• 
Number of participants with sputum culture conversion 
 
Every effort must be made to collect sputum samples. However, in general, the inability to 
produce sputum is treated as being equivalent to having a negative culture (favourable) result.  
A participant who never achieves culture negative status due to the inability to produce 
sputum, but has completed Week 26 (6 months) post treatment completion follow-up and is 
without clinical or biological evidence of relapse, will be considered to have a favourable 
outcome. 
TB Symptoms Profile:  
• 
The TB Symptoms Profile (Appendix 6) will record participants’ ratings of the severity of 
common TB symptoms.  
 
Patient Reported Health Status Variables and Procedures:  
• 
The Patient Reported Health Status variables will be collected at the time points 
described in the Synopsis Flow Chart and Procedures (Section 1.2). Patient Reported 
Health Status will be collected using the EQ-5D-5L Health Questionnaire (Appendix 7). 
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This descriptive system consists of five health-related quality of life dimensions, each of 
which will be recorded using five levels of severity.  
 
Methodology: The Patient Reported Health Status methodology and requirements will be 
described in a separate document/guideline which will be provided prior to the trial start. 
7.3 
Safety and Tolerability Assessments 
The following safety and tolerability variables will be collected at the time points described in 
the Synopsis Flow Chart and Procedures and assessed for evaluation of the safety 
endpoints: 
• 
Laboratory parameters. The safety laboratory sampling methodology and requirements 
will be described in a separate document, the Safety Laboratory Manual, which will be 
provided prior to the trial start. The following analyses will be performed: 
 
o Full Blood Count (haemoglobin, haematocrit, red blood cell count, white blood 
cell count with differential, platelet count) 
o Clinical Chemistry (albumin, serum urea, creatinine, direct, indirect and total 
bilirubin, uric acid, total protein, ALP, AST, ALT, lipase, phosphate, sodium, 
potassium, calcium (corrected for albumin), chloride, magnesium, glucose, 
bicarbonate/CO2, creatine phosphokinase (CPK). GGT is only routinely included at 
the Screening visit (Day -9 to -1).  
o When managing participants with elevated liver enzymes at an Unscheduled visit, 
the investigator can request additional tests, in addition to the repeat LFT [e.g. 
Gamma Glutamyl Transferase (GGT), screening for Hepatitis A, B, C; to assist in 
ruling out other causes of a dysfunctional liver test (e.g. alcohol induced hepatic 
cell injury, hepatobiliary disease, hepatic viral infection)]. 
o Urinalysis (pH, specific gravity, protein, glucose, micro-albumin, ketones, 
bilirubin, creatinine, nitrite, sodium, urobilinogen, blood, leukocytes). Microscopy 
will be completed as follow up to abnormal urinalysis per discretion of Investigator 
• 
12-lead ECG: 
o Investigator assessment: normal or abnormal 
o Central cardiologist assessment: heart rate, PR interval, RR interval, QT, corrected 
QT Interval (QTc) (QTcB and QTcF), QRS. 
o Methodology: 
 
Timing and registration technique for ECGs will be standardized for all 
participants and will be described in a separate document which will be provided 
prior to the trial start 
 
ECGs are to be recorded for 10 seconds 
 
ECGs are to be performed during a single visit 
 
ECGs should be done before any phlebotomy when both included in a visit 
 
For each participant, the ECGs should, to every extent possible, be collected at 
approximately the same time of day (+/- 1 hours) and in the same fed/fast state 
throughout the trial (e.g. 4 hours after lunch) 
• 
Vital signs: 
o Vital signs (should be done before any phlebotomy in light clothing and with no 
shoes) 
o Systolic and diastolic blood pressure (mmHg) to be measured in a supine position 
(after 5 minutes of rest) using an appropriately sized cuff, and using the same type of 
sphygmomanometer, if possible by the same observer, at each relevant visit 
o Heart rate (beats per minute) 
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o Respiratory rate (breaths per minute)  
o Axillary body temperature (°C) 
• 
Physical Examination:  
o Height (m) is measured at the screening visit only 
o Full (complete) and limited (gross neurological, pulmonary, cardiovascular and 
abdominal) examinations will be performed and any clinically significant findings will 
be recorded 
o Weight (kg) (in light clothing and with no shoes) 
o Using the variables of weight and height, the body mass index (BMI) will be 
calculated 
• 
Ophthalmology Slit Lamp Examination: 
o To be done by an Ophthalmologist trained on Age-Related Eye Disease Scale 2 
(AREDS2) assessment. The ophthalmology slit lamp methodology and requirements 
will be described in a separate document, the Ophthalmology Guideline. The 
following analyses will be performed: AREDS2 opacity typing and grading. 
• 
Adverse events 
• 
Investigator assessment:  
o The Investigator will review the participant status at specified visits in the Synopsis 
Flow Chart and Procedures, including any time the Investigator determines that the 
participant fulfils the criteria for the primary outcome of treatment failure. The 
Investigator will assess whether TB treatment is considered a “success” or “failure”.  
If it is considered a failure, the Investigator should specify if the assessment is based 
on bacteriology and/or clinical deterioration and/or radiological deterioration. 
7.4 
PK Variables and Procedures 
Plasma concentrations from sparse sampling (see Section 1.2) will be used to update 
population PK models for bedaquiline and its M2 metabolite, pretomanid, moxifloxacin and 
pyrazinamide to further evaluate the effects of covariates on model parameters in this trial 
population. 
 
PK data from the current trial may be combined with prior data (e.g., from the NC-005 trial) to 
enhance this population PK analysis. The models will be used to estimate individual exposure 
metrics (e.g., Cmin, Cmax, AUCτ, Cmean, and time above minimum inhibitory concentration) for 
subsequent analyses exploring relationships between drug exposure and efficacy and safety 
endpoints. 
 
7.5 
Mycobacteriology Characterization Variable and Procedures 
The following Mycobacterial Characterization variables will be collected: 
Positive Culture (for MTB) from: 
 
• 
Day 1 or if Day 1 is not available, first positive result between screening through Week 
4 
• 
Pre-screening culture that was used for the tests that qualified the participant for 
inclusion into the trial to be sub-cultured and sent to the central microbiology 
laboratory from the applicable local microbiology laboratory, for relevant participants / 
no positive cultures from screening through week 4  
• 
When applicable, at last visit of the treatment period (Week 17 for the 4-month 
treatment arm and Week 26 for the 6-month treatment arm) or visits with positive 
cultures, during the post-treatment follow-up period 
 
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The MTB isolates will be processed at the central microbiology laboratory for: 
 
• 
MIC against bedaquiline, pretomanid and moxifloxacin  
• 
Drug Susceptibility Testing in liquid culture for streptomycin, rifampicin, isoniazid, 
ethambutol, moxifloxacin and pyrazinamide, and second line TB drugs including but 
not limited to fluoroquinolones, and injectables 
• 
Extraction of organismal (MTB) DNA for whole genome sequencing, and the 
comparison of sequences from baseline and relapse isolates. 
 
All Day 1 (Baseline) MTB isolates and isolates from positive cultures to be stored at the local 
and central microbiology laboratories, until trial closure.  Extracted MTB DNA to be stored at 
the central microbiology laboratory until trial closure. The extracted MTB DNA and isolates will 
then be stored for potential further work to advance new assay tools and understanding of 
MTB as a pathogen for a maximum of 5 years after trial closure.  
 
The MTB isolates will be processed at the trial microbiology laboratories for positive MTB 
complex at/after the last visit of the treatment period (Week 17 for the 4-month treatment arm 
and Week 26 for the 6-month treatment arm) via Hain MTBDRplus and HainMTBRsl. 
 
8.0 
Adverse Events 
8.1 
Definitions 
8.1.1 
Adverse Event (AE) 
Any untoward medical occurrence in a clinical investigation participant, temporally associated 
with the use of a trial treatment whether or not considered related to trial treatment. An AE can 
therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease (new or exacerbated) temporally associated with the use of a trial 
treatment, whether or not related to the trial treatment. 
8.1.2 
Serious Adverse Event (SAE) 
Any untoward medical occurrence that at any dose: 
• 
Results in death 
• 
Is life threatening (any event in which the participant was at risk of death at the time of 
the event; it does not refer to an event, which hypothetically might have caused death 
if it were more severe) 
• 
Requires inpatient hospitalisation or prolongation of existing hospitalisation; In general, 
hospitalisation signifies that the participant has been detained (usually involving at 
least an overnight stay) at the hospital or emergency ward for observation and/or 
treatment that would not have been appropriate in the physician’s office or outpatient 
setting. Complications that occur during hospitalisation are AEs. If a complication 
prolongs hospitalisation or fulfils any other serious criteria, the event is serious. When 
in doubt as to whether “hospitalisation” occurred, or was necessary, the AE should be 
considered serious. Hospitalisation for elective treatment of a pre-existing condition 
that did not worsen from baseline is not considered an AE. 
• 
Results in persistent or significant disability/incapacity; the term disability means a 
substantial disruption of a person’s ability to conduct normal life functions. This 
definition is not intended to include experiences of relatively minor medical significance 
such as uncomplicated headache, nausea, vomiting, diarrhoea, influenza, and 
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accidental trauma (e.g., sprained ankle) which may interfere with or prevent everyday 
life functions but do not constitute a substantial disruption. 
• 
Is a congenital anomaly/birth defect; or 
• 
Is a medically important event 
Note:  Medical and scientific judgment should be exercised in deciding which is a medically 
important event that may not be immediately life-threatening or result in death or 
hospitalisation, but may jeopardize the participant or may require medical or surgical 
intervention to prevent one of the outcomes listed above.   
Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias or convulsions that do not result in hospitalisation, or the 
development of drug dependency or drug abuse. A “suspected transmission of infectious 
agent by a medicinal product” is also considered a serious adverse event under the SAE 
criterion “Other medically important condition”.     
8.1.3 
Attribution/Causality 
• 
The Investigator is obligated to assess the relationship between trial treatment and 
each occurrence of each AE/SAE 
• 
The Investigator will use clinical judgment to determine the relationship 
• 
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to trial treatment 
administration will be considered and investigated 
• 
The Investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment 
• 
For each AE/SAE, the Investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality 
• 
There may be situations in which an SAE has occurred and the Investigator has 
minimal information to include in the initial report to the Sponsor/designee. However, 
it is very important that the Investigator always assesses causality for every event 
before the initial transmission of the SAE data to the Sponsor/designee. 
• 
The Investigator may change his/her opinion of causality in light of follow-up 
information and send a SAE follow-up report with the updated causality assessment 
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Table 6: Adverse Events Attribution/Causality Ratings  
Relatedness Rating 
Definition 
Not Related 
An AE, which is not related to the use of the drug. 
Unlikely 
An AE for which an alternative explanation is more likely, e.g., 
concomitant drug(s) or concomitant disease(s), and/or the 
relationship in time suggests that a causal relationship is unlikely. 
Possible 
An AE, which might be due to the use of the drug.  An alternative 
explanation, e.g., concomitant drug(s) or concomitant disease(s), is 
inconclusive.  The relationship in time is reasonable; therefore, the 
causal relationship cannot be excluded. 
Probable 
An AE, which might be due to the use of the drug.  The relationship 
in time is suggestive, e.g., confirmed by de-challenge.  An alternative 
explanation is less likely, e.g., concomitant drug(s) or concomitant 
disease(s). 
Certain 
An AE, which is listed as a possible adverse reaction and cannot be 
reasonably explained by an alternative explanation, e.g., concomitant 
drug(s) or concomitant disease(s).   
 
8.1.4 
Severity 
Table 7: Definitions for Adverse Event Severity Gradings 
Grade 
Severity Rating 
Definition 
GRADE 1 
Mild 
Transient or mild discomfort (< 48 hours); no medical 
intervention/therapy required. 
GRADE 2 
Moderate 
Mild to moderate limitation in activity - some assistance 
may be needed; no or minimal medical intervention/therapy 
required. 
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. 
 
See Appendix 2 for full DMID Toxicity Tables. Above ratings should be used to estimate the 
grade for abnormalities NOT found elsewhere in the Toxicity Tables. 
8.2 
Reporting 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about AE 
occurrences. 
All AEs will be collected by the Investigator from the time a participant signs the Informed 
Consent Form through to their Week 104 (Month 24) follow-up visit. The exception to this is 
early withdrawal participants who will only have SAEs collected from their time of early 
withdrawal to their Week 104 (Month 24) follow-up visit at the timepoints specified in the 
Synopsis Flow Chart and Procedures (Section 1.2) and recorded in the CRF.   
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Medical occurrences that begin after obtaining informed consent will be recorded as AEs. If 
an AE started before signing of the informed consent, but is ongoing at trial start, it should be 
recorded as medical history.  If the pre-existing medical occurrence worsens during the trial, 
an AE will be recorded. 
All SAEs will be recorded and reported to the Sponsor or designee within 24 hours of the 
information becoming known to the Investigator, as noted in the SAE reporting guidelines. The 
Investigator will submit any updated SAE data to the Sponsor within 24 hours of information 
becoming known to the Investigator.  
The Sponsor/Investigator/designee will inform Regulatory Authorities and/or EC/IRB of all 
SAEs in accordance with local requirements and ICH guidelines for GCP. 
The Sponsor/designee will forward Safety Notification letters to the investigator for submission 
to the EC/IRB. 
Investigators are not obligated to actively seek AE or SAE information in former trial 
participants. However, if the Investigator learns of any SAE, including a death, at any time 
after a participant has been discharged from the trial, and he/she considers the event to be 
reasonably related to the trial treatment or trial participation, the Investigator must promptly 
notify the Sponsor, EC/IRB and regulatory authorities in an expedited basis, in accordance 
with local requirements and ICH GCP Guidelines. 
8.2.1 
Follow up of Adverse Events 
All AEs will be followed until: 
• 
Satisfactory clinical resolution or stabilization; or 
• 
The end of the follow-up period; and  
• 
All queries on these AEs have been resolved.   
Certain long-term AEs cannot be followed until resolution within the setting of this protocol. In 
these cases, follow-up will be the responsibility of the Investigator.  However, this will have to 
be agreed upon with the Sponsor Medical Monitor. 
The Investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by sponsor or 
representative to elucidate the nature and/or causality of the AE or SAE as fully as possible. 
This may include additional laboratory tests or investigations, histopathological examinations, 
or consultation with other health care professionals.  The Investigator should contact the 
Sponsor/designee to discuss appropriate medical follow-up if consultation is required.  
If a participant dies during participation in the trial or during a recognized follow-up period, the 
Investigator will provide the Sponsor/representative with a copy of any post-mortem findings, 
including histopathology. 
New or updated information will be recorded in the originally completed CRF and submitted to 
the Sponsor within 24 hours of receipt, per SAE reporting guidelines. 
8.2.2 
Clinical Laboratory Adverse Events 
Changes in the results of the clinical laboratory assessment results and which the Investigator 
determines are clinically significant will be reported as AEs.  It is the Investigators’ 
responsibility to review the results of all laboratory tests as they become available.  This review 
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must be documented by the Investigators’ dated signature on the laboratory report.  For each 
abnormal laboratory test result, the Investigator needs to ascertain and document if this is a 
clinically significant change from baseline for that individual participant.  This determination, 
however, does not necessarily need to be made the first time an abnormal value is observed.  
The Investigator may repeat the laboratory test or request additional tests to verify the results 
of the original laboratory tests.  If this laboratory value is determined by the Investigator to be 
a clinically significant change from baseline for that participant, it is considered to be an AE. 
8.2.3 
Disease Symptoms During Trial 
Symptoms of the disease under trial (Tuberculosis) experienced by the participant while on 
the trial will be assessed by the Investigator.  If the symptom has: 
o worsened while the participant is in the trial; and  
o the Investigator assesses it as clinically significant; 
it will be recorded as an adverse event. If there is: 
o no change; and  
o the Investigator assesses the symptom as due to the participant’s TB; and  
o not clinically significant; 
it will not be recorded as an AE and this will be noted in the participant’s source documentation. 
All TB related symptoms that meet SAE criteria will be recorded and reported as a SAE. 
8.2.4 
Overdose 
Overdose of the IMP experienced by the participant while on the trial, will be assessed by the 
Investigator to determine whether the overdose led to an adverse event, including if the taking 
of the suspected medicine led to suicidal intention and subsequent overdose of the suspected 
medicine, or other medication. In this case it will be recorded as an adverse event. If it does 
not lead to an adverse event, it will not be recorded as an AE and this will be noted in the 
participant’s source documentation. 
8.2.5 
Drug Interaction 
If the Investigator becomes aware that the participant has experienced a drug interaction 
which has resulted in an adverse event, it will be recorded as an adverse event. 
8.2.6 
Pregnancy 
The Investigator will immediately notify the Sponsor of any pregnancy that is discovered during 
IMP administration or which started during IMP administration.  Pregnancy forms will be 
completed for all pregnancies reported during the clinical trial, as defined below. In addition, 
the investigator will report to the Sponsor any follow up information regarding the outcome of 
the pregnancy, including perinatal and neonatal outcome.  Infants will be followed-up for 6 
months.   
All women of childbearing potential will be instructed to contact the investigator immediately if 
they suspect they might be pregnant (for example, missed or late menses) for the following 
time-periods: 
• 
Any time during the trial 
• 
Within 6 months after the last dose of IMP 
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If a pregnancy is suspected while the participant is receiving IMP, the IMP will be withheld 
immediately until the result of the pregnancy test is known.  If pregnancy is confirmed, the IMP 
will be permanently discontinued in an appropriate manner and the participant withdrawn from 
the trial. Protocol-required procedures for trial discontinuation and follow-up will be performed 
unless contraindicated by the pregnancy. 
Pregnancy reporting will follow the same timelines for a SAE (see above). Instructions and 
forms will be provided separately. SAE reporting will also occur if the pregnancy outcome is a 
congenital anomaly.  This will follow the reporting procedures described above for SAE 
reporting. 
8.3 
Monitoring for Specific Toxicities  
Monitoring for specific toxicities is based upon target organs as defined in the preclinical 
toxicity studies of the Investigator’s Brochures[8, 15] and Package Inserts.[19, 20, 22, 40] 
AEs still ongoing at the end of the treatment period in the trial will be followed until satisfactory 
clinical resolution or stabilization, or until the end of the follow-up period and until all queries 
on these AEs have been resolved.   
Grade 3 and Grade 4 laboratory abnormalities, and laboratory abnormalities considered 
clinically significant should be followed until satisfactory resolution or stabilization. 
Note: For Grade 3 or 4 laboratory toxicities, participants should have a confirmatory 
measurement within 48 hours, where possible. The recommendations for managing 
participants below assumes that the laboratory abnormalities of concern have been 
confirmed. 
 
8.3.1 
ALT, AST and Bilirubin Elevations 
The Investigator should refer to Appendix 8 Liver Toxicity Management, to appropriately 
monitor significant elevations of AST, ALT or Bilirubin. A separate Hepatoxicity Management 
Guideline document has been developed to aid investigators in the management of 
participants. 
When managing participants with elevated liver enzymes at an Unscheduled visit, the 
investigator can request additional tests, in addition to the repeat LFT [e.g. Gamma Glutamyl 
Transferase (GGT), screening for Hepatitis A, B, C; to assist in ruling out other causes of a 
dysfunctional liver test (e.g. alcohol induced hepatic cell injury, hepatobiliary disease, hepatic 
viral infection)]. 
8.3.2 
Lipase 
Grade 3 (> 2.0 to ≤ 5.0 x ULN) or Grade 4 (> 5.0 x ULN): 
• 
Contact the Sponsor Medical Monitor to review. Participants with confirmed Grade 3 
or 4 elevations of lipase, the Investigator should consider pausing the full regimen, 
pending further evaluation. 
8.3.3 
Neurological 
Participants co-administration with a serotonergic agent, including anti-depressants, should 
be monitored closely for signs of serotonin syndrome.  The Investigator should determine 
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whether the full regimen or the concomitant agent should be discontinued for those who 
experience signs or symptoms of serotonin syndrome such as cognitive dysfunction, 
hyperrexia, hyperreflexia and incoordination. 
8.3.4 
Musculoskeletal System and Cardiac Muscle Myalgia 
Grade 2 (muscle tenderness at a site other than sites of injection and/or venepuncture or with 
moderate impairment of activity) or Grade 3 (severe muscle tenderness with marked 
impairment of activity) or Grade 4 (frank myonecrosis): 
• 
Participants with Grade 2 signs and symptoms should be followed closely. Participants 
with Grade 3 or 4 signs and symptoms should be discussed with the Sponsor Medical 
Monitor to consider pausing trial medication, pending further evaluation. 
8.3.5 
Cardiac Rhythm Disturbances 
Cardiac rhythm disturbances that are Grade 3 (recurrent, persistent, symptomatic arrhythmia 
requiring treatment) or Grade 4 (unstable dysrhythmia requiring treatment): 
• 
Participants should be monitored closely.  The Investigator should discuss with the 
Sponsor Medical monitor to consider pausing the full regimen, pending further 
evaluation. 
QTc prolongation  
If QTcF is equal to or greater than 500 msec, the ECG should be repeated and serum 
electrolytes should be evaluated. If the second ECG also has a QTcF of > 500 msec, the 
Sponsor Medical monitor should be consulted to consider pausing the full regimen, pending 
further evaluation. 
New left bundle branch block (LBBB) or Mobitz type 2 or complete heart block. Recordings 
with artifacts that interfere with the interpretation of the ECG should be repeated to confirm 
the findings. If the finding is from the centralized ECG machine reading the result is to be 
checked and confirmed by the Investigator.  If this is confirmed by the Investigator, dosing is 
to be paused until the reading has been confirmed by the central cardiologist and the 
participant is to be treated per the Investigator’s clinical judgment. If it is confirmed by the 
central cardiologist, the participant is to be withdrawn from the full regimen.  Contact Sponsor 
Medical monitor to review.  
8.4 
Safety Monitoring by Data Monitoring Committee 
A Data Safety Monitoring Committee (DSMC) will be appointed for the trial. The primary 
responsibility of the DSMC will be to act in an advisory capacity to the Sponsor to safeguard 
the interests of trial participants by monitoring participant safety, assess participant risk versus 
benefit, and assess data quality and general evaluation of the trial progress. Its activities will 
be delineated in a DSMC charter that will define the membership, responsibilities and the 
scope and frequency of data reviews.  
The DSMC will operate on a conflict-free basis independently of the Sponsor and the trial 
team. It will comprise at least 3 voting members that include at least 2 clinicians and one 
statistician.   
The DSMC may have an organizational meeting prior to commencement of the trial. The 
DSMC will have meetings where it will review unblinded data during a closed session. These 
meetings will be planned at regular intervals.  
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The Sponsor or the DSMC may convene ad hoc meetings based on rates of SAEs and/or to 
review results of the futility analysis, or if safety concerns arise during the trial.  After its 
assessment, the DSMC will recommend to the Sponsor continuation, modification or 
termination of the clinical trial.  
9.0 
Statistical Analysis 
The statistical analysis plan (SAP), which will contain details of the analyses specified in this 
section, will be written and signed off prior to first patient randomized. 
9.1 
Analysis Populations 
There will be three main analyses of the primary efficacy endpoint: An intent to treat (ITT) 
analysis; a modified intent to treat (mITT) analysis and a per protocol (PP) analysis 
• 
The ITT population is defined as all randomized participants excluding late screening 
failures. Late screening failures are participants withdrawn from treatment because 
they were found to be ineligible (late exclusions from the trial), based on data collected 
prior to randomization. 
• 
The mITT population is defined as the ITT population with extra exclusions (described 
in the SAP). 
• 
The PP population is defined as the mITT population with extra exclusions (described 
in the SAP). 
• 
The mITT analysis will be considered primary, with consistent findings required from 
the other main analysis populations to support the primary conclusion. 
9.2 
Sample Size 
For the primary endpoint, time-to-culture conversion at 8 weeks,150 participants per arm (DS-
TB participants) will provide at more than 90% power (5% 2-sided significance) to detect a 
hazard ratio (HR) of at least 2 assuming 50% of control participants are culture negative by 8 
weeks. If only 25% of the control arm remain culture positive at 8 weeks, then this sample size 
will still retain more than 90% power to detect a HR of least 2.  Currently no formal interim 
analysis is planned. (See Section 9.4.1) 
For the key secondary endpoint of clinical outcome at 12 months from randomization, 150 
patients per arm will provide 74% power based on assumptions using data from the largest 
most recent and completed phase 3 TB treatment trial which used the same control arm.[41]  
That is, assuming 16% unfavourable (see Section 9.4.2) in the control arm and 13% 
unassessable (see Section 9.6) at 52 weeks post randomization. A 12% margin of non-
inferiority was chosen to preserve at least 75% of the estimated control arm effect against 
placebo (estimated to be 54%)[41, 42] which is considered an acceptable proportion on which to 
declare non-inferiority of the test regimen. 
9.3 
Interim Analyses 
There is no planned interim analysis in this trial. 
9.4 
Primary and Secondary Efficacy Endpoint Analysis 
9.4.1 
Primary Efficacy Endpoint, Time to Culture Conversion at 8 Weeks 
The primary analysis will be conducted using culture results from liquid culture (MGIT) media. 
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Participants will be classified as being culture positive, culture negative, dead or unassessable 
at 8 weeks.  The proportion culture negative will be those classified as being culture negative 
divided by the total considered culture negative, culture positive or have died. This proportion 
will be estimated from the Kaplan Meier estimates from the time to culture conversion to 
negative status analysis and groups compared using a hazard ratio and 95% confidence 
interval. 
Non-inferiority of the key secondary endpoint of clinical outcome will be assessed using the 
upper bound of the one-sided 97.5% confidence interval for the difference between the 
proportion of participants who are classified as having an unfavourable status on the 
intervention less the control regimen.  If the upper bound of the one-sided 97.5% confidence 
limit for this difference in proportions is less than 12% (the margin of inferiority) the intervention 
will be non-inferior to the control arm. 
9.4.2 
Key Secondary Efficacy Endpoint, Clinical Outcome at 52 Weeks from 
Randomization  
For the key secondary endpoint of clinical outcome (bacteriologic failure or relapse or clinical 
failure), participants will be classified as having a favourable, unfavourable or unassessable 
outcome status which will be defined in detail in the SAP.  In general, participants achieving 
and maintaining culture negative status without any additional treatment will be considered 
favourable; participants who fail on treatment or relapse in follow-up will be considered 
unfavourable and participants who are not assessable (and who have not already been 
declared as unfavourable) will be considered unassessable and excluded from the analysis. 
9.4.3 
Other Secondary Efficacy Endpoints 
The secondary efficacy endpoints and analyses are as follows are: 
• 
Clinical outcome (bacteriologic failure or relapse or clinical failure) at 104 weeks from the 
start of therapy.  
• 
Proportion of participants with sputum culture conversion to negative status in liquid culture 
(MGIT) at 4, 6, 12 and 17 weeks to be explored as a potential biomarker of outcome at 
52 weeks from start of therapy. 
• 
Change from baseline in weight will be summarised and presented. 
• 
Proportion of participants experiencing a change from baseline in TB symptoms. 
• 
Change from baseline in Patient Reported Health Status will be summarised and 
presented. 
9.5 
Safety and Tolerability Assessments 
• 
The incidence of all-cause mortality will be summarized. 
• 
All adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) and will be presented by Preferred Term within each MedDRA System Organ 
Class (SOC). 
• 
Treatment-emergent adverse events (TEAEs) are defined as AEs which started at or after 
the first administration of IMP and includes those events started prior to the first 
administration of IMP but which worsened after the first intake.  Adverse events starting 
after the last administration of IMP until the last scheduled visit/assessment/measurement 
will be regarded as treatment-emergent. 
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• 
The incidence of the following events will be summarized for further medical analysis: 
o Incidence of TEAEs; 
o Incidence of TEAEs by Severity; 
o Incidence of TEAEs by DMID toxicity grade; 
o Incidence of Drug-Related TEAEs; 
o Incidence of Serious TEAEs; 
o Incidence of TEAEs Leading to Early Withdrawal; 
o Incidence of TEAEs leading to Death. 
9.6 
Pharmacokinetics 
For each analyte and each scheduled sampling time/window, the plasma concentration will 
be summarized by descriptive statistics including the mean, SD, coefficient of variation (CV), 
median, minimum, maximum, geometric mean and geometric CV (%). 
In addition, mean and/or median concentration-versus-time graphs will be provided, with error 
bars and/or scatter plots as appropriate. 
Plasma concentrations from sparse sampling will be used to update existing population PK 
models and derive exposure metrics (e.g., Cmin, Cmax, AUC) for bedaquiline and its M2 
metabolite, pretomanid, moxifloxacin, and pyrazinamide. Effects of baseline covariates on 
exposure will be assessed; so, too, will the effects of concomitant medications including ART, 
as feasible. Data from other trials may be included to enhance the model-based analysis.  
Detailed plans for the PopPK analysis will be outlined in a separate modelling plan, and results 
will be reported in separate modelling report. 
9.7 
Pharmacokinetics/Pharmacodynamics 
Relationships will be explored between drug exposure and efficacy and safety endpoints. 
These exploratory PK/PD analyses may include HIV status as a covariate. Planning details 
and results will be included in the separate modelling plan and report. 
10.0 Records Management 
10.1 Data Collection 
All relevant CRF/eCRF pages will be completed for each participant who receives any amount 
of IMP, depending on visits attended.  For screening failure participants, specific eCRF pages 
will be completed as described in the eCRF Completion Guidelines. For participants who are 
prematurely withdrawn, all the visits the participant attended including withdrawal and follow-
up visits need to be completed. 
10.2 Source Documents 
Source documents are defined as all information in original records and certified copies of 
original records of clinical findings, observations, or other activities in a clinical trial necessary 
for the reconstruction and evaluation of the trial.  Source documents will include, but are not 
limited to, progress notes, in-patient hospital records, electronic data, screening logs, and 
recorded data from automated instruments. 
All source documents pertaining to this trial will be maintained by the Investigators.  The 
Investigator 
must 
permit 
trial 
related 
monitoring, 
audits, 
Independent 
Ethics 
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Committee/Institutional Review Board (EC/IRB) review and regulatory inspections providing 
authorized personnel direct access to source documents, including documents required to 
confirm inclusion/exclusion and relevant in-patient records while participants are on trial 
treatment. 
10.3 File Management at the Trial Centre 
It is the responsibility of the Investigators to ensure that the trial centre files are maintained in 
accordance with International Good Clinical Practice Guidelines and the ethical principles that 
have their origin in the Declaration of Helsinki. 
10.4 Records Retention at the Trial Centre 
The Investigator is obliged to retain records and data from the trial for safety reasons and for 
audit and inspection after trial completion.  The essential documents should be retained for 
not less than 2 years after the last approval of a marketing application and until there are no 
pending or contemplated marketing applications or at least 2 years have elapsed since the 
formal discontinuation of clinical development of the IMP.  Investigator should notify the 
Sponsor/designees prior to destroying any records pertaining to the trial. 
 
11.0 Quality Control and Assurance  
11.1 Site Procedures 
The Investigator undertakes to perform the clinical trial in accordance with this protocol, local 
regulations, International GCP, and the ethical principles that have their origin in the 
Declaration of Helsinki. 
The Investigator undertakes to complete the CRFs according to the Sponsor’s requirements, 
in a timely, accurate and legible manner. CRF entries will be verifiable to source 
documentation other than the CRF. 
Site Standard Operating Procedures (SOPs), where available, will be adhered to for all clinical 
and bioanalytical activities relevant to the quality of the trial.  Participant compliance will be 
monitored throughout the trial. 
The Investigator will sign and date any analysis results (e.g., laboratory, ECG, etc.) to verify 
that the results have been reviewed. 
The Investigator may appoint other sub-Investigators to assist with the trial. However, the 
Investigator maintains responsibility for the trial and will supervise the sub-Investigators. 
Written EC/IRB approval of the trial will be obtained prior to involvement in the trial. 
The Investigator will ensure that all site personnel are adequately trained in GCP, local 
regulations, the protocol, IBs/package inserts and all trial procedures and requirements. 
11.2 Monitoring 
The Investigator is responsible for the validity of all data collected at the clinical site and must 
accept the various monitoring procedures employed by the Sponsor.  The purpose of 
monitoring is to verify that the rights and well-being of human participants are protected; that 
trial data are accurate, complete and verifiable with source data; and that the trial is conducted 
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in compliance with the protocol, International GCP, the ethical principles that have their origin 
in the Declaration of Helsinki and the applicable regulatory requirements.  
Monitors assigned by the Sponsor will conduct regular site visits before, during and after the 
trial for monitoring various aspects of the trial, and to assure appropriate conduct of the trial in 
accordance with ICH GCP.  Visits will take place usually within a predetermined interval, but 
this may vary during the trial.  The Investigator and site staff will allow the trial monitor and 
authorized representatives of the Sponsor to (1) inspect all CRFs, written informed consent 
documents and corresponding source documents (e.g., original medical records), patient 
records and laboratory raw data, site SOPs, training records, facilities and other trial related 
systems/processes, and (2) access clinical supplies, dispensing and storage areas.  The 
Investigator and site staff should also (1) agree to assist with monitoring activities if requested 
and (2) provide adequate time and space for monitoring visits.  
The monitor will query any missing, confusing, spurious, or otherwise ambiguous data with 
the Investigator.  All queries should be resolved in a timely manner.  A monitoring log will be 
maintained recording each visit, the reason for the visit, the monitor’s signature and 
Investigator or designee’s confirmation signature. 
11.3 Protocol Deviations 
A protocol deviation is any noncompliance with the clinical trial protocol, GCP, or Monitoring 
Plan requirements. The noncompliance may be either on the part of the participant, the 
Investigator, or the trial site staff. Because of deviations, corrective actions are to be developed 
by the site and implemented promptly.  
It is the responsibility of the site to use continuous vigilance to identify and report deviations. 
All deviations must be addressed in trial source documents and reported to Sponsor/designee. 
Protocol deviations must be sent to the local IRB per their guidelines. The site PI/trial staff is 
responsible for knowing and adhering to their IRB requirements. 
11.4 Auditing 
For compliance with International GCP and regulatory agency guidelines, it may be necessary 
for Sponsor-authorized Quality Assurance personnel and/or authorized personnel from an 
external regulatory agency to conduct an audit or inspection of the investigational site.  The 
purpose of an audit is to assess the quality of data about accuracy, adequacy and consistency, 
and to assure that trials are in accordance with the guidelines.  Having the highest quality data 
from trials is an essential aspect of drug development.  
The Investigator and site staff will be given sufficient notice to prepare for such visits, which 
will usually last between one and two days and may be conducted at any stage during the 
trial.  The audit will involve the review of all trial-related documentation required by GCP to be 
maintained by each site; drug storage, dispensing and return; all trial-related supplies; and 
source documents against the CRFs to assure the adequacy and accuracy of the information 
which has been recorded, including the verification of any AEs which have occurred. The 
auditors or inspectors may also review site SOPs, training records, site facilities and other trial 
related systems/processes. 
In the event of the site being notified of a Regulatory Inspection, the Sponsor will help with 
preparation.  It is essential that the Sponsor be notified of the inspection as soon as possible. 
 
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12.0 Ethics and Regulatory 
12.1 Basic Principles 
This research will be carried out in accordance with International GCP, the ethical principles 
that have their origin in the Declaration of Helsinki and the applicable regulatory requirements. 
12.2 Independent Ethics Committee/Institutional Review Board (EC/IRB) 
Review 
The protocol and required trial related documents will be reviewed by the sites respective 
EC/IRB.  The trial will not start until the EC/IRB has approved the protocol, written informed 
consent, any written information to be provided to the participant or any modification thereof, 
plus any other trial related documents required for review.  The EC/IRB shall be constituted 
and shall operate in accordance with International GCP, the ethical principles that have their 
origin in the Declaration of Helsinki. The Investigator will maintain an accurate and complete 
record of all submissions made to, and responses from the IRB/EC.  The records should be 
filed in the Investigator’s Trial File, and copies will be sent to the Sponsor. 
12.3 Regulatory Authorities 
The Regulatory Authorities will receive the protocol, amendments, reports on SAEs, and the 
Integrated Clinical Trial Report according to national regulations.  As required by local 
legislation, written approval will be obtained from the Regulatory Authorities prior to 
commencement of the trial and implementation of e.g. amendments as applicable. 
12.4 Informed Consent 
Written informed consent will be obtained from all participants (or legally acceptable 
representative) before any trial-related procedures (including any screening or pre-treatment 
procedures) are performed.  Investigators may discuss the availability of the trial and the 
opportunity for entry with a potential participant without first obtaining consent.  However, 
informed consent must be obtained and documented prior to initiation of any procedures that 
are performed solely for determining eligibility for research, including withdrawal from current 
medication(s).  When this is done in anticipation of, or in preparation for, the research, it is 
part of the research. 
The Investigators have both ethical and legal responsibility to ensure that each participant 
being considered for inclusion in this trial is given a full explanation of the protocol.  Participants 
must be informed that their participation is voluntary.  The Investigator or his/her 
representative will explain the nature of the trial to the participant or his/her legally authorized 
representative and answer all questions regarding the trial. This shall be documented on a 
written informed consent form that shall be approved by the same EC/IRB responsible for 
approval of this protocol.  Each informed consent form shall include the elements required by 
the international GCP and must adhere to the ethical principles that have their origin in the 
Declaration of Helsinki.  
The trial will be included and updated in the appropriate Country registry and referenced in 
the informed consent forms (ICF). 
Once the appropriate essential information has been provided to the participant and fully 
explained by the Investigators (or qualified designees) and it is felt that the participant 
understands the implications of participating, the EC/IRB approved written informed consent 
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form will be signed and dated by both the participant and the person obtaining consent 
(Investigators or designees), and by any other parties required by the EC/IRB. Ongoing 
participants must be re-consented to the most current version of the ICF(s) during their 
participation in the trial. 
The original signed informed consent form will be kept with the trial records and a copy of 
signed informed consent form will be provided to the participant or the participant’s legally 
authorized representative.  Another copy of the signed informed consent form and a source 
document identifying the trial and recording the dates of participation will be placed in the 
participant’s medical record. 
The monitor will inspect the original completed consent form(s) for all participants. 
12.5 Confidentiality 
All site staff, the Sponsor, and any Sponsor representatives will preserve the confidentiality of 
all participants taking part in the trial, in accordance with International GCP, applicable local 
legislation/regulations.  Participant to the requirement for source data verification by the trial 
personnel by reference to the participant’s notes, confidentiality of all participant identities will 
be maintained.  Unique identifiers will be used on the CRF and in all trial correspondence, as 
permitted.  No material bearing a participant’s name will be kept on file by the Sponsor. The 
written informed consent will contain a clause granting permission for review of the 
participants’ source data by the Sponsor or designees. 
 
13.0 Publication Policy 
The definition of publication for this purpose is any public presentation of the data emerging 
from this trial.  
All unpublished information given to the Investigator by the Sponsor shall not be published or 
disclosed to a third party, other than to the responsible EC/IRB, within the understanding of 
the confidentiality of their nature, without the prior written consent of the Sponsor. 
Results of this research will be submitted for publication as soon as feasible upon completion 
of the trial in the form of a joint publication(s) between Sponsor and Investigator(s), including 
site clinical and laboratory Investigators, as appropriate. Publication and authorship will be in 
accord with the International Association of Journal Editors.[43]  
Because the Trial is funded, in whole or in part, by the Bill and Melinda Gates Foundation (the 
“Foundation”), all peer-reviewed published research relating to the Trial must comply with the 
Foundation’s 
Open 
Access 
Policy 
as 
described 
from 
time 
to 
time 
at 
http://www.gatesfoundation.org/How-We-Work/General-Information/Open-Access-Policy. 
Specifically, (a) all peer-reviewed published research relating to the Trial must be submitted 
for publication by TB Alliance through the Chronos Open Access Publishing Service 
established by the Foundation to ensure the immediate and unrestricted access and reuse of 
all peer-reviewed published research funded, in whole or in part, by the Foundation without 
any embargo period, and (b) all data underlying the peer-reviewed published research results 
must be immediately made accessible and open to the public in accordance with the 
Foundation’s Open Access Policy. 
 
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14.0 Protocol Amendment Policy 
Any change to the protocol will be affected by means of a protocol amendment.  Any changes 
which affect participant safety or welfare will be submitted to the EC/IRB and Regulatory 
Authorities prior to implementation.  The Investigator, EC/IRB, and Sponsor must agree on all 
amendments.  No amendment will be implemented until approved by the relevant Authorities 
and/or EC/IRB and signed by all required parties.  Exceptions to this are when the Investigator 
considers that the participant’s safety is compromised.  
Protocol amendments detailing minor administrative changes should be submitted by the 
Investigator to the EC/IRB and Regulatory Authorities, either for notification purposes or 
approval as appropriate. 
 
15.0 Sponsor, Financial Aspects, Insurance and Indemnity 
The trial Sponsor is the Global Alliance for TB Drug Development (TB Alliance).  The TB 
Alliance is a not for profit, product development partnership accelerating the discovery and 
development of new TB drugs that will shorten treatment, be effective against susceptible and 
resistant strains, be compatible with antiretroviral therapies for those HIV-TB participants 
currently on such therapies, and improve treatment of latent infection. 
The TB Alliance works with public and private partners worldwide.  It is committed to ensuring 
that approved new regimens are affordable, adopted and available to those who need them. 
The TB Alliance operates with funding mainly from the Bill & Melinda Gates Foundation, the 
Netherlands Ministry of Foreign Affairs (DGIS), the United Kingdom Department for 
International Development (DFID), and the United States Agency for International 
Development (USAID). 
The participants will not receive any incentives for their involvement in the trial.  The Sponsor 
has made provision to reimburse the participants for out-of-pocket expenses such as travelling 
to and from the trial site and other miscellaneous costs as a result of their trial participation. 
The Sponsor certifies that it has liability insurance coverage for itself and will provide an 
associated certificate upon request.  The insurance does not relieve the Investigators of the 
obligation to maintain their own liability insurance as required by applicable law. The Sponsor 
does not assume any obligation for the medical treatment of other injuries and illnesses.
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16.0 References 
1. 
Maggi N, Pasqualucci CR, Ballotta R, Sensi P. Rifampicin: a new orally active 
rifamycin. Chemotherapy. 1966;11(5):285-292. 
2. 
Jindani A, Aber VR, Edwards EA, Mitchison DA. The early bactericidal activity of drugs 
in patients with pulmonary tuberculosis. Am Rev Respir Dis. 1980;121(6):939-949. 
3. 
Dietze R, Teixeira L, Rocha LM, Palaci M, Johnson JL, Wells C, et al. Safety and 
bactericidal activity of rifalazil in patients with pulmonary tuberculosis. Antimicrob 
Agents Chemother. 2001;45(7):1972-1976. 
4. 
Donald PR, Sirgel FA, Venter A, Parkin DP, Seifart HI, van de Wal BW, et al. Early 
bactericidal activity of antituberculosis agents. Expert Rev Anti Infect Ther. 
2003;1(1):141-155. 
5. 
Johnson JL, Hadad DJ, Boom WH, Daley CL, Peloquin CA, Eisenach KD, et al. Early 
and extended early bactericidal activity of levofloxacin, gatifloxacin and moxifloxacin 
in pulmonary tuberculosis. Int J Tuberc Lung Dis. 2006;10(6):605-612. 
6. 
Rustomjee R, Diacon AH, Allen J, Venter A, Reddy C, Patientia RF, et al. Early 
bactericidal activity and pharmacokinetics of the diarylquinoline TMC207 in treatment 
of pulmonary tuberculosis. Antimicrob Agents Chemother. 2008;52(8):2831-2835. 
7. 
Package insert: Sirturo.  Janssen Therapeutics, September 2014 Available at: 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/204384s000lbl.pdf. 
8. 
Investigator’s Brochure: TMC207 (bedaquiline).  Edition 10. Janssen Research and 
Development, 02 Dec 2016. 
9. 
Koul A, Dendouga N, Vergauwen K, Molenberghs B, Vranckx L, Willebrords R, et al. 
Diarylquinolines target subunit c of mycobacterial ATP synthase. Nat Chem Biol. 
2007;3(6):323-324. 
10. 
Andries K, Verhasselt P, Guillemont J, Gohlmann HW, Neefs JM, Winkler H, et al. A 
diarylquinoline drug active on the ATP synthase of Mycobacterium tuberculosis. 
Science. 2005;307(5707):223-227. 
11. 
Huitric E, Verhasselt P, Andries K, Hoffner SE. In vitro antimycobacterial spectrum of 
a 
diarylquinoline 
ATP 
synthase 
inhibitor. 
Antimicrob 
Agents 
Chemother. 
2007;51(11):4202-4204. 
12. 
Koul A, Vranckx L, Dendouga N, Balemans W, Van den Wyngaert I, Vergauwen K, et 
al. Diarylquinolines are bactericidal for dormant mycobacteria as a result of disturbed 
ATP homeostasis. J Biol Chem. 2008;283(37):25273-25280. 
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Protocol Version: Russia V1.0 / 10 Jul 2018, Incorporating Protocol V2.0 / 21 Feb 2018 
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Page 80 of 99 
13. 
Nuermberger E, Rosenthal I, Tyagi S, Williams KN, Almeida D, Peloquin CA, et al. 
Combination chemotherapy with the nitroimidazopyran PA-824 and first-line drugs in 
a murine model of tuberculosis. Antimicrob Agents Chemother. 2006;50(8):2621-2625. 
14. 
Nuermberger E, Tyagi S, Tasneen R, Williams KN, Almeida D, Rosenthal I, et al. 
Powerful bactericidal and sterilizing activity of a regimen containing PA-824, 
moxifloxacin, and pyrazinamide in a murine model of tuberculosis. Antimicrob Agents 
Chemother. 2008;52(4):1522-1524. 
15. 
Investigator's Brochure: Pretomanid (PA-824).  Global Alliance for TB Drug 
Development, 22 December 2016. 
16. 
Stover CK, Warrener P, VanDevanter DR, Sherman DR, Arain TM, Langhorne MH, et 
al. A small-molecule nitroimidazopyran drug candidate for the treatment of 
tuberculosis. Nature. 2000;405(6789):962-966. 
17. 
Lenaerts AJ, Gruppo V, Marietta KS, Johnson CM, Driscoll DK, Tompkins NM, et al. 
Preclinical testing of the nitroimidazopyran PA-824 for activity against Mycobacterium 
tuberculosis in a series of in vitro and in vivo models. Antimicrob Agents Chemother. 
2005;49(6):2294-2301. 
18. 
Tyagi S, Nuermberger E, Yoshimatsu T, Williams K, Rosenthal I, Lounis N, et al. 
Bactericidal activity of the nitroimidazopyran PA-824 in a murine model of tuberculosis. 
Antimicrob Agents Chemother. 2005;49(6):2289-2293. 
19. 
Package insert: Moxifloxacin.  MacLeods Pharmaceuticals Ltd., January 2014. 
20. 
Package insert: Pyrazinamide.  MacLeods Pharmaceuticals Ltd., November 2012. 
21. 
Zhang Y, Mitchison D. The curious characteristics of pyrazinamide: a review. Int J 
Tuberc Lung Dis. 2003;7(1):6-21. 
22. 
Package insert: HRZE Combination Tablets.  MacLeods Pharmaceuticals Ltd., 
September 2011. 
23. 
World Health Organization. Global tuberculosis report 2012.  2015. WHO Press, 
Geneva, Switzerland. 
24. 
Pym AS, Diacon AH, Tang S-J, Conradie F, Danilovits M, Chuchottaworn C, et al. 
Bedaquiline safety data in a broad patient population treated for drug-resistant TB 
including XDR-TB (C209 trial). Tuberculosis. 2016;47:394-402. 
25. 
Lee M, Lee J, Carroll MW, Choi H, Min S, Song T, et al. Linezolid for treatment of 
chronic extensively drug-resistant tuberculosis. N Engl J Med. 2012;367(16):1508-
1518. 
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Protocol Version: Russia V1.0 / 10 Jul 2018, Incorporating Protocol V2.0 / 21 Feb 2018 
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CONFIDENTIAL 
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26. 
A Phase 3 Trial Assessing the Safety and Efficacy of Bedaquiline Plus PA-824 Plus 
Linezolid in Subjects With Drug Resistant Pulmonary Tuberculosis. ClinicalTrials.gov,  
Available at: https://www.clinicaltrials.gov/ct2/show/NCT02333799, Updated 28 
February 2017. 
27. 
Mdluli K, Nuermberger E. Pre-Clinical Drug Combination Trials to Identify Novel 
Regimens for TB.  2009. in Recent Advances in TB Drug Development Symposium. 
40th Union World Conference, International Union Against TB and Lung Disease. 
Cancun, Mexico. 
28. 
Tasneen R, Li SY, Peloquin CA, Taylor D, Williams KN, Andries K, et al. Sterilizing 
activity of novel TMC207- and PA-824-containing regimens in a murine model of 
tuberculosis. Antimicrob Agents Chemother. 2011;55(12):5485-5492. 
29. 
Singh R, Manjunatha U, Boshoff HI, Ha YH, Niyomrattanakit P, Ledwidge R, et al. PA-
824 kills nonreplicating Mycobacterium tuberculosis by intracellular NO release. 
Science. 2008;322(5906):1392-1395. 
30. 
Manjunatha U, Boshoff HI, Barry CE. The mechanism of action of PA-824: Novel 
insights from transcriptional profiling. Commun Integr Biol. 2009;2(3):215-218. 
31. 
Manjunatha UH, Boshoff H, Dowd CS, Zhang L, Albert TJ, Norton JE, et al. 
Identification of a nitroimidazo-oxazine-specific protein involved in PA-824 resistance 
in Mycobacterium tuberculosis. Proc Natl Acad Sci U S A. 2006;103(2):431-436. 
32. 
Nuermberger E, Tyagi S, Williams KN, Rosenthal I, Bishai WR, Grosset JH. 
Rifapentine, moxifloxacin, or DNA vaccine improves treatment of latent tuberculosis in 
a mouse model. Am J Respir Crit Care Med. 2005;172(11):1452-1456. 
33. 
Tasneen R, Betoudji F, Tyagi S, Li SY, Williams K, Converse PJ, et al. Contribution of 
Oxazolidinones to the Efficacy of Novel Regimens Containing Bedaquiline and 
Pretomanid in a Mouse Model of Tuberculosis. Antimicrob Agents Chemother. 
2015;60(1):270-277. 
34. 
Diacon AH, Dawson R, du Bois J, Narunsky K, Venter A, Donald PR, et al. Phase II 
dose-ranging trial of the early bactericidal activity of PA-824. Antimicrob Agents 
Chemother. 2012;56(6):3027-3031. 
35. 
Burman WJ, Goldberg S, Johnson JL, Muzanye G, Engle M, Mosher AW, et al. 
Moxifloxacin versus ethambutol in the first 2 months of treatment for pulmonary 
tuberculosis. Am J Respir Crit Care Med. 2006;174(3):331-338. 
36. 
Rustomjee R, Lienhardt C, Kanyok T, Davies GR, Levin J, Mthiyane T, et al. A Phase 
II trial of the sterilising activities of ofloxacin, gatifloxacin and moxifloxacin in pulmonary 
tuberculosis. Int J Tuberc Lung Dis. 2008;12(2):128-138. 
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CONFIDENTIAL 
Page 82 of 99 
37. 
Conde MB, Efron A, Loredo C, De Souza GR, Graca NP, Cezar MC, et al. Moxifloxacin 
versus ethambutol in the initial treatment of tuberculosis: a double-blind, randomised, 
controlled phase II trial. Lancet. 2009;373(9670):1183-1189. 
38. 
Dorman SE, Johnson JL, Goldberg S, Muzanye G, Padayatchi N, Bozeman L, et al. 
Substitution of moxifloxacin for isoniazid during intensive phase treatment of 
pulmonary tuberculosis. Am J Respir Crit Care Med. 2009;180(3):273-280. 
39. 
Investigator's Brochure: Bayer HealthCare AG, moxifloxacin.  01 October 2011. 
40. 
Package insert: HR Combination Tablets.  MacLeods Pharmaceuticals Ltd., 
September 2011. 
41. 
Gillespie SH, Crook AM, McHugh TD, Mendel CM, Meredith SK, Murray SR, et al. 
Four-month moxifloxacin-based regimens for drug-sensitive tuberculosis. N Engl J 
Med. 2014;371(17):1577-1587. 
42. 
Tiemersma EW, van der Werf MJ, Borgdorff MW, Williams BG, Nagelkerke NJ. Natural 
history of tuberculosis: duration and fatality of untreated pulmonary tuberculosis in HIV 
negative patients: a systematic review. PLoS One. 2011;6(4):e17601. 
43. 
Recommendations for the Conduct, Reporting, Editing, and Publication of Scholarly 
work 
in 
Medical 
Journals. 
 
Available 
at: 
http://www.icmje.org/icmje-
recommendations.pdf, Updated December 2016. 
44.  
Reuben A (2004). “Hy’s Law”. Landmarks in Hepatology 39(2): 574-578. 
45. 
Temple 
RJ 
(2006). 
“Hy’s 
Law: 
predicting 
serious 
hepatotoxicity”. 
Pharmacoepidemoiology and Drug Safety 15: 241-243. 
 
 
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Appendices 
Appendix 1: The IUATLD Scale 
The IUATLD scale proposes five groups for reporting the results of reading smears for acid 
fast bacilli. They should be recorded as follows: 
FINDING 
RECORDING 
No acid-fast bacilli found in at least 100 fields 
negative 
1 to 9 acid-fast bacilli per 100 fields 
scanty positive 
10 to 99 acid-fast bacilli per 100 fields 
+ 
1 to 10 acid-fast bacilli per field in at least 50 
fields 
++ 
More than 10 acid-fast bacilli per field in at least 
20 fields 
+++ 
Reference: The Public Health Service National Tuberculosis Reference Laboratory and the 
National Laboratory Network. Minimum Requirements, Role and Operation in a Low-Income 
Country. International Union Against Tuberculosis and Lung Disease 1998. 
 
 
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Appendix 2: Division of Microbiology and Infectious Disease (DMID) Toxicity 
Table 
Source:  U.S. National Institute of Allergy and Infectious Diseases, DMID, November 2007 
(Draft) 
ABBREVIATIONS:  Abbreviations utilized in the Table: 
ULN = Upper Limit of Normal 
LLN = Lower Limit of Normal 
Rx = Therapy 
Req = Required 
Mod = Moderate 
IV  = Intravenous 
ADL = Activities of Daily Living 
Dec = Decreased 
 
ESTIMATING SEVERITY GRADE 
For abnormalities NOT found elsewhere in the Toxicity Tables use the scale below to estimate 
grade of severity: 
Grade 
Severity Rating 
Definition 
GRADE 1 
Mild 
Transient or mild discomfort (< 48 hours); no medical 
intervention/therapy required. 
GRADE 2 
Moderate 
Mild to moderate limitation in activity - some assistance may be 
needed; no or minimal medical intervention/therapy required. 
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. 
 
SERIOUS OR LIFE-THREATENING AEs 
ANY clinical event deemed by the clinician to be serious or life-threatening should be 
considered a grade 4 event. Clinical events considered to be serious or life-threatening 
include, but are not limited to: seizures, coma, tetany, diabetic ketoacidosis, disseminated 
intravascular coagulation, diffuse petechiae, paralysis, acute psychosis, severe depression. 
COMMENTS REGARDING THE USE OF THESE TABLES 
• 
Standardized and commonly used toxicity tables (Division of Acquired Immune Deficiency 
Syndrome (AIDS), NCI’s Common Toxicity Criteria (CTC), and World Health Organization 
(WHO)) have been adapted for use by the DMID and modified to better meet the needs of 
participants in DMID trials. 
• 
For parameters not included in the following Toxicity Tables, sites should refer to the 
“Guide For Estimating Severity Grade” located above. 
• 
Criteria are generally grouped by body system. 
• 
Some protocols may have additional protocol specific grading criteria, which will 
supersede the use of these tables for specified criteria. 
 
 
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HEMATOLOGY 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Hemoglobin 
9.5 - 10.5 gm/dL 
8.0  - 9.4gm/dL 
6.5 - 7.9 gm/dL 
< 6.5 gm/dL 
Absolute Neutrophil 
Count 
1000-1500/mm3 
750-999/mm3 
500-749/mm3 
<500/mm3 
Platelets 
75,000- 
99,999/mm3 
50,000- 
74,999/mm3 
20,000- 
49,999/mm3 
<20,000/mm3 
WBCs 
11,000-13,000/ 
mm3 
13,000-15,000 
/mm3 
15,000- 
30,000/mm3 
>30,000 or <1,000 
/mm3 
% Polymorphonuclear 
Leucocytes + Band 
Cells 
 
> 80% 
 
90 – 95% 
 
>95% 
 
---------- 
 
 
Abnormal Fibrinogen 
Low: 
100-200 mg/dL 
High: 
400-600 mg/dL 
Low: 
<100 mg/dL 
High: 
>600 mg/dL 
Low: 
< 50 mg/dL 
 
---------- 
Fibrinogen 
associated with 
gross bleeding or 
with disseminated 
coagulation 
Fibrin Split Product 
20-40 mcg/ml 
41-50 mcg/ml 
51-60 mcg/ml 
> 60 mcg/ml 
Prothrombin Time (PT) 
1.01 - 1.25 x ULN 
1.26-1.5 x ULN 
1.51 -3.0 x ULN 
>3 x ULN 
Activated 
Partial 
Thromboplastin (APPT) 
1.01 -1.66 x ULN 
1.67 - 2.33 x ULN 
2.34 - 3 x ULN 
> 3 x ULN 
Methemoglobin 
5.0 - 9.9 % 
10.0 - 14.9 % 
15.0 - 19.9% 
> 20.0 % 
 
CHEMISTRIES 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
 
Hyponatremia 
 
130-135 mEq/L 
 
123-129 mEq/L 
 
116-122 mEq/L 
< 116 mEq/L or abnormal 
sodium with mental status 
changes or seizures 
 
Hypernatremia 
 
146-150 mEq/L 
 
151-157 mEq/L 
 
158-165 mEq/L 
> 165 mEq/L or abnormal 
sodium with mental status 
changes or seizures 
 
 
Hypokalemia 
 
 
3.0 - 3.4 mEq/L 
 
 
2.5 - 2.9 mEq/L 
2.0 - 2.4 mEq/L or 
intensive 
replacement 
therapy or 
hospitalization 
required 
 
< 2.0 mEq/L or abnormal 
potassium with paresis, ileus 
or life-threatening arrhythmia 
 
Hyperkalemia 
 
5.6 - 6.0 mEq/L 
 
6.1 - 6.5 mEq/L 
 
6.6 - 7.0 mEq/l 
> 7.0 mEq/L or abnormal 
potassium with life- 
threatening arrhythmia 
 
Hypoglycemia 
 
55-64 mg/dL 
 
40-54 mg/dL 
 
30-39 mg/dL 
<30 mg/dL or abnormal 
glucose with mental status 
changes or coma 
Hyperglycemia 
(non-fasting and no 
prior diabetes) 
 
116 - 160 mg/dL 
 
161- 250 mg/dL 
 
251 - 500 mg/dL 
> 500 mg/dL or abnormal 
glucose with ketoacidosis or 
seizures 
 
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Hypocalcemia 
(corrected 
for 
albumin) 
 
8.4 - 7.8 mg/dL 
 
7.7 - 7.0 mg/dL 
 
6.9 - 6.1 mg/dL 
< 6.1 mg/dL or abnormal 
calcium with life threatening 
arrhythmia or tetany 
Hypercalcemia 
(correct for albumin) 
 
10.6 - 11.5 mg/dL 
11.6 - 12.5 
mg/dL 
 
12.6 - 13.5 mg/dL 
> 13.5 mg/dL or abnormal 
calcium with life threatening 
arrhythmia 
 
Hypomagnesemia 
 
1.4 - 1.2 mEq/L 
 
1.1 - 0.9 mEq/L 
 
0.8 - 0.6 mEq/L 
< 0.6 mEq/L or abnormal 
magnesium with life- 
threatening arrhythmia 
 
Hypophosphatemia 
 
2.0 - 2.4 mg/dL 
1.5 -1.9 mg/dL 
or replacement 
Rx required 
1.0 -1.4 mg/dL 
intensive therapy or 
hospitalization 
required 
< 1.0 mg/dL or abnormal 
phosphate with life- 
threatening arrhythmia 
Hyperbilirubinemia 
(when accompanied 
by any increase in 
other liver function 
test) 
 
 
1.1 - <1.25 x ULN 
 
1.25 - <1.5 x 
ULN 
 
 
1.5 – 1.75 x ULN 
 
 
> 1.75 x ULN 
Hyperbilirubinemia 
(when 
other 
liver 
function are in the 
normal range) 
 
1.1 - <1.5 x ULN 
 
1.5 - <2.0 x ULN 
 
2.0 – 3.0 x ULN 
 
> 3.0 x ULN 
BUN 
1.25 - 2.5 x ULN 
2.6 - 5 x ULN 
5.1 - 10 x ULN 
> 10 x ULN 
Hyperuricemia (uric 
acid) 
7.5 – 10.0 mg/dL 
10.1 – 12.0 
mg/dL 
12.1 – 15.0 mg/dL 
>15.0 mg/dL 
Creatinine 
1.1 - 1.5 x ULN 
1.6 - 3.0 x ULN 
3.1 - 6 x ULN 
> 6 x ULN or dialysis 
required 
 
ENZYMES 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
AST (SGOT) 
1.1 - <2.0 x ULN 
2.0 – <3.0 x ULN 
3.0 – 8.0 x ULN 
> 8 x ULN 
ALT (SGPT) 
1.1 - <2.0 x ULN 
2.0 – <3.0 x ULN 
3.0 – 8.0 x ULN 
> 8 x ULN 
GGT 
1.1 - <2.0 x ULN 
2.0 – <3.0 x ULN 
3.0 – 8.0 x ULN 
> 8 x ULN 
Alkaline Phosphatase 
1.1 - <2.0 x ULN 
2.0 – <3.0 x ULN 
3.0 – 8.0 x ULN 
> 8 x ULN 
Amylase 
1.1 - 1.5 x ULN 
1.6 - 2.0 x ULN 
2.1 - 5.0 x ULN 
> 5.1 x ULN 
Lipase 
1.1 - 1.5 x ULN 
1.6 - 2.0 x ULN 
2.1 - 5.0 x ULN 
> 5.1 x ULN 
 
 
URINALYSIS 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
 
Proteinuria 
1+ or 200 mg - 1 
gm loss/day 
2-3+ or 1- 2 gm 
loss/day 
4+ or 2-3.5 gm 
loss/day 
nephrotic 
syndrome or > 3.5 
gm loss/day 
 
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CONFIDENTIAL 
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Hematuria 
 
microscopic only 
<10 rbc/hpf 
 
gross, no clots >10 
rbc/hpf 
gross, with or 
without clots, OR 
red blood cell 
casts 
obstructive or 
required 
transfusion 
 
CARDIOVASCULAR 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Cardiac Rhythm 
 
asymptomatic, 
transient signs, no 
Rx required 
recurrent/persistent 
; symptomatic Rx 
required 
unstable 
dysrythmia; 
hospitalization and 
treatment required 
Hypertension 
transient increase 
> 20 mm/Hg; no 
treatment 
recurrent, chronic 
increase 
> 
20mm/Hg. 
/treatment required 
acute 
treatment 
required; 
outpatienttreatm 
ent 
or 
hospitalization 
possible 
end organ damage 
or 
hospitalization 
required 
Hypotension 
transient 
orthostatic 
hypotension with 
heart 
rate 
increased by <20 
beat/min 
or 
decreased by <10 
mm Hg systolic 
BP, No treatment 
required 
symptoms due to 
orthostatic 
hypotension or BP 
decreased by <20 
mm 
Hg 
systolic; 
correctable with oral 
fluid treatment 
requires IV fluids; 
no hospitalization 
required 
mean 
arterial 
pressure <60mm/ 
Hg or end organ 
damage or shock; 
requires 
hospitalization and 
vasopressor 
treatment 
Pericarditis 
minimal effusion 
mild/moderate 
asymptomatic 
effusion, 
no 
treatment 
symptomatic 
effusion; pain; EKG 
changes 
tamponade; 
pericardiocentesis 
or surgery required 
Hemorrhage, Blood 
Loss 
microscopic/occult 
mild, no transfusion 
gross blood loss; 
1-2 
units 
transfused 
massive blood 
loss; > 3 units 
transfused 
 
RESPIRATORY 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
 
Cough 
Transient - no 
treatment 
persistent 
cough; 
treatment responsive 
Paroxysmal cough; 
uncontrolled with 
treatment 
 
-------------------- 
 
Bronchospasm, 
Acute 
transient; no 
treatment; 70% - 
80% FEV1 of peak 
flow 
requires treatment; 
normalizes with 
bronchodilator; FEV1 
50% - 70% (of peak 
flow) 
no normalization with 
bronchodilator;FEV1 
25% - 50% of peak 
flow; or retractions 
present 
cyanosis: FEV1 < 
25% of peak flow 
or intubation 
necessary 
Dyspnea 
dyspnea on exertion 
dyspnea with normal 
activity 
dyspnea at rest 
dyspnea requiring 
Oxygen therapy 
 
GASTROINTESTINAL 
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CONFIDENTIAL 
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Grade 1 
Grade 2 
Grade 3 
Grade 4 
Nausea 
mild or transient; 
maintains 
reasonable intake 
moderate 
discomfort; intake 
decreased 
significantly; some 
activity limited 
no 
significant 
intake; requires IV 
fluids 
hospitalization 
required; 
Vomiting 
1 episode in 24 
hours 
2-5 episodes in 24 
hours 
>6 episodes in 24 
hours or needing 
IV fluids 
physiologic 
consequences 
requiring 
hospitalization 
or 
requiring 
parenteral nutrition 
Constipation 
requiring 
stool 
softener or dietary 
modification 
requiring laxatives 
obstipation 
requiring manual 
evacuation 
or 
enema 
obstruction or toxic 
megacolon 
Diarrhea 
mild or transient; 3- 
4 loose stools/day 
or 
mild 
diarrhea 
last < 1 week 
moderate 
or 
persistent; 5-7 loose 
stools/day 
or 
diarrhea lasting >1 
week 
>7 loose stools/day 
or bloody diarrhea; 
or 
orthostatic 
hypotension 
or 
electrolyte 
imbalance or >2L 
IV fluids required 
hypotensive shock 
or 
physiologic 
consequences 
requiring 
hospitalization 
Oral 
Discomfort/Dysphagia 
mild discomfort; no 
difficulty 
swallowing 
some limits on 
eating/drinking 
eating/talking very 
limited; unable to 
swallow solid foods 
unable to drink 
fluids; requires IV 
fluids 
 
NEUROLOGICAL 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Neuro-Cerebellar 
slight 
incoordination 
dysdiadochokinesis 
intention 
tremor, 
dysmetria, slurred 
speech; nystagmus 
locomotor ataxia 
incapacitated 
Psychiatric 
mild anxiety or 
depression 
moderate anxiety or 
depression; therapy 
required; change in 
normal routine 
severe 
mood 
changes requiring 
therapy; or suicidal 
ideation; 
or 
aggressive ideation 
acute 
psychosis 
requiring 
hospitalization;  or 
suicidal 
gesture/attempt or 
hallucinations 
Muscle Strength 
Subjective 
weakness 
no 
objective 
symptoms/ signs 
mild 
objective 
signs/symptoms no 
decrease in function 
objective 
weakness function 
limited 
paralysis 
Paresthesia (burning, 
tingling, etc.) 
mild discomfort; no 
treatment required 
moderate 
discomfort; 
non- 
narcotic analgesia 
required 
severe discomfort; 
or 
narcotic 
analgesia required 
with symptomatic 
improvement 
incapacitating; or 
not responsive to 
narcotic analgesia 
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Protocol Name: 
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CONFIDENTIAL 
Page 89 of 99 
Neuro-sensory 
mild impairment in 
sensation 
(decreased 
sensation, 
e.g., 
vibratory, pinprick, 
hot/cold in great 
toes) in focal area 
or 
symmetrical 
distribution; 
or 
change in 
taste, 
smell, vision and/or 
hearing 
moderate 
impairment 
(mod 
decreased 
sensation, 
e.g., 
vibratory, pinprick, 
hot/cold to ankles) 
and/or joint position 
or mild impairment 
that 
is 
not 
symmetrical 
severe impairment 
(decreased or loss 
of 
sensation 
to 
knees or wrists) or 
loss of sensation of 
at 
least 
mod 
degree in multiple 
different 
body 
areas (i.e., upper 
and 
lower 
extremities) 
sensory 
loss 
involves limbs and 
trunk; paralysis; or 
seizures 
 
MUSCULOSKELETAL 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Arthralgia (joint pain) 
mild pain not 
interfering with 
function 
moderate 
pain, 
analgesics 
and/or 
pain interfering with 
function but not with 
activities 
of 
daily 
living 
severe pain; pain 
and/or analgesics 
interfering 
with 
activities of daily 
living 
disabling pain 
Arthritis 
mild 
pain 
with 
inflammation, 
erythema or joint 
swelling – but not 
interfering 
with 
function 
moderate pain with 
inflammation, 
erythema 
or 
joint 
swelling – interfering 
with function, but not 
with 
activities 
of 
daily living 
severe pain with 
inflammation, 
erythema or joint 
swelling 
–and 
interfering 
with 
activities of daily 
living 
permanent and/or 
disabling 
joint 
destruction 
Myalgia 
myalgia 
with 
no 
limitation of activity 
muscle tenderness 
(at 
other 
than 
injection site) or with 
moderate 
impairment 
of 
activity 
severe 
muscle 
tenderness 
with 
marked impairment 
of activity 
frank 
myonecrosis 
 
SKIN 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Mucocutaneous 
erythema; pruritus 
diffuse, 
maculo 
papular rash, dry 
desquamation 
vesiculation or moist 
desquamation 
or 
ulceration 
exfoliative 
dermatitis, mucous 
membrane 
involvement 
or 
erythema, 
multiforme 
or 
suspected Stevens- 
Johnson or necrosis 
requiring surgery 
Induration 
< 15mm 
15-30 mm 
>30mm 
 
Erythema 
< 15mm 
15-30 mm 
>30mm 
 
Edema 
< 15mm 
15-30 mm 
>30mm 
 
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CONFIDENTIAL 
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Rash at Injection 
Site 
< 15mm 
15-30 mm 
>30mm 
 
Pruritus 
slight itching at 
injection site 
moderate itching at 
injection extremity 
itching over entire 
body 
 
 
SYSTEMIC 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
 
Allergic Reaction 
 
pruritus without rash 
 
localized urticaria 
generalized 
urticaria; 
angioedema 
 
anaphylaxis 
 
Headache 
mild, no treatment 
required 
transient, moderate; 
treatment required 
severe; responds to 
initial 
narcotic 
therapy 
intractable; requires 
repeated 
narcotic 
therapy 
Fever: oral 
37.7 - 38.5 C or 
100.0 - 101.5 F 
38.6 - 39.5 C or 
101.6 - 102.9 F 
39.6 - 40.5 C or 103 
- 105 F 
> 40 C or > 105 F 
 
Fatigue 
normal 
activity 
reduced < 48 hours 
normal 
activity 
decreased 25- 50% 
> 48 hours 
normal 
activity 
decreased > 50% 
can’t work 
unable to care for 
self 
 
 
 
 
 
 
 
 
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CONFIDENTIAL 
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Appendix 3: Who Clinical Staging of HIV/AIDS for Adults and Adolescents  
Primary HIV Infection 
Asymptomatic 
Acute retroviral syndrome 
Clinical Stage 1 
Asymptomatic 
Persistent generalized lymphadenopathy 
Clinical Stage 2 
Moderate unexplained weight loss (<10% of presumed or measured body weight) 
Recurrent respiratory infections (sinusitis, tonsillitis, otitis media, and pharyngitis) 
Herpes zoster 
Angular cheilitis 
Recurrent oral ulceration 
Papular pruritic eruptions 
Seborrheic dermatitis 
Fungal nail infections 
Clinical Stage 3 
Unexplained severe weight loss (>10% of presumed or measured body weight) 
Unexplained chronic diarrhea for >1 month 
Unexplained persistent fever for >1 month (>37.6ºC, intermittent or constant) 
Persistent oral candidiasis (thrush) 
Oral hairy leukoplakia 
Pulmonary tuberculosis (current) 
Severe presumed bacterial infections (e.g., pneumonia, empyema, pyomyositis, 
bone or joint infection, meningitis, bacteremia) 
Acute necrotizing ulcerative stomatitis, gingivitis, or periodontitis 
Unexplained anemia (hemoglobin <8 g/dL) 
Neutropenia (neutrophils <500 cells/µL) 
Chronic thrombocytopenia (platelets <50,000 cells/µL) 
Clinical Stage 4 
HIV wasting syndrome 
Pneumocystis pneumonia 
Recurrent severe bacterial pneumonia 
Chronic herpes simplex infection (orolabial, genital, or anorectal site for >1 month or 
visceral herpes at any site) 
Esophageal candidiasis (or candidiasis of trachea, bronchi, or lungs) 
Extrapulmonary tuberculosis 
Kaposi sarcoma 
Cytomegalovirus infection (retinitis or infection of other organs) 
Central nervous system toxoplasmosis 
HIV encephalopathy 
Cryptococcosis, extrapulmonary (including meningitis) 
Disseminated nontuberculosis mycobacteria infection 
Progressive multifocal leukoencephalopathy 
Candida of the trachea, bronchi, or lungs 
Chronic cryptosporidiosis (with diarrhea) 
Chronic isosporiasis 
Disseminated mycosis (e.g., histoplasmosis, coccidioidomycosis, penicilliosis) 
Recurrent nontyphoidal Salmonella bacteremia 
Lymphoma (cerebral or B-cell non-Hodgkin) 
Invasive cervical carcinoma 
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Protocol Name: 
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CONFIDENTIAL 
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Atypical disseminated leishmaniasis 
Symptomatic HIV-associated nephropathy 
Symptomatic HIV-associated cardiomyopathy 
Reactivation of American trypanosomiasis (meningoencephalitis or myocarditis) 
 
REF: World Health Organization. WHO Case Definitions of HIV for Surveillance and Revised Clinical Staging and Immunological 
Classification of HIV-Related Disease in Adults and Children; 2007 
Vital Signs 
The following abnormalities will be defined for vital signs: 
Abnormality Code 
Vital Signs Parameter 
 
Pulse 
DBP 
SBP 
RR 
Abnormalities on actual values 
“Abnormally low” 
≤ 50 bpm 
≤ 50 mmHg 
≤ 90 mm Hg 
<12 
Breaths per minute 
“Grade 1 or mild” 
- 
> 
90 
mmHg-
<100 mmHg 
> 140 mmHg-
<160 mmHg 
17-20 
Breaths per minute 
“Grade 2 or moderate” 
- 
≥ 100 mmHg-
<110 mmHg 
≥ 160 mmHg-
<180 mmHg 
21-25 
Breaths per minute 
“Grade 3 or severe” 
- 
≥ 110 mmHg 
≥ 180 mmHg 
>25 
Breaths per minute 
“Abnormally high or Grade 
4” 
≥ 120 bpm 
- 
- 
Intubation 
 
 
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CONFIDENTIAL 
Page 93 of 99 
Appendix 4: Cardiovascular Safety 
CARDIOVASCULAR 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Cardiac 
Rhythm 
 
asymptomatic, 
transient signs, 
no Rx required 
recurrent/persiste
nt; symptomatic 
Rx required 
unstable 
dysrythmia; 
hospitalization and 
treatment required 
Hypertension 
transient increase > 
20 mm/Hg; no 
treatment 
recurrent, 
chronic increase 
> 20mm/Hg. 
/treatment 
required 
acute treatment 
required; 
outpatient 
treatment or 
hospitalization 
possible 
end organ damage 
or hospitalization 
required 
Hypotension 
transient orthostatic 
hypotension with 
heart rate increased 
by <20 beat/min or 
decreased by <10 
mm Hg systolic BP, 
no treatment 
required. 
symptoms due to 
orthostatic 
hypotension or 
BP decreased by 
<20 mm Hg 
systolic; 
correctable with 
oral fluid 
treatment 
requires IV fluids; 
no hospitalization 
required 
mean arterial 
pressure <60mm/ 
Hg or end organ 
damage or shock; 
requires 
hospitalization and 
vasopressor 
treatment 
Pericarditis 
minimal effusion 
mild/moderate 
asymptomatic 
effusion, no 
treatment 
symptomatic 
effusion; pain; 
EKG changes 
tamponade; 
pericardiocentesis 
or surgery required 
Hemorrhage, 
Blood Loss 
microscopic/occult 
mild, no 
transfusion 
gross blood loss; 
1-2 units 
transfused 
massive blood loss; 
> 3 units transfused 
All-important abnormalities from the ECG readings will be reported. 
The percentage of participants with increases in QTc of <30, 30-60, or > 60 ms from baseline 
will also be tabulated at each time point. 
Abnormality Code 
ECG parameter 
 
HR 
PR 
QRS 
QTcorrected 
Abnormalities on actual values 
“Abnormally low” 
≤ 50 bpm 
NAP 
≤ 50 ms 
- 
“Abnormally high” 
≥ 120 bpm 
≥ 210 ms 
≥ 120 ms 
- 
“]450 ms, 480 ms] 
- 
- 
- 
450 ms < QTc ≤ 480 ms 
“]480 ms, 500 ms] 
- 
- 
- 
480 ms < QTc ≤ 500 ms 
“More than 500 ms 
- 
- 
- 
QTc > 500 ms 
Abnormalities on changes from baseline 
“[30; 60] ms” 
- 
- 
- 
[30; 60] ms 
“> 60 ms” 
- 
- 
- 
> 60 ms 
 
 
 
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CONFIDENTIAL 
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Appendix 5: Karnofsky Performance Status Scale Definitions Rating (%) Criteria 
Description 
% 
Able to carry on normal activity 
and to work; no special care 
needed. 
Normal no complaints; no evidence of disease. 
100 
Able to carry on normal activity; minor signs or 
symptoms of disease. 
90 
Normal activity with effort; some signs or symptoms 
of disease.  
80 
Unable to work; able to live at 
home 
and 
care 
for 
most 
personal needs; varying amount 
of assistance needed. 
Cares for self; unable to carry on normal activity or 
to do active work. 
70 
Requires occasional assistance, but is able to care 
for most of his personal needs. 
60 
Requires considerable assistance and frequent 
medical care.  
50 
Unable to care for self; requires 
equivalent of institutional or 
hospital care; disease may be 
progressing rapidly. 
Disabled; requires special care and assistance. 
40 
Severely disabled; hospital admission is indicated 
although death not imminent. 
30 
Very sick; hospital admission necessary; active 
supportive treatment necessary. 
20 
Moribund; fatal processes progressing rapidly. 
10 
Dead 
0 
 
Ref: Oxford Textbook of Palliative Medicine, Oxford University Press.  1993; 109. 
 
 
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CONFIDENTIAL 
Page 95 of 99 
Appendix 6: Tuberculosis Symptoms Profile 
 
 
 
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Appendix 7: Patient Reported Health Status Questionnaire  
 
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Page 97 of 99 
 
 
 
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Appendix 8: Liver Toxicity Management 
Standard anti-TB chemotherapy is known to cause derangement of liver function tests 
in a substantial number of patients. In many cases this will be asymptomatic and self-limiting. 
In some cases, severe hepatitis and even fulminant liver failure and death can occur. 
In pre-marketing clinical trials of new drugs and regimens it is especially important to identify 
and carefully manage any trial participants who are at risk of progression to serious liver 
injury. The observation of altered liver function to a degree that has a high risk of progressing 
to liver failure as been referred to informally as Hy’s Law;(44, 45); this reflects that pure 
hepatocellular injury sufficient to cause hyperbilirubinemia is an ominous indicator of the 
potential for a drug to cause serious liver injury. Briefly, Hy’s Law cases have the following 
three components: 
1. The drug causes hepatocellular injury, generally shown by a higher incidence of 3-
fold or greater elevations above the ULN of ALT or AST than the (non-hepatotoxic) 
control drug or placebo. 
2. Among trial participants showing such aminotransferase (AT) elevations, often with 
ATs much greater than 3x ULN, one or more also show elevation of serum total 
bilirubin (TBL) to >2x ULN, without initial findings of cholestasis (elevated serum 
alkaline phosphatase (ALP)). 
3. No other reason can be found to explain the combination of increased AT and total 
bilirubin level (TBL), such as viral hepatitis A, B, or C; pre-existing or acute liver 
disease; or another drug capable of causing the observed injury. 
 
During the trial, liver function will be monitored regularly with clinical assessment and blood 
tests in trial participants and this will assist in follow up laboratory measurements that can 
document either resolution of abnormalities or signal the potential for drug-induced liver 
injury (DILI). In a clinical trial of new drugs and combinations it is especially important for 
Investigators to follow closely any participants who have evidence of hepatic inflammation 
or potential toxicity. The following procedure describes the management of deranged liver 
function tests in trial participants. 
Procedure 
Blood tests for liver function will be taken routinely at screening (Day -9 to -1) and at the 
specific time points designated in the protocol, and at Early Withdrawal. If at any other visit 
the clinician suspects derangement of liver function, e.g. the participant describes nausea 
and vomiting, right upper abdominal pain or is jaundiced, blood should be taken for liver 
function tests and the participant comprehensively assessed for evidence of hepatitis or 
hepatic impairment and any potentially contributing causes. 
Suspected liver toxicity (or elevated liver enzymes detected in the absence of symptoms) 
must be taken seriously and detailed guidance will be provided in a separate document, 
Management of Hepatotoxicity Guideline. Investigators should refer to this document as a 
guide to management in cases of suspected or proven liver toxicity. Importantly, the 
Sponsor Medical Monitor is available to provide further assistance if there is any uncertainty or 
additional questions. 
The laboratory source (print-out of any results) should be stored alongside or transcribed into 
the clinical source document. Each abnormal value should be marked as clinically significant 
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CONFIDENTIAL 
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(CS) or non-clinically significant (NCS); the assessment of significance is at the discretion 
of the Investigator. All clinically significant abnormal results must be recorded as Adverse 
Events in the eCRF and graded clinically as per the DMID adult toxicity table grading, 
(Appendix 2). Assessments and decision making for elevations in aminotransferase values or 
bilirubin of various levels of concern are detailed below: 
Elevated liver enzymes considered of clinical significance, but not accompanied by other 
signs and symptoms, should be reported as an adverse event and should usually be 
recorded as elevated liver enzymes. If the term "hepatitis" is used, the Safety Data Manager 
will question the site for additional evidence to support the diagnosis, such as clinical signs 
and serological or biopsy data. While a liver biopsy is not required to make a diagnosis 
of hepatitis, the term "hepatitis" should be reserved in most instances for cases where 
there is supportive evidence beyond a liver enzyme abnormality. However, if the 
Investigator will confirm the diagnosis of hepatitis just on the basis of clinical signs and 
laboratory values the diagnosis will be accepted. Should other symptoms or signs be present, 
these should also be recorded as adverse events. 
Temporarily Stopping and Restarting Trial Medication 
Liver function tests that are improving should be repeated regularly, such as every 3 days for 
the first week then once a week until they return to near baseline values for the participant. 
Manage the participant symptomatically as required using medications that are not potentially 
hepatotoxic and discontinue any concomitant drugs, if clinically warranted, that may be 
hepatotoxic. Infection control issues must be carefully managed whilst TB medications are 
being withheld, especially if the participant is still culture positive for acid fast bacilli. 
If t r i a l  medication has been temporarily stopped, once the liver function values have 
decreased substantially a decision must be made about further TB management. This will be 
dependent on the clinical context and a decision must be made in discussion with the Sponsor 
Medical Monitor. Investigational treatment can only be restarted if the Sponsor Medical 
Monitor is in agreement with the plan. In all cases treatment should be recommenced under 
close supervision for any evidence of recurrent liver function abnormalities. 
If there is a further significant elevation of hepatic enzymes or bilirubin or symptoms of 
clinical concern after resumption of trial medication, the trial medication should be withdrawn 
permanently. Participants who permanently discontinue trial medication should be managed 
as clinically indicated according to local National TB Programme guidelines. The Sponsor 
Medical Monitor can be contacted for further advice when referring to the National Treatment 
Program. 
The Sponsor Medical Monitor is available to assist the Investigators in both the management 
of liver toxicity and decisions regarding the holding or re-introduction of trial medication. 
Investigators must involve the Sponsor Medical Monitor in any decisions regarding medication 
hold or re-start, and there should always be a low threshold for contacting the Sponsor 
Medical Monitor in cases of elevated liver enzymes.  
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Protocol Amendment
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CONFIDENTIAL
This document is proprietary and shall not be reproduced without prior written permission from TB Alliance.
Protocol Name / Number:
SimpliciTB / NC-008 (B-Pa-M-Z)
Protocol Title:
An Open-Label, Partially Randomized Trial to Evaluate the Efficacy, Safety and Tolerability of a 4-month 
Treatment of Bedaquiline plus Pretomanid plus Moxifloxacin plus Pyrazinamide (BPaMZ) Compared to a 6-
month Treatment of HRZE/HR (Control) in Adult Participants with Drug-Sensitive Smear-Positive Pulmonary 
Tuberculosis (DS-TB) and a 6-month Treatment of BPaMZ in Adult Participants with Drug Resistant, Smear-
Positive Pulmonary Tuberculosis (DR-TB).
Reasons for Protocol Amendment:
1
Additional text, Synopsis Section Statistical Methods:  Exploratory, ‘The responses of participants with DR-TB receiving BPaMZ will be 
compared for consistency with those responses of the DS-TB participants on the same regimen.’
2
Additional text, Section 1.2 Synopsis Flow Chart and Procedures, Item s. ‘Weeks 39, 65, 78 and 104 (for bedaquiline, bedaquiline 
metabolite M2): PK samples are to be obtained at any time on the day of the scheduled visit.
3
Amended text, Section 2.5.1 Bedaquiline (B) 2nd paragraph… ‘Bedaquiline is currently registered in many countries to be administered to 
patients with pulmonary tuberculosis by the following scheme: 400mg once daily for Days 1-14 followed by 200mg three times per week for 
the remainder of treatment. In this trial bedaquiline will be administered as 200 mg daily for 8 weeks then 100 mg daily for 9 weeks in 
participants with DS-TB and 200 mg daily for 8 weeks then 100 mg daily for 18 weeks in participants with DR-TB.’  
4
Additional text, Section 5.2 Trial Population, ‘It is the intent of the protocol that the participants are hospitalized according to local practices 
and at the judgment of the treating physician / investigator.’
5
Additional 14th Exclusion Criteria, Section 5.2, ‘Participants with lactose intolerance, lactase deficiency and/or glucose-galactose 
malabsorption’.
6
Change in number sequence of Section 5.2 Exclusion Criteria, Previous and Concomitant Therapy numbers 13-22, changed to 14-23, due to 
the addition of the Exclusion Criteria #14, as described above
7
Change and addition of text in Section 7.4 PK Variables and Procedures, to updated population PK models for pyrazinamide and 
moxifloxacin, remove the reference to linezolid, and to reference the NC-005 study and at the same time removing the reference to the Nix 
study.
8
Change the text in Section 9.2 Sample Size (end 1st paragraph) to make it consistent with the text in Section 9.3 Interim Analysis, to read 
‘Currently no formal interim analysis is planned’.
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Global Alliance for TB Drug Development
Protocol Number:                      NC-008
Protocol Amendment Version:  Russia V1.0 / 10 Jul 2018
Protocol Name:                         SimpliciTB
Protocol Amendment
TMP02-C V3.0 dated 06Dec2017
CONFIDENTIAL
This document is proprietary and shall not be reproduced without prior written permission from TB Alliance.
#
Section
Previous Text
Version 2.0 dated 21 Feb 2018
Amended Text
Russia V1.0 dated 10 Jul 2018
Additional text - bold font. Deleted text – strike-through.
Reason for 
Change
Insert reason # from 
table above
1
Synopsis
Statistical Methods, Exploratory
No formal statistical comparisons will be made for 
the participants enrolled with DR-TB.
Statistical Methods, Exploratory
No formal statistical comparisons will be made for 
the participants enrolled with DR-TB. The 
responses of participants with DR-TB receiving 
BPaMZ will be compared for consistency with 
those responses of the DS-TB participants on 
the same regimen.  
1
2
Section 1.2
Synopsis Flow Chart and Procedures, Item s.
Weeks 39, 65, 78 and 104: PK samples are to be 
obtained at any time on the day of the scheduled 
visit
Synopsis Flow Chart and Procedures, Item s.
Weeks 39, 65, 78 and 104 (for bedaquiline, 
bedaquiline metabolite M2): PK samples are to be 
obtained at any time on the day of the scheduled 
visit
2
3
Section 2.5.1 
Bedaquiline (B), 2nd paragraph
Bedaquiline is currently registered in many 
countries to be administered to patients with 
pulmonary tuberculosis by the following scheme: 
400mg once daily for Days 1-14 followed by 
200mg three times per week for the remainder of 
treatment. In this trial bedaquiline will be 
administered as 200 mg daily for 8 weeks followed 
by 100 mg daily for the remaining 17 weeks or 30 
weeks if treatment is extended.
Bedaquiline (B), 2nd paragraph
Bedaquiline is currently registered in many countries 
to be administered to patients with pulmonary 
tuberculosis by the following scheme: 400mg once 
daily for Days 1-14 followed by 200mg three times 
per week for the remainder of treatment. In this trial 
bedaquiline will be administered as 200 mg daily 
for 8 weeks then 100 mg daily for 9 weeks in 
participants with DS-TB and 200 mg daily for 8 
weeks then 100 mg daily for 18 weeks in 
participants with DR-TB.
3
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585 of 852


Global Alliance for TB Drug Development
Protocol Number:                      NC-008
Protocol Amendment Version:  Russia V1.0 / 10 Jul 2018
Protocol Name:                         SimpliciTB
Protocol Amendment
TMP02-C V3.0 dated 06Dec2017
CONFIDENTIAL
This document is proprietary and shall not be reproduced without prior written permission from TB Alliance.
#
Section
Previous Text
Version 2.0 dated 21 Feb 2018
Amended Text
Russia V1.0 dated 10 Jul 2018
Additional text - bold font. Deleted text – strike-through.
Reason for 
Change
Insert reason # from 
table above
4
Section 5.2 
Trial Population
NA
Trial Population
It is the intent of the protocol that the 
participants are hospitalized according to local 
practices and at the judgment of the treating 
physician / investigator
4
5
Section 5.2
Exclusion Criteria #14, Medical History and 
Concurrent Conditions
NA
Exclusion Criteria #14, Medical History and 
Concurrent Conditions
Participants with lactose intolerance, lactase 
deficiency and/or glucose-galactose 
malabsorption.
5
6
Section 5.2
Exclusion Criteria # 14 to 23, Previous 
Concomitant Therapy
NA
Exclusion Criteria # 14 to 23, Previous Concomitant 
Therapy
Previously numbered items 14 to 23, have been re-
numbered as 15 to 24 due to the additional 
exclusion criteria described above.
6
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586 of 852


Global Alliance for TB Drug Development
Protocol Number:                      NC-008
Protocol Amendment Version:  Russia V1.0 / 10 Jul 2018
Protocol Name:                         SimpliciTB
Protocol Amendment
TMP02-C V3.0 dated 06Dec2017
CONFIDENTIAL
This document is proprietary and shall not be reproduced without prior written permission from TB Alliance.
#
Section
Previous Text
Version 2.0 dated 21 Feb 2018
Amended Text
Russia V1.0 dated 10 Jul 2018
Additional text - bold font. Deleted text – strike-through.
Reason for 
Change
Insert reason # from 
table above
7
Section 7.4 
PK Variables and Procedures
Plasma concentrations from sparse sampling (see
Section 1.2) will be used to update population PK 
models for bedaquiline and its M2 metabolite, 
pretomanid and linezolid to further evaluate the 
effects of covariates on model parameters in this 
trial population.  
PK data from the current trial may be combined 
with prior data (e.g., from the Nix trial) to enhance 
this population PK analysis. 
PK Variables and Procedures
Plasma concentrations from sparse sampling (see
Section 1.2) will be used to update population PK 
models for bedaquiline and its M2 metabolite, 
pretomanid, and linezolid moxifloxacin and 
pyrazinamide to further evaluate the effects of 
covariates on model parameters in this trial 
population.  
PK data from the current trial may be combined with 
prior data (e.g., from the Nix NC-005 trial) to 
enhance this population PK analysis. 
7
8
Section 9.2 
Sample Size
For the primary endpoint, time-to-culture 
conversion at 8 weeks,150 participants per arm 
(DS-TB participants) will provide at more than 90% 
power (5% 2-sided significance) to detect a hazard 
ratio (HR) of at least 2 assuming 50% of control 
participants are culture negative by 8 weeks. If 
only 25% of the control arm remain culture positive 
at 8 weeks, then this sample size will still retain 
more than 90% power to detect a HR of least 2.  
This sample size also allows for one planned 
interim analysis of the primary endpoint. (See
Section 9.4.1)
Sample Size
For the primary endpoint, time-to-culture conversion 
at 8 weeks,150 participants per arm (DS-TB 
participants) will provide at more than 90% power 
(5% 2-sided significance) to detect a hazard ratio 
(HR) of at least 2 assuming 50% of control 
participants are culture negative by 8 weeks. If only 
25% of the control arm remain culture positive at 8 
weeks, then this sample size will still retain more 
than 90% power to detect a HR of least 2.  This 
sample size also allows for one planned interim 
analysis of the primary endpoint. Currently no 
formal interim analysis is planned. (See Section 
9.4.1)
8
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587 of 852


Global Alliance for TB Drug Development
Protocol Number:                      NC-008
Protocol Amendment Version:  Russia V1.0 / 10 Jul 2018
Protocol Name:                         SimpliciTB
Protocol Amendment
TMP02-C V3.0 dated 06Dec2017
CONFIDENTIAL
This document is proprietary and shall not be reproduced without prior written permission from TB Alliance.
Sponsor
I agree to the terms of this protocol amendment
Signature of Study Physician
Printed name
Date
5 of 10
588 of 852


Global Alliance for TB Drug Development
Protocol Number:                      NC-008
Protocol Amendment Version:  Russia V1.0 / 10 Jul 2018
Protocol Name:                         SimpliciTB
Protocol Amendment
TMP02-C V3.0 dated 06Dec2017
CONFIDENTIAL
This document is proprietary and shall not be reproduced without prior written permission from TB Alliance.
Principal Investigator
I hereby confirm I have read the above Protocol Amendment and agree to conduct this clinical trial as outlined in the above 
Protocol Amendment. I will provide copies of the Protocol Amendment and access to all of the information required to conduct the 
clinical trial according to the above Protocol Amendment to the site personnel under my supervision. I will discuss this material with 
them and ensure they are fully informed on all trial requirements. 
Signature of Principal Investigator
Printed name
Date
6 of 10
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Certificate Of Completion
Envelope Id: C7D376E71E674BD5843489A2D3FF934D
Status: Completed
Subject: Please DocuSign: SimpliciTB Protocol Russia Amendment Form V1.0 dated 10 Jul 2018.pdf
Source Envelope: 
Document Pages: 6
Signatures: 1
Envelope Originator: 
Certificate Pages: 4
Initials: 0
Leandra Lombard
AutoNav: Enabled
EnvelopeId Stamping: Disabled
Time Zone: (UTC-08:00) Pacific Time (US & Canada)
40 Wall St FL 24
New York, NY  10005
Leandra.Lombard@tballiance.org
IP Address: 31.146.205.162 
Record Tracking
Status: Original
             13 July 2018 | 09:38
Holder: Leandra Lombard
             Leandra.Lombard@tballiance.org
Location: DocuSign
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Morounfolu Olugbosi
morounfolu.olugbosi@tballiance.org
Senior Director, Clinical Development
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(Required)
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3DABF6C3-410E-4B8F-85E1-D6E511FA5A5F
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   I approve this document
Sent: 13 July 2018 | 09:39
Viewed: 13 July 2018 | 10:43 
Signed: 13 July 2018 | 10:43
Electronic Record and Signature Disclosure: 
      Accepted: 27 September 2017 | 05:45
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CONFIDENTIAL 
Page 1 of 98 
 
 
 
Protocol Number: 
NC-008 (BPaMZ) 
Title: 
An Open-Label, Partially Randomized Trial to Evaluate the 
Efficacy, Safety and Tolerability of a 4-month Treatment of 
Bedaquiline 
plus 
Pretomanid 
plus 
Moxifloxacin 
plus 
Pyrazinamide (BPaMZ) Compared to a 6-month Treatment of 
HRZE/HR (Control) in Adult Participants with Drug-Sensitive 
Smear-Positive Pulmonary Tuberculosis (DS-TB) and a 6-month 
Treatment of BPaMZ in Adult Participants with Drug Resistant, 
Smear-Positive Pulmonary Tuberculosis (DR-TB). 
Drug(s)/Combination(s): 
Bedaquiline tablets (B), pretomanid tablets (Pa), moxifloxacin 
tablets (M), pyrazinamide tablets (Z), HRZE tablets [isoniazid 
(H), rifampicin (R), pyrazinamide (Z) and ethambutol (E)] and HR 
tablets [isoniazid (H) plus rifampicin (R) combination tablets] 
Protocol Version/Date: 
 
Russia V2.0 / 25 Jan 2019, Incorporating Protocol V3.0 / 14 
January 2019 
Protocol Name: 
SimpliciTB 
 
 
 
 
 
594 of 852


TB Alliance 
Protocol Number: NC-008 (B-Pa-M-Z) 
Protocol Version: Russia V2.0 / 25 Jan 2019, Incorporating Protocol V3.0 / 14 Jan 2019 
Protocol Name: 
SimpliciTB 
PROTOCOL SIGNATURE PAGE 
Protocol Title: An Open-Label, Partially Randomized Trial to Evaluate the Efficacy, 
Safety and Tolerability of a 4-month Treatment of Bedaquiline plus Pretomanid plus 
Moxifloxacin plus Pyrazinamide (BPaMZ) Compared to a 6-month Treatment of 
HRZE/HR (Control) in Adult Participants with Drug-Sensitive Smear-Positive 
Pulmonary Tuberculosis (DS-TB) and a 6-month Treatment of BPaMZ in Adult 
Participants with Drug Resistant, Smear-Positive Pulmonary Tuberculosis (DR-TB). 
Protocol Number: 
NC-008 (BPaMZ) 
Protocol Date: 
14 January 2019 
Russia V2.0 / 25 January 2019, Incorporating Protocol V3.0 I 
Protocol Name: 
SimpliciTB 
SPONSOR: 
TB Alliance 
I agree to the terms of this trial protocol. 
1
oocuSigned by: 
I /.¼,r~ /Jwfbsi 
l(J 
Signer Name: Morounfolu Olugbosi 
Sig~J::~;St~~~t~fdi=~~i 
~
3DABF6C3410E488F85E1D6E511FA5A5F 
January 25, 2019 I 3:45 AM PST 
Date 
Morounfolu Olugbosi 
Printed Name 
40 Wall Street, 24th Floor 
New York, NY 10005 
Phone +27 87 700 3900 / +27 79 045 4917 
E-mail: morounfolu.olugbosi@tballiance.org 
Confidential 
Page 2 of98 
595 of 852


TB Alliance 
Protocol Number: NC-008 (B-Pa-M-Z) 
Protocol Version: Russia V2.0 / 25 Jan 2019, Incorporating Protocol V3.0 / 14 Jan 2019 
Protocol Name: 
SimpliciTB 
Confidential 
Page 3 of 98 
 
PRINCIPAL INVESTIGATOR PROTOCOL SIGNATURE PAGE 
 
An Open-Label, Partially Randomized Trial to Evaluate the Efficacy, Safety and 
Tolerability of a 4-month Treatment of Bedaquiline plus Pretomanid plus Moxifloxacin 
plus Pyrazinamide (BPaMZ) Compared to a 6-month Treatment of HRZE/HR (Control) in 
Adult Participants with Drug-Sensitive Smear-Positive Pulmonary Tuberculosis 
(DS-TB) and a 6-month Treatment of BPaMZ in Adult Participants with Drug Resistant, 
Smear-Positive Pulmonary Tuberculosis (DR-TB). 
Protocol Number:  
NC-008 (BPaMZ) 
Protocol Date:  
Russia V2.0 / 25 January 2018, Incorporating Protocol V3.0 / 14 
 
January 2018 
Protocol Name:  
SimpliciTB 
 
I hereby confirm that I have read the above protocol and agree to conduct this clinical trial as 
outlined in the above protocol. I will provide copies of the protocol and access to all the 
information required to conduct the clinical trial according to the above protocol to the site 
personnel under my supervision. I will discuss this material with them and ensure they are fully 
informed on all trial requirements. 
 
 
 
 
 
Signature 
 
Printed Name 
 
 
 
Date 
 
 
 
 
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TB Alliance 
Protocol Number: NC-008 (B-Pa-M-Z) 
Protocol Version: Russia V2.0 / 25 Jan 2019, Incorporating Protocol V3.0 / 14 Jan 2019 
Protocol Name: 
SimpliciTB 
Confidential 
Page 4 of 98 
List of Tables ...................................................................................................................... 7 
List of Figures ..................................................................................................................... 7 
List of Appendices .............................................................................................................. 7 
Abbreviations and Definition of Terms ................................................................................ 8 
1.0 
Synopsis .................................................................................................................... 10 
1.1 
Synopsis Summary ................................................................................................ 10 
1.2 
Synopsis Flow Chart and Procedures .................................................................... 17 
2.0 
Introduction and Rationale ......................................................................................... 22 
2.1 
Tuberculosis Disease ............................................................................................. 22 
2.2 
Tuberculosis Clinical Research .............................................................................. 22 
2.3 
Trial Rationale ........................................................................................................ 24 
2.3.1 
Trial Design Rationale ...................................................................................................................... 24 
2.3.2 
Trial Drug Regimen Rationale .......................................................................................................... 25 
2.4 
Agents used within SimpliciTB ............................................................................... 26 
2.5 
Background of Agents to be Studied in SimpliciTB................................................. 28 
2.5.1 
Bedaquiline (B) ................................................................................................................................. 28 
2.5.2 
Pretomanid (P) ................................................................................................................................. 35 
2.5.3 
Moxifloxacin (M) .............................................................................................................................. 41 
2.5.4 
Pyrazinamide (Z) .............................................................................................................................. 43 
2.6 
Overall Benefit/Risk Assessment ........................................................................... 44 
2.6.1 
Bedaquiline (B) ................................................................................................................................. 44 
2.6.2 
Pretomanid (P) ................................................................................................................................. 45 
2.6.3 
Moxifloxacin (M) .............................................................................................................................. 46 
2.6.4 
Pyrazinamide (Z) .............................................................................................................................. 46 
2.6.5 
HRZE/HR Control .............................................................................................................................. 46 
3.0 
Trial Objectives .......................................................................................................... 46 
3.1 
Primary Endpoint ................................................................................................... 46 
3.2 
Secondary Endpoints ............................................................................................. 47 
3.3 
Exploratory Objectives ........................................................................................... 47 
4.0 
Trial Design ............................................................................................................... 48 
4.1 
Summary of Trial Design........................................................................................ 48 
4.2 
Treatment Plan: Schedule of Assessments ............................................................ 48 
5.0 
Trial Population ......................................................................................................... 49 
5.1 
Inclusion Criteria .................................................................................................... 49 
5.2 
Exclusion Criteria ................................................................................................... 51 
5.3 
Restrictions ............................................................................................................ 54 
5.4 
Treatment Discontinuation and/or Early Withdrawal ............................................... 56 
5.4.1 
Early Withdrawal ............................................................................................................................. 56 
5.4.2 
Unscheduled Visits ........................................................................................................................... 57 
5.4.3 
Lost-to-Follow-up ............................................................................................................................. 59 
5.4.4 
Early Withdrawal due to TB ............................................................................................................. 59 
5.5 
Participant Progress Definitions ............................................................................. 60 
5.6 
Trial Stopping Rules ............................................................................................... 60 
6.0 
Treatment .................................................................................................................. 61 
597 of 852


TB Alliance 
Protocol Number: NC-008 (B-Pa-M-Z) 
Protocol Version: Russia V2.0 / 25 Jan 2019, Incorporating Protocol V3.0 / 14 Jan 2019 
Protocol Name: 
SimpliciTB 
Confidential 
Page 5 of 98 
6.1 
IMP Administration ................................................................................................. 61 
6.1.1 
Instructions for Dosing of Test Regimen (BPaMZ): .......................................................................... 61 
6.1.2 
Instructions for Dosing Control Treatment Regimen (HRZE/HR): .................................................... 61 
6.2 
Participant Compliance .......................................................................................... 61 
6.3 
Treatment Modification(s) ...................................................................................... 61 
6.4 
IMP Packaging and Labelling ................................................................................. 62 
6.5 
Blinding and Procedures for Breaking the Blind ..................................................... 63 
6.6 
Handling, Storage and Accountability..................................................................... 63 
7.0 
Trial Variables and Procedures ................................................................................. 63 
7.1 
Demographic and Background Variables and Procedures ..................................... 64 
7.2 
Efficacy Variables and Procedures ........................................................................ 64 
7.3 
Safety and Tolerability Assessments ..................................................................... 65 
7.4 
PK Variables and Procedures ................................................................................ 67 
7.5 
Mycobacteriology Characterization Variable and Procedures ................................ 67 
8.0 
Adverse Events ......................................................................................................... 68 
8.1 
Definitions .............................................................................................................. 68 
8.1.1 
Adverse Event (AE) ........................................................................................................................... 68 
8.1.2 
Serious Adverse Event (SAE) ............................................................................................................. 68 
8.1.3 
Attribution/Causality ....................................................................................................................... 69 
8.1.4 
Severity ............................................................................................................................................ 70 
8.2 
Reporting ............................................................................................................... 70 
8.2.1 
Follow up of Adverse Events ............................................................................................................ 71 
8.2.2 
Clinical Laboratory Adverse Events .................................................................................................. 71 
8.2.3 
Disease Symptoms During Trial ....................................................................................................... 71 
8.2.4 
Overdose .......................................................................................................................................... 72 
8.2.5 
Drug Interaction ............................................................................................................................... 72 
8.2.6 
Pregnancy ........................................................................................................................................ 72 
8.3 
Monitoring for Specific Toxicities ............................................................................ 72 
8.3.1 
ALT, AST and Bilirubin Elevations ..................................................................................................... 73 
8.3.2 
Lipase ............................................................................................................................................... 73 
8.3.3 
Musculoskeletal System and Cardiac Muscle Myalgia .................................................................... 73 
8.3.4 
Cardiac Rhythm Disturbances .......................................................................................................... 73 
8.4 
Safety Monitoring by Data Monitoring Committee .................................................. 74 
9.0 
Statistical Analysis ..................................................................................................... 74 
9.1 
Analysis Populations .............................................................................................. 74 
9.2 
Sample Size........................................................................................................... 75 
9.3 
Interim Analyses .................................................................................................... 75 
9.4 
Primary and Secondary Efficacy Endpoint Analysis ............................................... 76 
9.4.1 
Primary Efficacy Endpoint, Time to Culture Conversion at 8 Weeks ................................................ 76 
9.4.2 
Key Secondary Efficacy Endpoint, Clinical Outcome at 52 Weeks from Randomization .................. 76 
9.4.3 
Other Secondary Efficacy Endpoints ................................................................................................ 76 
9.5 
Safety and Tolerability Assessments ..................................................................... 76 
9.6 
Pharmacokinetics................................................................................................... 77 
9.7 
Pharmacokinetics/Pharmacodynamics ................................................................... 77 
10.0 
Records Management ............................................................................................ 77 
10.1 
Data Collection ................................................................................................... 77 
598 of 852


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Protocol Number: NC-008 (B-Pa-M-Z) 
Protocol Version: Russia V2.0 / 25 Jan 2019, Incorporating Protocol V3.0 / 14 Jan 2019 
Protocol Name: 
SimpliciTB 
Confidential 
Page 6 of 98 
10.2 
Source Documents ............................................................................................. 77 
10.3 
File Management at the Trial Centre .................................................................. 78 
10.4 
Records Retention at the Trial Centre ................................................................ 78 
11.0 
Quality Control and Assurance............................................................................... 78 
11.1 
Site Procedures .................................................................................................. 78 
11.2 
Monitoring .......................................................................................................... 79 
11.3 
Protocol Deviations ............................................................................................ 79 
11.4 
Auditing .............................................................................................................. 79 
12.0 
Ethics and Regulatory ............................................................................................ 80 
12.1 
Basic Principles .................................................................................................. 80 
12.2 
Independent Ethics Committee/Institutional Review Board (EC/IRB) Review ..... 80 
12.3 
Regulatory Authorities ........................................................................................ 80 
12.4 
Informed Consent ............................................................................................... 80 
12.5 
Confidentiality ..................................................................................................... 81 
13.0 
Publication Policy ................................................................................................... 81 
14.0 
Protocol Amendment Policy ................................................................................... 82 
15.0 
Sponsor, Financial Aspects, Insurance and Indemnity ........................................... 82 
16.0 
References ............................................................................................................ 83 
Appendices .......................................................................................................................... 87 
 
 
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Protocol Number: NC-008 (B-Pa-M-Z) 
Protocol Version: Russia V2.0 / 25 Jan 2019, Incorporating Protocol V3.0 / 14 Jan 2019 
Protocol Name: 
SimpliciTB 
Confidential 
Page 7 of 98 
List of Tables 
Table 1.  Bedaquiline Adverse Drug Reactions .................................................................... 33 
Table 2.  Key findings of Pretomanid in Safety and Toxicity Trials........................................ 37 
Table 3.  Summary of Phase 2b trials in which moxifloxacin were administered as part of a 
four-drug regimen during the intensive phase of treatment (total treatment duration: 2 months)
 ............................................................................................................................................ 42 
Table 4: Treatment Groups .................................................................................................. 49 
Table 5: Follow-up Visits Required for Early Withdrawal Participants ................................... 57 
Table 6: Summary of Scenarios Requiring Unscheduled Visits for Mycobacteriology Testing
 ............................................................................................................................................ 58 
Table 7: Participant Progress Definitions.............................................................................. 60 
Table 8: Adverse Events Attribution/Causality Ratings ......................................................... 69 
Table 9: Definitions for Adverse Event Severity Gradings .................................................... 70 
 
List of Figures 
Figure 1.  Unified Drug Sensitive/Drug Resistant Regimen Development Path .................... 23 
Figure 2.  Log10 CFU Counts in Lungs ................................................................................ 36 
Figure 3.  Mean log Colony Forming Unit Values over Time Trial CL-010 ............................ 39 
 
List of Appendices 
Appendix 1: The IUATLD Scale ........................................................................................... 87 
Appendix 2: Division of Microbiology and Infectious Disease (DMID) Toxicity Table ............ 88 
Appendix 3: Who Clinical Staging of HIV/AIDS for Adults and Adolescents ......................... 95 
Appendix 4: Cardiovascular Safety ...................................................................................... 97 
Appendix 5: Karnofsky Performance Status Scale Definitions Rating (%) Criteria ................ 98 
 
 
 
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Protocol Number: NC-008 (B-Pa-M-Z) 
Protocol Version: Russia V2.0 / 25 Jan 2019, Incorporating Protocol V3.0 / 14 Jan 2019 
Protocol Name: 
SimpliciTB 
Confidential 
Page 8 of 98 
Abbreviations and Definition of Terms 
3TC 
Lamivudine 
ABC 
Abacavir 
AE  
Adverse Event  
AFB 
Acid-fast bacilli 
AIDS 
Acquired Immune Deficiency Syndrome 
ALP 
Alkaline Phosphatase 
ALT 
Alanine aminotransferase 
AREDS2 
Age Related Eye Disease Scale 2 
ART 
Anti-Retroviral Therapy 
AST 
Aspartate aminotransferase 
AUCτ 
Area Under Curve over a dosing interval 
B 
Bedaquiline 
BA 
Bacterial activity 
BMI 
Body Mass Index 
BPaMZ 
Combination of bedaquiline plus pretomanid plus moxifloxacin plus 
pyrazinamide 
C 
Clofazimine 
CFU 
Colony Forming Units 
C(max), (min) 
plasma Concentration (maximum), (minimum) 
CO2 
Carbon dioxide 
CPK 
Creatine Phosphokinase 
CYP3A4 
Cytochrome P450 3A4 
DMID 
Division of Microbiology and Infection Disease 
DNA 
Deoxyribonucleic Acid 
DR-TB 
Drug-resistant tuberculosis 
For this particular protocol defined as TB participants with  
1. mono-resistance to rifampicin or isoniazid, OR 
2. resistance to both rifampicin and isoniazid (MDR-TB) 
(participants with fluoroquinolone resistance are excluded) 
DS-TB 
Drug-sensitive tuberculosis 
DSMC  
DST 
Data Safety and Monitoring Committee 
Drug Susceptibility Testing 
E 
Ethambutol 
EBA 
Early Bactericidal Activity 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
EFV 
Efavirenz 
(e)CRF 
(electronic) Case Report Form 
EMS 
Early Morning Sputum 
EWD 
Early Withdrawal 
FTC 
Emtricitabine 
FSH 
Follicle-stimulating hormone 
GCP  
Good Clinical Practice 
GMR 
Geometric Mean Ratio 
H 
Isoniazid 
HR 
Hazard Ratio 
hERG 
Human Ether-à-go-go Related Gene 
HIV  
Human Immunodeficiency Virus 
HRZE 
Isoniazid, Rifampicin, Pyrazinamide, Ethambutol 
HR 
Isoniazid plus rifampicin combination tablet 
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ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IMP 
Investigational Medicinal Product 
IRB 
Institutional Review Board 
ITT 
Intent to Treat 
IUATLD 
International Union Against Tuberculosis and Lung Disease 
IWRS 
Interactive Web Randomization System 
kg 
Kilogram 
L 
Linezolid 
LH 
Luteinizing hormone 
LLN 
Lower Limit of Normal 
LPV 
Lopinavir 
LTFU 
Lost to follow-up  
M 
Moxifloxacin 
MBD 
Minimum Bactericidal Dose 
MIC 
Minimum Inhibitory Concentration 
MTB 
Mycobacterium tuberculosis 
MDR-TB 
Multi Drug Resistant Tuberculosis 
MGIT 
Mycobacterial Growth Inhibiting Tube 
mITT 
Modified Intent to Treat 
ms 
millisecond 
NVP 
Nevirapine 
NO 
Nitric Oxide 
NOAEL 
No Observed Adverse Effect Level 
NRTI 
(Triple) Nucleosidase Reverse Transcriptase Inhibitor 
Pa 
Pretomanid 
PD 
Pharmacodynamic 
PP 
Per Protocol 
PK 
Pharmacokinetic 
PR 
PR interval 
R 
Rifampicin 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SSCC 
Serial sputum colony counting 
TB 
Tuberculosis 
TDF 
Tenofovir 
TEAE 
Treatment Emergent Adverse Events 
TTP 
Time to Positivity  
ULN 
Upper Limit of Normal 
WGS 
Whole Genome Sequencing 
WHO 
World Health Organization 
XDR-TB 
Extensively Drug Resistant Tuberculosis 
μg(/ml) 
micrograms (per millilitre) 
Z 
Pyrazinamide (tablets) 
 
 
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1.0 
Synopsis 
1.1 
Synopsis Summary 
Synopsis 
Description  
Name of 
Sponsor/Company 
TB Alliance 
Name of Finished 
Products 
Bedaquiline tablets (B), pretomanid tablets (Pa), moxifloxacin 
tablets (M), pyrazinamide tablets (Z), HRZE tablets [isoniazid (H), 
rifampicin (R), pyrazinamide (Z) and ethambutol (E)] and HR 
tablets [isoniazid (H) plus rifampicin (R) combination tablets] 
Protocol Number/Title 
NC-008 (BPaMZ) An Open-Label, Partially Randomized Trial to 
Evaluate the Efficacy, Safety and Tolerability of a 4-month 
Treatment of Bedaquiline plus Pretomanid plus Moxifloxacin plus 
Pyrazinamide (BPaMZ) Compared to a 6-month Treatment of 
HRZE/HR (Control) in Adult Participants with Drug-Sensitive 
Smear-Positive Pulmonary Tuberculosis (DS-TB) and a 6-month 
Treatment of BPaMZ in Adult Participants with Drug Resistant, 
Smear-Positive Pulmonary Tuberculosis (DR-TB) 
Treatment Indication 
Pulmonary Tuberculosis (TB) 
Trial Objective(s) 
To evaluate the efficacy, safety and tolerability at 8 weeks (2-
months), 52 weeks (12-months), and 104 Weeks (24-months) 
post the start of the treatment regimens in participants with Drug 
Sensitive TB (DS-TB) and Drug Resistant TB (DR-TB). 
 
DR-TB is defined as participants with:  
 
1. mono-resistance to rifampicin or isoniazid, OR 
2. resistance to both rifampicin and isoniazid (MDR-TB) 
 
Trial Design 
Phase 2c multi-centre, open-label, partially randomized clinical 
trial in Drug Sensitive-TB (DS-TB) and Drug Resistant-TB (DR-
TB) participants.  
 
All participants will enter post-treatment follow-up which continues 
until Week 104 from start of treatment / randomisation. 
 
Participants with DS-TB: 
 
Participants with DS-TB will be randomized to one of two 
treatment arms. These participants will receive either BPaMZ daily 
for 17 weeks (4 months), or HRZE/HR tablets daily for 26 weeks 
(6 months). Participants will be stratified for co-infection with 
human immunodeficiency virus (HIV) and cavitation. 
 
Participants with DR-TB: 
 
Participants with DR-TB will be assigned to receive BPaMZ daily 
for 26 weeks (6 months). 
Participant Population 
Up to 450 male and female participants, diagnosed with DS-TB or 
DR-TB, aged 18 years and over with a target of up to 50% being 
HIV positive. 
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Protocol Name: 
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Synopsis 
Description  
 
300 DS-TB participants (150 per treatment arm) will be 
randomized and stratified for co-infection with HIV and cavitation. 
 
Up to 150 DR-TB participants will be enrolled. 
Test Product, Dose and 
Mode of Administration 
The Test Product (BPaMZ) consists of a combination of the 
following products and will be supplied as: 
 
Product 
Tablet Strength 
Abbreviation  
Bedaquiline 
100 mg  
(B) 
Pretomanid 
200 mg  
(Pa) 
Moxifloxacin 
400 mg 
(M) 
Pyrazinamide 
500 mg 
(Z) 
 
Instructions for Dosing BPaMZ:  
 
Investigational Medicinal Product (IMP) will be administered orally 
once daily, to be taken during breakfast, with a full glass of water 
(approximately 240 ml), for 17 weeks (4 months) or 26 weeks (6 
months) in the following dosing schemes: 
 
Participants with DS TB: 
Bedaquiline 200 mg daily for 8 weeks then 100 mg daily 
for 9 weeks, together with pretomanid 200 mg + 
moxifloxacin 400 mg + pyrazinamide 1500 mg daily for 17 
weeks (total treatment duration 4 months)  
 
OR 
 
Participants with DR-TB: 
Bedaquiline 200 mg daily for 8 weeks then 100 mg daily 
for 18 weeks, together with pretomanid 200 mg + 
moxifloxacin 400 mg + pyrazinamide 1500 mg daily for 26 
weeks (Total treatment duration 6 months). 
 
Positive Control 
Product, Dose and 
Mode of Administration 
The Control Treatment Regimen (HRZE/HR) will be supplied as:  
 
HRZE Tablets: isoniazid 75 mg plus rifampicin 150 mg plus 
pyrazinamide 400 mg plus ethambutol 275 mg combination 
tablets. This combination will be given for the first 8 weeks. 
 
AND 
 
HR Tablets: isoniazid 75 mg plus rifampicin 150 mg combination 
tablets. This combination will be given from Weeks 9 to 26. 
 
Instructions for Dosing Control Treatment Regimen 
 
To be taken with a glass of water (approximately 240 ml).  HRZE 
or HR should not be taken with a meal (generally, no closer to 
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Synopsis 
Description  
meals than 1 hour before or 2 hours after a meal) in the following 
dosing schemes: 
 
Treatment will be administered orally once daily to the HRZE/HR 
randomized DS-TB participants as follows: 
 
 
Weeks 1-26: HRZE/HR tablets daily dose per the 
 
participant’s weight as follows:  
 
 
Weight Band 
Weight Range 
Number of 
tablets  
1 
30-39 kg 
2 
2 
40-54 kg 
3 
3 
55-70 kg 
4 
4 
≥ 71 kg 
5 
 
The participant’s weight at the Screening (HRZE) and Week 8 
(HR) visits will be used to determine which weight band and HRZE 
and HR dose to administer. 
 
Vitamin B6 daily supplement to be taken with the HRZE/HR 
treatment, as per each country’s TB Treatment Guidelines.  
 
Treatment 
Interruptions/Pauses 
For All Trial Regimens  
The trial treatment regimens may require interruptions/pauses due 
to toxicities. All dose interruptions/pauses should be discussed 
with the Sponsor’s Medical Monitor prior to implementation, unless 
an interruption/pause is required urgently for a safety concern.   
Action required for participants missing the following number of 
doses within the trial treatment regimens:  
• 
Up to 7 consecutive doses: restart treatment, no extension 
of treatment required. 
• 
If more than 7 and to ≤ 35 consecutive doses missed, 
before the end of the treatment period (Week 17/26): 
restart treatment, extend the treatment by the number of 
consecutive doses missed. In this case, the last visit of the 
treatment period should also be pushed out to the date of 
the last dose 
• 
If more than 35 consecutive doses: discontinue treatment 
and withdraw participant from the trial  
• 
If the participant misses a total of 56 cumulative missed 
doses, discontinue the IMP and withdraw the participant 
from the trial. 
• 
If more than 7 to ≤ 35 consecutive doses are missed, 
these must be made up with the same treatment 
combination or dose, that was missed.  
 
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Synopsis 
Description  
Any participant for whom the trial IMP is discontinued (including 
for non-adherence) should be discussed with the Sponsor Medical 
Monitor and, if applicable, the participant will be restarted on trial 
IMP as soon as possible. 
Statistical Methods: 
A general description of the statistical methods planned to be used to analyse efficacy data is 
outlined below. Specific details will be provided in the statistical analysis plan (SAP,) which 
will be written and signed off prior to the interim analysis. 
 
Criteria for Evaluation 
 
Primary Endpoint 
 
The primary efficacy endpoint will be time to culture negativity over 8 weeks. The primary 
hypothesis to be evaluated is:  
 
• 
In the participants with DS-TB in the experimental BPaMZ treatment regimen, the time to 
culture negativity by 8 weeks will be superior, compared to the participants who are 
treated with the standard HRZE/HR regimen. 
 
 
Secondary Endpoints 
 
• 
A key secondary efficacy endpoint will be the proportion of participants experiencing 
bacteriologic failure or relapse or clinical failure (unfavourable outcome) at 52 weeks.  
 
The hypothesis to be evaluated for this endpoint is: 
 
• 
In the participants with DS-TB in the experimental BPaMZ treatment regimen, the 
proportion experiencing an unfavourable outcome will be non-inferior compared to the 
participants who are treated with the standard HRZE/HR regimen. 
 
Abbreviated Definitions, full definitions will be described in the Statistical Analysis Plan (SAP): 
 
• 
Bacteriologic failure: During the treatment period, failure to attain or maintain culture 
conversion to negative.  
• 
Bacteriologic relapse: During the follow-up period, failure to maintain culture conversion to 
negative status, with culture conversion to positive status with a strain of Mycobacterium 
tuberculosis (MTB) genetically identical to the infecting strain at baseline.  
• 
Clinical failure: A change from protocol-specified TB treatment to a new regimen before 
end of protocol specified treatment due to treatment failure, retreatment for TB during 
follow up, or TB-related death.  
 
Note:  
 
o Culture conversion requires at least 2 consecutive culture negative/positive samples at 
least 7 days apart.  
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Synopsis 
Description  
o Participants who are documented at a visit as unable to produce sputum and who are 
clinically considered to be responding well to treatment will be considered to be culture 
negative at that visit.  
 
Other Secondary Endpoints 
 
Efficacy: 
 
• 
Incidence of bacteriologic failure or relapse or clinical failure at 104 weeks from the start of 
treatment.  
• 
Proportion of participants with sputum culture conversion to negative status in liquid 
culture (MGIT) at 4, 6, 12 and 17 weeks to be explored as a potential biomarker of 
outcome at 52 weeks from start of treatment. 
• 
Change from baseline in weight. 
• 
Change from baseline in TB symptoms. 
• 
Change from baseline in Participant Reported Health Status. 
 
Safety and Tolerability: 
 
• 
Incidence of Treatment Emergent Adverse Events (TEAEs) presented by incidence, 
severity, drug relatedness, seriousness, leading to early withdrawal, and leading to death.  
• 
Quantitative and qualitative clinical safety laboratory measurements, including observed 
and change from baseline. 
• 
Quantitative and qualitative electrocardiogram (ECG) results (heart rate, RR interval, PR 
interval, QRS interval, QT interval and QTc interval), including observed. QT/QTc 
intervals, change from baseline, will be categorized as these will be centrally read. 
• 
Changes in male reproductive hormones. 
• 
Changes in lens opacities. 
 
These data will be presented as descriptive analyses, and no inferential tests will be carried 
out. 
 
Pharmacokinetics (PK) and Pharmacokinetics/Pharmacodynamics (PK/PD): 
 
Plasma concentrations from sparse sampling will be used to update existing population PK 
models and derive exposure metrics (e.g., minimum plasma concentration [Cmin], maximum 
plasma concentration [Cmax], area under curve over a dosing interval [AUC]) for bedaquiline 
and its M2 metabolite, pretomanid, moxifloxacin, and pyrazinamide.  
 
Effects of baseline covariates on exposure will be assessed; so too, will the effects of 
concomitant medications, including antiretroviral therapy (ART), where feasible. Data from 
other trials may be included to enhance the model-based analysis. Relationships will be 
explored between drug exposure and efficacy and safety endpoints. These exploratory PK/PD 
analyses may include HIV status as a covariate. 
 
Exploratory Objectives: 
 
Evaluate whether any of the secondary endpoints predict relapse free cure. Subgroup 
analysis of populations by HIV status will be performed. 
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Synopsis 
Description  
 
No formal statistical comparisons will be made for the participants enrolled with DR-TB. The 
responses of participants with DR-TB receiving BPaMZ will be compared for consistency with 
those responses of the DS-TB participants on the same regimen.   
 
 
Sample Size 
 
Primary endpoint: 150 participants per arm (DS-TB patients) will provide at least 90% power 
(5% 2-sided significance) to detect a hazard ratio (HR) of at least 2 assuming 50% of control 
participants are culture negative by 8 weeks.  
 
Additional efficacy parameters will be evaluated including the incidence of bacteriologic failure 
or relapse or clinical failure (unfavourable outcome) at 52 weeks and 104 weeks from the start 
of treatment. Time to unfavourable outcome from assignment of trial treatment through follow-
up as a function of time will be analysed using Kaplan-Meier analysis. 
 
Interim Analysis 
 
There is one planned interim efficacy analysis which will occur after approximately 60 
assessable participants have been randomised to the control arm and have reached the 8-
week primary endpoint. Time to culture negative status in liquid media up to 8 weeks will be 
analysed using a Cox regression model, censoring for death and lost to follow up/withdrawal 
to estimate the hazard ratio (HR). Following a review of these interim findings, the following 
considerations will be given to modify the trial objectives and sample size: 
If the observed HR (time to culture negativity, experimental arm vs. HRZE control arm) is >2, 
the sample size may be increased to adequately power the trial on the key secondary efficacy 
endpoint (clinical and microbiological outcome at 52 weeks from randomization), which will 
then become the primary efficacy endpoint. The trial efficacy objectives will be updated as 
follows: 
• 
Primary Objective 
 
To determine the incidence of bacteriologic failure or  
relapse or clinical failure at 
52 weeks from the start of  
treatment / randomisation.  
• 
Secondary Objective 
 
To evaluate the time to culture negativity over 8 weeks,  
from the start of treatment / 
randomisation. 
All other trial objectives will remain unchanged. 
To achieve 90% power and overall 5% 2-sided significance after adjusting for the 
interim analysis, this will mean increasing the sample size to 225 participants per randomised 
arm, i.e., to a total of 450 DS-TB participants (and up to 225 DR-TB participants). This 
adaptation is based on the Multi-arm Multi-stage (MAMS) framework [46,47,48] and full details 
are provided in the Statistical Analysis Plan. 
 
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Page 16 of 98 
Synopsis 
Description  
Trial Duration: 
Approximately 4 years (18-month enrolment period for DS-TB participants, up to 26 week-
treatment, and follow-up until 104 weeks from start of treatment). Depending on the DR-TB 
recruitment rate, enrolment into this arm may continue after enrolment into the DS-TB arms 
are complete.  
 
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1.2 
Synopsis Flow Chart and Procedures 
Period 
Screen-
inga 
Treatment 
Follow-Upc 
Visitb 
Day -9 to -1 
Day 1 
(Baseline)d 
Week 1 
Week 2 
Week 3 
Week 4 
Week 5 
Week 6 
Week 7 
Week 8  
Week 12 
Week 17 
4-mth treatmente 
Week 17  
6-mth treatmente 
Week 22  
Week 26  
4-mth treatmente 
Week 26  
6-mth treatmente 
Week 39 
Week 52 
Week 65 
Week 78 
Week 104 
Early 
Withdrawalc 
Visit Windowv 
N/A 
+/- 3 Days 
+/- 5 Days 
+/- 14 Days 
Written Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/Treatment/ Smoking History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sputum Samplingf,g 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HIV Statush and CD4 Counti 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Karnofsky Scorex 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Drug Screenj 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Pregnancy Testk 
X 
X 
 
 
 
 
 
 
 
X 
 
X 
X 
 
X 
X 
 
 
 
 
 
X 
Laboratory Safety Testl 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
 
 
 
 
X 
Male Reproductive Hormone Testsm 
X 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
 
 
 
 
12-lead ECGn 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
X 
 
 
 
 
X 
Chest X-Rayo 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TB Symptoms Profile 
X 
X 
 
X 
 
X 
 
 
 
X 
 
X 
X 
 
X 
X 
 
X 
 
 
X 
X 
Patient Reported Health Status  
X 
X 
 
X 
 
X 
 
 
 
X 
 
X 
X 
 
X 
X 
 
X 
 
 
X 
X 
Vital Signs and weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Ophthalmic Examinationp 
X 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
X 
X 
X 
 
 
 
 
X 
Physical Examination – fullq 
X 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
Physical Examination – limitedr 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
Pharmacokinetic Samplings 
 
X 
 
X 
 
 
 
 
 
X 
X 
X 
X 
 
 
 
X 
 
X 
X 
X 
 
IMP Randomization/ Assignmentt 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IMP Compliance Checku 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 Xe 
 
X 
 
 
 
 
 
Xt 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Investigator Assessmentv 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
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Page 18 of 98 
GENERAL: Vital signs and blood draws are to be performed before dosing, unless 
otherwise specified. Vital signs and/or ECGs should be done before blood draws 
(safety and PK) on days with those assessments. 
 
a. Screening: Screening assessments can occur on different days within nine days 
before to Day 1 (Baseline).  
b. Visit Schedule (due to unforeseen circumstances): If the duration of treatment is 
extended due to dose interruptions / pauses (7 to ≤ 35 consecutive doses), the last 
visit of the corresponding treatment period should also be pushed out to the date of 
the last dose. It is not necessary to have an unscheduled visit at the time that the last 
visit of the treatment period would have been scheduled on.   
c. Follow-up Visits for Early Withdrawal Participants: Once a participant has been 
permanently withdrawn from the trial, they will be required to attend an Early 
Withdrawal visit (Week 52, if not already performed) and Week 104 follow-up visits. 
The Week 52 and Week 104 visits will be performed to collect Serious Adverse Event 
(SAE) information (including verification of survival) and the participant reported TB 
outcome information only, and may be performed telephonically, at home or a site visit. 
Visits will occur at Week 52 and/or Week 104 after the participant’s start of treatment 
date.  Refer to Table 5 for additional guidance. 
d. Day 1 (Baseline): All procedures are to be completed before dosing.  
e. Last Visit of the Treatment Period: Investigational Medicinal Product (IMP) 
Compliance Check is not performed at the Week 22 visit for participants who have 
completed treatment at Week 17. 
f. Sputum Sampling: The sputum sampling methodology/requirements and tests will be 
described in a separate document, the Mycobacteriology Laboratory Manual. 
 
• 
Screening (Days -9 to -1). Two spot sputum samples taken 30 minutes apart will 
be collected at the research site under the coaching and observation of the trial 
staff. The following analyses will be performed on the first of these samples: 
o Smear microscopy for acid-fast bacilli (AFB); 
o Rapid molecular tests for fluoroquinolones, isoniazid and rifampicin 
resistance (Hain MTBDplus and Hain MTBRsl);  
o Liquid Culture (MGIT) for Mycobacterium tuberculosis (MTB), followed by 
a speciation test to detect the presence or absence of MTB and obtain the 
time to positivity (TTP) when positive. 
o The second sample is collected as a back-up sample to the first sample in 
case it is technically not possible to obtain a result/s from the first sample. 
If the Screening spot sputum smear shows an indeterminate result or is 
AFB negative, the test may be repeated on the back-up sample or on a 
freshly collected spot sputum, and then that result will be used.  
• 
Day 1 (Baseline) to Week 104 and Unscheduled visits for additional sputum 
samples:  
o Two sputum samples are collected, ideally one Early Morning Sputum 
(EMS) brought from home and one spot sputum sample at the research 
site, under the coaching and observation of the trial staff. If the participant 
forgets to bring in the EMS, then two spot sputum samples are to be 
collected at the site, at least 30 min apart, and this altered sample collection 
is captured within case report form (CRF).   
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Page 19 of 98 
o If both sputum cultures at Weeks 8 or later are contaminated, the participant 
should return for an unscheduled visit(s) to give additional sputum samples 
or to document that the participant is not able to produce a sputum sample.  
 
• 
If after having converted to culture negative, and the participant has a MTB 
confirmed positive culture at or after the last visit of the treatment period (Week 17 
or Week 26), the participant should return for an unscheduled visit/s to provide 
additional sputum samples, at a minimum of 7 days apart, or to document that the 
participant is not able to produce a sputum sample.  
• 
Additional samples may be required to define a participants’ primary outcome 
status as described in Sections 5.4.2 and 7.2.  
• 
Liquid Culture (MGIT) for MTB, followed by a speciation test to detect the presence 
or absence of MTB and obtain TTP when positive, will be performed on all samples. 
g. Mycobacteriology Characterisation Tests performed: 
• 
Day 1 (Baseline) sputum sample (or any positive sample from Screening to Week 
4, if the baseline cultures are contaminated or negative); 
• 
MTB confirmed positive cultures (after the participant has previously converted to 
culture negative) at or after the last visit of the treatment period (Week 17 or Week 
26) or visits with positive cultures, during the post-treatment follow-up period. 
• 
Refer to Mycobacteriology Laboratory Manual for full details.   
Mycobacterial Characterization - MTB isolates (from the first MTB positive culture) will 
be processed for: 
• 
Rapid molecular tests for fluoroquinolones, injectables, isoniazid and rifampicin 
resistance (only on MTB positive cultures in the follow-up period); 
• 
Minimum Inhibitory Concentration (MIC) against bedaquiline, pretomanid, and 
moxifloxacin;  
• 
Drug Susceptibility Testing (DST) for streptomycin, rifampicin, isoniazid, 
ethambutol, moxifloxacin, and pyrazinamide in liquid culture; 
• 
Extraction of organismal (MTB) DNA for whole genome sequencing (WGS), and 
comparison of sequences from baseline and relapse isolates. 
 
h. HIV Testing: If HIV status is a confirmed known positive, a repeated HIV test is not 
needed provided that a documented HIV test result (ELISA, Western Blot or Electro-
Chemiluminescence) is available. If the HIV status is unknown or suspected negative, 
a HIV test will be requested. If an ELISA and/or Western Blot and/or Electro-
Chemiluminescence based HIV test was performed within 4 weeks prior to screening, 
it should not be repeated if documentation of testing method and negative HIV results 
can be provided. Repeated HIV testing, during the Screening period is permitted for 
indeterminate HIV results. 
i. 
CD4 Count: Required for all HIV-positive participants.  
j. 
Urine 
Drug 
Screen: 
Cannabinoids, 
cocaine, 
amphetamines, 
opiates, 
benzodiazepines, barbiturates, at Screening only. Investigator to utilize this result to 
determine whether participant meets Exclusion Criteria 2. Positive results will not 
automatically exclude a participant from the trial. 
k. Urine Pregnancy Test: Women of childbearing potential only, whether they are 
sexually active or not.  
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Page 20 of 98 
l. 
Safety Laboratory Assessments: The safety laboratory sampling methodology and 
requirements will be described in a separate document, the Safety Laboratory Manual, 
which will be provided prior to the trial start. The following analyses will be performed: 
• 
Full Blood Count (haemoglobin, haematocrit, red blood cell count, white blood cell 
count with differential, platelet count).  
• 
Clinical Chemistry (albumin, serum urea, creatinine, direct, indirect and total 
bilirubin, uric acid, total protein, alkaline phosphatase [ALP], aspartate 
aminotransferase [AST], alanine aminotransferase [ALT], lipase, phosphate, 
sodium, potassium, calcium (corrected for albumin), chloride, magnesium, 
glucose, bicarbonate/carbon dioxide [CO2], creatine phosphokinase [CPK]). GGT 
is only routinely included at the Screening visit (Day -9 to -1).  
• 
Urinalysis (pH, specific gravity, protein, glucose, micro-albumin, ketones, bilirubin, 
creatinine, nitrite, sodium, urobilinogen, blood, leukocytes). Microscopy will be 
completed as follow-up to abnormal urinalysis per discretion of Investigator.  
• 
When managing participants with elevated liver enzymes at an Unscheduled visit, 
the investigator can request additional tests, in addition to the repeat LFT [e.g. 
Gamma Glutamyl Transferase (GGT), screening for Hepatitis A, B, C; to assist in 
ruling out other causes of a dysfunctional liver test (e.g. alcohol induced hepatic 
cell injury, hepatobiliary disease, hepatic viral infection)]. 
m. Male Reproductive Hormone Tests: Testosterone, follicle-stimulating hormone 
(FSH), luteinizing hormone (LH) and Inhibin B to be done on male participants in ALL 
treatment groups. 
n. Single 12-Lead ECG: ECGs to be performed prior to pre- and post-dose PK 
sampling as described below: 
• 
Day 1: pre-dose (within 2 hours prior to dosing) 
• 
Week 2: pre-dose (within 2 hours prior to dosing), 1.5–3 hours post-dose and 4-6 
hours post-dose 
• 
Week 8: pre-dose (within 2 hours prior to dosing), 1.5–3 hours post-dose and 4-6 
hours post-dose 
• 
Week 12: pre-dose (within 2 hours prior to dosing)  
• 
Week 17 or at early withdrawal if prior to week 17: pre-dose (within 2 hours prior 
to dosing) and 1.5–3 hours post-dose 
  
Central ECG analysis will be performed. Results from central reading of Screening 
ECG must be used to determine eligibility.  
o. Chest X-Ray: A chest x-ray (digital image only) within 6 months prior to or at the 
Screening visit, will be obtained and read locally by the Investigator or designee. Digital 
images will be provided to the Sponsor and this process will be described in a separate 
document, the Radiology Manual. 
p. Slit Lamp Ophthalmic Examination: Slit lamp examination will be done at the 
Screening visit, the last visit of the treatment period (Week 17 or 26) and at Week 39 
for both treatment groups.  An additional slit lamp at Week 26 will be done for the 4-
month treatment group. Slit lamp ophthalmology examination will be performed by an 
Ophthalmologist with AREDS2 training. Ophthalmology examinations may occur at 
any time within the window period for the applicable visit i.e. they do not have to be 
performed on the same day as the trial procedures. 
q. Physical Examination, Full: Height (m) will only be collected at Screening.  
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r. Physical Exam, Limited: Limited physical exams will include weight and gross 
neurological, pulmonary, cardiovascular and abdominal exam(s). 
s. Pharmacokinetic (PK) Sampling: This process will be described in a separate 
document, the PK Sampling Manual. No PK samples will be collected for the HRZE/HR 
treatment arm.  Blood draws for PK samples collected pre-and post-dose must be done 
after the ECG is performed.  The dates and times of IMP taken prior to all pre-dose PK 
samples will be collected.  Specific PK blood draws will be obtained as follows: 
 
• 
Day 1: pre-dose (within 2 hours prior to dosing) 
• 
Week 2: pre-dose (within 2 hours prior to dosing), 1.5–3 hours post-dose and 4-6 
hours post-dose 
• 
Week 8: pre-dose (within 2 hours prior to dosing), 1.5–3 hours post-dose and 4-6 
hours post-dose 
• 
Week 12: pre-dose (within 2 hours prior to dosing)  
• 
Week 17 or at early withdrawal if prior to week 17: pre-dose (within 2 hours prior 
to dosing) and 1.5–3 hours post-dose 
• 
Weeks 39, 65, 78 and 104 (for bedaquiline, bedaquiline metabolite M2): PK 
samples are to be obtained at any time on the day of the scheduled visit. 
Only bedaquiline and M2 will be measured. 
If IMP is not administered during Week 2, 8 and or 17, then only a single PK sample is 
required to be obtained at any time during the visit assessment.  
t. Investigational 
Medicinal 
Product 
(IMP) 
Randomization/Assignment: 
Randomization/Assignment may occur once all the Screening results are available and 
the Investigator has determined that the participant is eligible for the trial. 
u. IMP/Compliance Check: IMP administration will be supervised per local site practice 
to assure compliance to the regimen. Performed at all visits and Early Withdrawal 
(EWD), if during the treatment period.  
v. Investigator Assessment: Investigator to review the participant status and assess 
whether IMP or TB treatment at Week 52 and 104 is considered a “success” or “failure”.  
If considered a failure, the Investigator should specify if the assessment is based on 
bacteriology and/or clinical deterioration and/or radiological deterioration. Investigator 
Assessment to be completed, at Week 52 and 104, and at any time the Investigator 
determines that the participant fulfils the criteria for outcome of treatment failure. 
w. Visit Windows: The windows noted on the flowchart for timing of visit also apply to 
the timing within a visit.  Procedures should be performed within +/- 3 days of 
scheduled visit from Day 1 to Week 8 or +/- 5 Days of scheduled visit from Week 12 to 
Week 26 or +/- 14 days of scheduled visit at or after Week 39.  Sites should make 
every effort to ensure all procedures are done on the same day, when possible. 
x. Karnofsky Score: Only to be performed on HIV+ participants. 
 
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2.0 
Introduction and Rationale 
2.1 
Tuberculosis Disease 
Although some progress has been made in recent years in controlling tuberculosis (TB) 
globally, TB has remained a persistent problem in the developing countries of Africa, Asia and 
South America.  TB is currently one of the top three killer infectious diseases, and there is 
more TB in the world today than at any other time in history.  The current first-line anti-
tuberculosis agents have been in use for over 40 years and are relatively ineffective in 
controlling TB as a public health problem.  Although the current regimens and drugs have 
been very successful in controlled clinical trials resulting in the permanent cure of more than 
95% of trial participants, treatment takes 6 months or more to complete. This, long duration 
treatment plus side effects, result in poor adherence which particularly occurs after the 
second month of treatment.  
The current TB treatment regimens and treatments for drug-sensitive TB are decades old. The 
available treatments have a lengthy duration of treatment, involve multi-drug therapy, and 
require large commitments of resources and infrastructure. High rates of noncompliance are 
common, which often results in increased mortality and chronic, infectious, drug-resistant 
cases. The present TB epidemic and the challenge of current treatment options demonstrate 
the clear need for effective novel TB drugs and drug regimens that are safe for drug sensitive 
and drug resistant TB disease and that are well-tolerated and will shorten the current treatment 
duration for patients. 
The full application of the Directly Observed Treatment, Short-Course strategy is becoming 
more and more difficult in the developing countries of the world that are also battling to control 
the HIV-epidemic.  Because of poor treatment adherence, drug resistance is becoming more 
common and fears of an epidemic with virtually untreatable strains of TB are growing.  Since 
the discovery of the rifamycins,[1] and their introduction into standard antituberculosis 
regimens, very few new classes of drugs have been evaluated with a view to their registration 
as antituberculosis agents.  On December 28, 2012 the U.S. Food and Drug Administration 
approved bedaquiline (B) as part of combination therapy to treat adults with multi-drug 
resistant (MDR) pulmonary tuberculosis (TB) when other alternatives are not available. 
Following the declaration of TB as a global emergency by the World Health Organization 
(WHO) in 1993, there has been a resurgence of efforts to develop improved TB therapies and 
several promising new agents are presently in or approaching clinical evaluation.   
New combination regimens are desperately needed for two reasons: to shorten treatment to 
a duration more easily manageable by patients and public health services, and to provide 
more efficacious, safer and better tolerated, affordable treatments for the growing number of 
patients suffering from multidrug-resistant and extensively drug-resistant tuberculosis. 
2.2 
Tuberculosis Clinical Research 
TB currently must be treated with multiple drugs to achieve maximal efficacy and prevent 
resistance. To transform treatment, novel TB regimens are needed. To telescope the time, it 
takes to develop novel, tolerable multi-drug treatments, it is necessary to use the regimen 
development paradigm. This approach tests promising combinations of drugs together to find 
the most impactful treatment once the individual drug candidates have been tested in a robust 
pre-clinical program and the establishment of the individual drug candidates’ safety and 
efficacy have been evaluated.  It evaluates novel combinations of TB drugs — instead of single 
drugs — as part of a single development program, enabling the development of novel TB drug 
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regimens that have potential to transform treatment for drug-sensitive and drug-resistant 
tuberculosis. This approach offers the potential to reduce the time previously needed to 
develop a novel treatment regimen by up to 75%, shortening the clinical development from 
decades to years. The steps followed in this development model are shown in Figure 1 
Between each step on the unified development pathway a decision is made as to whether to 
proceed. 
Figure 1.  Unified Drug Sensitive/Drug Resistant Regimen Development Path 
 
Early Bactericidal Activity (EBA) Trials 
EBA trials are the backbone clinical trials to quantify the bactericidal action of anti-tuberculosis 
agents alone or in combination by either trialling the fall in the number of colony forming units 
(CFU) or measuring the TTP in liquid culture of M. tuberculosis (MTB) present in the sputum 
of participants with microscopy smear-positive pulmonary TB. EBA trials have been conducted 
over 2, 5, 7 and 14 days.[2]. A review of EBA trials conducted on the key anti-TB drugs has 
shown the value these trials offer to demonstrate the early anti-TB effect that a new therapeutic 
agent may have and to explore the relationships between dose, pharmacokinetics and 
bactericidal activity in participants.[3] 
8-week Bactericidal Activity (BA) Trials 
EBA methodology of quantitative colony counting on solid medium has been adapted to Phase 
2, 8-week TB treatment trials based on serial sputum colony counting (SSCC) or measurement 
of TTP liquid culture to provide a more sensitive efficacy endpoint than the previously used 
binary endpoint of rate of sputum conversion measured after 8 weeks of treatment.[4-6] Such 
trials are conducted to provide data on which to base the selection of treatment-shortening 
regimens.  
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2.3 
Trial Rationale 
The  SimpliciTB NC-008 (BPaMZ) trial will evaluate and support that, in additional to previous 
studies evaluated with BPaMZ, this drug regimen (BPaMZ) will be safe and effective, is well-
tolerated and could potentially shorten the current treatment duration compared to the 
standard HRZE/HR treatment for patients with drug sensitive TB disease. This trial will also 
evaluate if the BPaMZ drug regimen given for 6 months will be safe and effective in drug 
resistant TB disease. 
Therefore, the trial design addresses the need to find and evaluate a potentially effective and 
shorter regimen compared to regimens (standard HRZE/HR) that are currently being used. 
2.3.1 
Trial Design Rationale 
The SimpliciTB NC-008 (BPaMZ) trial is a Phase 2c multi-centre, open-label, partially 
randomized clinical trial in DS-TB and DR-TB participants. This trial is to evaluate the 
combination regimen of Bedaquiline (B) plus Pretomanid (Pa) plus Moxifloxacin (M) plus 
Pyrazinamide (Z), (BPaMZ), in participants with pulmonary TB. 
All participants will enter post-treatment follow-up which continues until Week 104 after start 
of treatment / randomisation. 
 
Participants with DS-TB: 
Participants with DS-TB will be randomized to one of two treatment arms. These 
participants will receive either: 
• 
BPaMZ daily for 17 weeks (4 months),  
 
OR 
• 
 HRZE/HR combination tablets daily for 26 weeks (6 months).  
 
Participants will be stratified for co-infection with HIV and cavitation. 
Participants with DR-TB are defined as: 
1. mono-resistance to rifampicin or isoniazid, OR 
2. resistance to both rifampicin and isoniazid (multi-drug resistant tuberculosis [MDR-
TB]) 
Up to 150 participants with DR-TB will be assigned to receive BPaMZ daily for 26 weeks (6 
months).  Approximately 300 DS-TB participants (150 per treatment arm) will be randomized 
and stratified for co-infection with HIV and cavitation to either BPaMZ for 4 months or 
HRZE/HR for 6 months.  
 
The trial is sufficiently statistically powered to not only show superiority of 8 Weeks culture 
conversion but should also demonstrate non-inferiority for cure at 52 Weeks (this is in the 
participants with DS-TB in the experimental BPaMZ treatment regimen, the proportion 
experiencing an unfavourable outcome will be non-inferior compared to the participants who 
are treated with the standard HRZE regimen). 
 
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There is one planned interim efficacy analysis which will occur after approximately 60 
assessable participants have been randomised to the control arm and have reached the 8-
week primary endpoint. Time to culture negative status in liquid media up to 8 weeks will be 
analysed using a Cox regression model, censoring for death and lost to follow up/withdrawal 
to estimate the hazard ratio (HR). Following a review of these interim findings, the following 
considerations will be given to modify the trial objectives and sample size: 
If the observed HR (time to culture negativity, experimental arm vs. HRZE control arm) is >2, 
the sample size may be increased to adequately power the trial on the key secondary efficacy 
endpoint (clinical and microbiological outcome at 52 weeks from randomization), which will 
then become the primary efficacy endpoint. The trial efficacy objectives will be updated as 
follows: 
- 
Primary Objective 
To determine the incidence of bacteriologic failure or relapse or clinical failure 
at 52 weeks from the start of treatment / randomisation.  
- 
Secondary Objectives 
To evaluate the time to culture negativity over 8 weeks, from the start of 
treatment / randomisation. 
All other trial objectives will remain unchanged. 
To achieve 90% power and overall 5% 2-sided significance after adjusting for the 
interim analysis, this will mean increasing the sample size to 225 participants per randomised 
arm, i.e., to a total of 450 DS-TB participants (and up to 225 DR-TB participants). This 
adaptation is based on the Multi-arm Multi-stage (MAMS) framework [46, 47, 48] and full details 
are provided in the Statistical Analysis Plan.  
 
As previously described in the background information, in order to telescope the time it takes 
to develop novel, tolerable multi-drug treatments, it is necessary to use the regimen 
development paradigm and utilize data generated in non-clinical and clinical studies regarding 
combining of anti-tuberculosis agents which could contribute significantly to the sterilization of 
lesions and thus treatment shortening. Therefore, the trial design and proposed trial regimen 
(BPaMZ) which is supported with previous non-clinical and clinical studies outlined below 
should address the need and manner of evaluating an effective shorter regimen compared to 
regimes that are currently being used. 
2.3.2 
Trial Drug Regimen Rationale 
The BPaMZ regimen has been studied singularly and in different combinations as outlined 
above. Moxifloxacin has been added to the B-Pa-Z regimen because of the high rate of 
pyrazinamide resistance seen in MDR-TB participants in the NC-002 trial. It essentially 
provides protection against the development of new resistance to the B-Pa-Z drugs. Based on 
the exciting and promising results seen in NC-005, this regimen can be initiated in drug 
sensitive and drug resistant TB participants whom are sensitive to the individual drugs in the 
regimen (excluding extensively drug-resistant tuberculosis [XDR-TB]) and has the potential to 
shorten TB treatment to less than 4 months in drug sensitive TB. These are also oral regimens, 
removing the need for injectables as part of MDR-TB treatment and also project to be markedly 
less expensive than current MDR-TB therapy. Additionally, these regimens can be 
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administered in a fixed dose for all patients, and will therefore be simpler for health systems 
to deliver and patients to use. 
2.4 
Agents used within SimpliciTB 
Bedaquiline (TMC207; SirturoTM package insert)[7]  is a novel agent approved for TB 
treatment. As detailed in the Investigator’s Brochure,[8] bedaquiline is a diarylquinoline that 
offers a novel mechanism of anti-tuberculosis action by specifically inhibiting mycobacterial 
adenosine triphosphate synthase.[9, 10]) In vitro, bedaquiline potently inhibits both drug-
sensitive and drug-resistant M. Tb isolates,[10, 11], and is also bactericidal against non-
replicating M. Tb.[12] In the murine model of TB, bedaquiline was as active as the triple 
combination of isoniazid (H), rifampin (R), and pyrazinamide (Z). Addition of bedaquiline to 
HRZ results in accelerated clearance of M. Tb.[3, 4] There appears to be a synergistic 
interaction with pyrazinamide: 100% of mice were culture negative after 8 weeks of treatment 
with bedaquiline and pyrazinamide compared to 0% of mice treated with the standard regimen 
of rifampicin, isoniazid and pyrazinamide.[13] Collectively, these findings in the mouse model 
have led to the suggestion that regimens containing bedaquiline and pyrazinamide could be 
effective in the treatment of both DS- and MDR-TB and shorten treatment duration in patients. 
While the combination of bedaquiline and pretomanid in the murine model of TB appeared 
somewhat antagonistic relative to bedaquiline alone, it was as active as the triple combination 
of HRZ[13] and in a subsequent trial it was more active in the mouse model than HRZ.[14] Thus, 
a novel regimen with a bedaquiline plus pretomanid core could be effective in the treatment of 
MDR-TB by providing two novel drugs for which there is no known pre-existing resistance.  
Pretomanid, (Pa)[15]  is a new chemical entity being developed by TB Alliance for the treatment 
of TB.  It is a member of a class of compounds known as nitroimidazo-oxazines, which possess 
significant anti-tuberculosis activity and a unique mechanism of action.[16] PRETOMANID has 
been under development for several years, and entered clinical trials in 2005. Several trials of 
pretomanid have also been conducted previously in healthy volunteers.  Collectively, these 
trials in participants with active TB and healthy participants have defined the efficacy, safety 
and pharmacokinetic features of the drug.  Overall, pretomanid has mycobactericidal activity 
in participants and is well tolerated and bioavailable after oral dosing.  Pretomanid 
demonstrated in vitro activity against both drug-sensitive (DS) and MDR-TB,[17] and in vivo 
activity in a mouse model of TB[17, 18] with a significant promise for shortening treatment of 
active TB. 
Moxifloxacin (M)[19]  is a microbial compound, approved in most countries around the world 
for the treatment of acute bacterial sinusitis, acute bacterial exacerbation of chronic bronchitis, 
community-acquired pneumonia, skin and soft tissue infections.  Clinical studies have been 
carried out for many additional indications (urinary tract infections, pelvic infections, 
pharyngitis/tonsillitis, and tuberculosis). Moxifloxacin is an 8-methoxyquinolone whose oral 
formulation (which will be used in this trial) has enhanced activity against Gram-positive 
pathogens, and anaerobes while retaining useful activity against Gram-negative organisms. 
Moxifloxacin is not metabolized by or induces the cytochrome P450 system, thus the risk of 
clinically relevant drug interactions is reduced. It has a positive safety profile within the 
fluoroquinolone class at the approved daily dose of 400 mg. Moxifloxacin while not approved 
for TB by most regulatory authorities, it is regularly used in second line MDR-TB treatment. 
The WHO TB Treatment Guidelines place moxifloxacin in the category of Group 3 drugs and 
notes that “all patients [with MDR-TB] should receive a Group 3 medication if the MTB strain 
is susceptible or if the agent is thought to have efficacy. One of the higher generation 
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fluoroquinolones, such as levofloxacin or moxifloxacin, is the fluoroquinolone of choice.[5]” It is 
currently in late stage clinical development for first-line TB treatment in combination with other 
TB drugs, including pyrazinamide in two different four-month long regimens.  
Pyrazinamide (Z)[20] is a pyrazine analogue of nicotinamide and an approved anti-tuberculosis 
agent which is indicated for the initial treatment of active tuberculosis in adults and children 
when combined with other anti-tuberculosis agents and contributes significantly to the 
sterilization of lesions and thus treatment shortening.[21]   
Control Group: HRZE/HR 
The HRZE/HR combination [HRZE tablets [isoniazid (H), rifampicin (R), pyrazinamide (Z) and 
ethambutol (E)] and HR tablets [isoniazid (H) plus rifampicin (R) combination tablets] is 
approved indicated and commonly used as a 6-month treatment for drug-sensitive TB patients.  
Participants with DS-TB that are randomized to the HRZE/HR control arm in this trial will be 
given standard weight-adjusted doses of HRZE.  Please see the HRZE package insert for 
more information.[22]   
Additional background data supporting the combined use of new novel agents in this 
BPaMZ regimen for the treatment of TB: 
Data from preclinical studies suggest that a regimen consisting of moxifloxacin plus 
pretomanid plus pyrazinamide may not only be appropriate for treating both DS and MDR-TB 
but may also shorten duration of therapy.  Results from an 8-week Phase 2b SSCC trial, 
NC-002-(M-Pa-Z), showed that this combination regimen was effective as measured by time 
dependent decline of viable bacteria in participants with DS pulmonary TB.  The combination 
was also shown to be safe and well tolerated supporting the evaluation of this combination in 
a Phase 3 trial. In this NC-002 trial 71.4% of participants with DS-TB treated with PaMZ at the 
100-mg daily dose of pretomanid converted sputum to negative for MTB growth in liquid 
culture in comparison with only 37.8 % of participants treated with the HRZE control (p<0.05).  
Studies in mice infected with MTB demonstrated reductions in cultured colony counts from 
lungs over an 8-week period when treated with the PaMZ regimen that were substantially, and 
statistically significantly greater, than the reductions in mice treated with an HRZ control.  
Experiments in mice found that mice did not relapse with MTB infection when treated with 
PaMZ for 4 months and followed for 3 months off treatment, in comparison to mice that 
required 6 months of treatment with HRZ to prevent relapse.[14]   
Drug Resistant TB Background: 
Although some progress has been made in recent years in controlling tuberculosis (TB) 
globally, TB has remained a persistent problem in many countries. TB is the world’s leading 
cause for mortality from infectious disease and is responsible for more deaths than HIV.[23] It 
is the leading cause of death among HIV-infected individuals, and there is more TB in the 
world today than at any other time in history. Because of poor treatment adherence, in addition 
to primary transmission, drug resistance is becoming more common and fears of an epidemic 
with strains of extensively drug-resistant TB (XDR-TB) that is very difficult to treat are growing.  
Novel drugs and regimens for TB are needed for the growing number of patients with drug 
resistant-TB.  
The regulatory approvals of bedaquiline and delamanid have given hope that outcomes for 
patients with drug resistant TB might be improved when added to background regimens. 
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Experience recently published from the C209 uncontrolled trial of bedaquiline given on a 
background of multiple drugs notes that the subset of 38 participants with XDR-TB had rates 
of sputum culture conversion to negative of 62.2%.[24] However, in this trial only one participant 
with XDR-TB was co-infected with HIV. All participants were required to have Mycobacterium 
tuberculosis (MTB) isolates susceptible to at least 3 drugs at enrolment and participants had 
a median of only 5.4 months of treatment-free follow-up. This trial added bedaquiline for 6 
months to a background regimen of many drugs given for 18 months or longer. While 
treatment success for MDR-TB is better than for XDR-TB, overall success in treating MDR-
TB is still approximately 50% according to the World Health Organization 2015 Global TB 
Report.[23]  This report presented that overall, the proportion of MDR-TB patients in the 2012 
cohort who successfully completed treatment (i.e. cured or treatment completed) was 50%; 
16% died, 16% were lost to follow-up, 10% failed treatment, and for 8% there was no outcome 
information.   
With such poor historical outcomes for patients with drug resistant-TB and with the complexity, 
expense and toxicity of treatments for all forms of drug resistant TB, novel drug 
combinations are desperately needed to improve treatment outcomes. Linezolid was 
identified in a small trial as a potentially efficacious drug in patients with XDR-TB when added 
to a failing regimen[25] and this drug has increasingly been added to complex regimens to treat 
patients with MDR-TB. 
With the current availability of the following three drugs for which there is little, if any, pre-
existing resistance among strains of MTB (pretomanid [Pa], bedaquiline [B], and linezolid [L]). 
Mice infected with MTB had relapse-free cures with 3 months of treatment with a B-Pa-L 
regimen. While it is not known whether that treatment duration will translate to humans, the 
ongoing Nix-TB clinical trial hypothesizes patients with pulmonary XDR-TB or MDR-TB not 
responsive to or intolerant to therapy may have relapse-free cure after as little as 6 months’ 
treatment with the B-Pa-L regimen.[26]  Moxifloxacin has been added to the B-Pa-Z regimen 
because of the high rate of pyrazinamide resistance seen in MDR-TB participants in the NC-
002 trial. The proposed trial [SimpliciTB] allows the opportunity to assess the efficacy, safety 
and tolerability of BPaMZ, a new 6 months regimen that may be administered orally once daily 
to treat patients with drug resistant -TB (excluding participants with XDR-TB). 
Therefore, the overall purpose of the present proposed trial [SimpliciTB] is to assess the 
efficacy, safety and tolerability of the BPaMZ regime after 4 months of treatment in adult 
participants with drug sensitive TB and after 6 months of treatment in participants with multi 
drug-resistant TB. The trial will also generate data of the potential for a shorted treatment 
duration with the BPaMZ regime after 4 months compared to a 6-month HRZE/HR (control) 
treatment regime in adult participants with drug sensitive TB. 
This trial will be conducted in accordance with the Protocol, ICH Guidelines for Good Clinical 
Practice (GCP), the ethical principles that have their origin in the Declaration of Helsinki and 
the applicable regulatory requirement(s). 
2.5 
Background of Agents to be Studied in SimpliciTB 
2.5.1 
Bedaquiline (B) 
Bedaquiline (formerly known as TMC-207; SirturoTM package insert[7]) is approved agent for 
TB treatment. As detailed in the Investigator’s Brochure,[8] bedaquiline is a diarylquinoline that 
offers a novel mechanism of anti-tuberculosis action by specifically inhibiting mycobacterial 
adenosine triphosphate  synthase.[11] In vitro, bedaquiline potently inhibits both drug-sensitive 
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and drug-resistant MTB isolates,[11, 12] and is also bactericidal against non-replicating MTB[12] 
In the murine model of TB, bedaquiline was as active as the triple combination of isoniazid 
(H), rifampicin (R), and pyrazinamide (Z). Addition of bedaquiline to HRZ results in accelerated 
clearance of MTB.[1, 2]. There appears to be a synergistic interaction with pyrazinamide: 100% 
of mice were culture negative after 8 weeks of treatment with bedaquiline and pyrazinamide 
compared to 0% of mice treated with the standard regimen of rifampicin, isoniazid and 
pyrazinamide.[27].Collectively, these findings in the mouse model have led to the suggestion 
that regimens containing bedaquiline and pyrazinamide could be effective in the treatment of 
both drug sensitive and drug resistant TB and shorten treatment duration in patients. While 
the combination of bedaquiline and pretomanid in the murine model of TB appeared somewhat 
antagonistic relative to bedaquiline alone, it was as active as the triple combination of HRZ[27] 
and in a subsequent trial it was more active in the mouse model than HRZ.[28]. Thus, a novel 
regimen with a bedaquiline plus pretomanid core could be effective in the treatment of MDR-
TB/XDR-TB by providing two novel drugs for which there is no known pre-existing resistance. 
Bedaquiline is currently registered in many countries to be administered to patients with 
pulmonary tuberculosis by the following scheme: 400mg once daily for Days 1-14 followed by 
200mg three times per week for the remainder of treatment. In this trial bedaquiline will be 
administered as 200 mg daily for 8 weeks then 100 mg daily for 9 weeks in participants with 
DS-TB and 200 mg daily for 8 weeks then 100 mg daily for 18 weeks in participants with DR-
TB.  This daily dosing scheme will allow more convenient dosing that should ultimately 
enhance patient adherence and may allow the formulation of fixed dose combinations with 
other drugs.  This daily dosing regimen is supported by safety and efficacy demonstrated in 
the NC-005 trial that administered bedaquiline 200 mg daily over 8 weeks, and by 
pharmacokinetic modelling and simulation of the daily dosing scheme.  This supportive 
information is detailed below. 
2.5.1.1 
Bedaquiline Non-Clinical Studies 
Full details of the preclinical studies are provided in the current bedaquiline Investigator’s 
Brochure,[8] and Sirturo 
TM label.[7] In vitro studies have demonstrated that the range of 
minimum inhibitory concentrations (MICs) for MTB H37Rv, the international reference strain, 
and 6 fully drug-susceptible clinical isolates, was 0.030 to 0.120 μg/ml. The activity of 
bedaquiline appears to be specific for mycobacteria, as the MICs for non- mycobacteria were 
at least 500-fold higher. The activity of the main metabolite of bedaquiline, M2, was determined 
against MTB.  H37Rv in both solid and liquid media and its MIC was found to be 0.1 μg/ml. 
This MIC shows that M2 is active against MTB but 3-6 times less active than the parent 
compound bedaquiline. Bedaquiline demonstrated similar in vitro efficacy against MTB clinical 
isolates resistant to the known anti-TB drugs (isoniazid, rifampicin, pyrazinamide, 
streptomycin, ethambutol, or fluoroquinolones). As expected, from the lack of cross-resistance 
with currently used anti-tuberculosis agents, bedaquiline retained activity against MDR-TB 
isolates. 
The non-clinical safety evaluation of bedaquiline includes pharmacology, pharmacokinetics, 
toxicology and metabolism studies that were conducted in accordance with current 
International Council for Harmonisation (ICH) guidelines. Repeated dose toxicity studies were 
performed with dosing durations up to 3 months in mice and up to 6 months in rats and in 
dogs. Recovery was studied in rats and dogs. In repeated dose toxicity studies, up to 3 months 
in mice, up to 6 months in the rat and up to 9 months in dogs, bedaquiline was associated with 
target organ changes in the mononuclear phagocytic system (indicative of phospholipidosis), 
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stomach, liver, pancreas, and muscle. Toxicity was often associated with an increased 
presence of neutrophils in some tissues such as the female genital tract and this was preceded 
by a peripheral neutrophilia. For more detailed information please refer to the bedaquiline IB.[8] 
Respiratory parameters in rats were unaffected by treatment. There were no effects 
suggestive of neurological impairment or delayed neurotoxicity in rats. In single dose toxicity 
studies, there were no mortalities following oral doses of up to 200 mg/kg in mice and rats. No 
mutagenicity or clastogenic effects were seen in a series of in vitro and in vivo genotoxicity 
tests. Bedaquiline was evaluated for possible developmental toxicity effects in the rat and the 
rabbit. No teratogenic effects were found. In vitro, bedaquiline slightly to moderately inhibited 
the delayed rectifier potassium current (IKr) in the human ether-à-go-go-related gene (hERG) 
model. Bedaquiline and M2 had no notable effects on IKr at 0.01 μM (0.006 and 0.005 μg/mL, 
respectively). However, at higher concentrations (0.03 to 3 μM), both compounds had a slight 
to strong concentration-dependent effect with a 50% inhibitory concentration (IC50) of 0.37 μM 
(0.2 μg/mL) for bedaquiline and up to 0.45 μM (0.24 μg/mL) for M2. However, this effect did 
not manifest as a prolongation of repolarization in subsequent in vivo studies. 
There were no relevant effects on the isolated right atrium of guinea pigs in vitro, or in the 
isolated Langendorff-perfused rabbit heart. In vivo, positive chronotropic effects were seen in 
the anesthetized guinea pig after IV administration, but not in the conscious dog. In conscious, 
telemetered dogs, oral bedaquiline had no relevant effects on cardio-hemodynamic and ECG 
parameters. 
Prior to the use of pretomanid in combination with bedaquiline in clinical trial NC-001, a 
preclinical cardiovascular safety pharmacology trial was conducted in unrestrained beagle 
dogs with both drugs to explore the potential for additive effects on QT prolongation induced 
by the combination. Results indicate that administration of 100 mg/kg bedaquiline daily, for 7 
days, causes a small increase in QTc interval by Day 6 in some animals that is not influenced 
by the addition of 100 mg/kg pretomanid on Day 7.[28] 
 The effect of pretomanid dosing alone 
on QT interval appeared to be due to discomfort related to the SC route of administration and 
not related to the plasma exposure (please see the pretomanid) Investigators Brochure for 
more detail. 
2.5.1.2 
Bedaquiline Clinical Studies 
In the clinical studies conducted to date, a total of approximately 645 participants (including 
265 healthy volunteers) have been exposed to bedaquiline in the Phase 1 and 2 clinical trials 
conducted as a part of the development program for the treatment of MDR-TB. An additional 
45 participants received bedaquiline, either as monotherapy (B) or in combination with other 
agents (B-Pa or B-Z) in trial NC-001, and 45 more in trial NC-003 (B-Pa-Z, B-Pa-C, B-Pa-Z-
C). Four short-term Phase 2a trials enrolled treatment-naïve participants (C202, TMC207-
CL001, NC-001 and NC-003). One long-term, open-label, Phase 2 trial, in MDR-TB 
participants (bedaquiline- TiDP13-C209) and one long-term, Phase 2b trial, consisting of 2 
different stages in participants infected with newly diagnosed sputum smear-positive 
pulmonary MDR-TB (bedaquiline-TiDP13-C208), have been completed. The principal findings 
of these trials are summarized below. Full details of the completed clinical studies are provided 
in the current bedaquiline IB,[8] and Sirturo
TM label.[7]. 
The Phase 1 trials have provided a basic understanding of bedaquiline’s pharmacokinetic 
characteristics, drug- drug interaction potential, and short-term safety/tolerability profile in 
healthy participants. Bedaquiline was well absorbed with time to reach the maximum plasma 
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concentration at approximately 5 hours post-dose. The maximum plasma concentration and 
AUC increased proportionally up to the highest doses studied (up to 700 mg in a single dose-
ranging trial, 800 mg single dose in trial bedaquiline-TBC1003 and 400 mg q.d. multiple 
doses). Accumulation from Days 1 to 14 was approximately 2-fold expressed as increase in 
AUC, while trough concentrations increased up to 3.5-fold. The pharmacokinetics of 
bedaquiline were comparable between healthy participants and participants with pulmonary 
TB. The apparently close to steady-state concentrations in plasma after 14 days of daily 
treatment is ascribed to the important amount of the drug that is eliminated from the circulation 
during the ἀ and β phases of the plasma concentration-time curve. The average terminal 
elimination half-life of bedaquiline and metabolite M2 noted on extended follow-up after repeat 
dosing of participants with TB infection is about 5.5 months. 
Administration of bedaquiline as the tablet formulation with food, increased the relative 
bioavailability (by 95%) compared to administration without food, and drug-drug interaction 
trials confirmed the role of cytochrome P450 3A4 (CYP3A4) in the metabolism of bedaquiline 
to M2. A recently completed trial (DMID 10-0043) demonstrated that when given in 
combination, rifampicin, and to a lesser degree rifabutin, decreased exposure to bedaquiline 
presumptively due to induction of P450 enzymes. The clinical significance of these findings is 
unknown, however the current trial (NC-005) will not permit the concomitant use of bedaquiline 
with any rifamycin. 
The efficacy of bedaquiline was initially demonstrated in two monotherapy EBA studies C202 
and TMC207- CL001. Trial C202 was a 7-day trial of three daily doses of bedaquiline (25, 100 
and 400mg) in treatment-naïve participants with MDR-TB. In this trial, the 400mg dose group 
demonstrated positive EBA and was numerically superior to the 25 and 100mg doses. In trial 
TMC207-CL001, doses of 100, 200, 300 and 400mg daily (following a 2-day loading dose) 
were studied in participants with newly-diagnosed pulmonary TB for 14 days. There were no 
statistically significant differences between the treatment groups, although there was a 
numerical trend suggesting a positive dose-response relationship. Taken together, these 
studies establish that bedaquiline monotherapy has EBA in participants with TB and that 
higher doses appear to have greater efficacy. 
A 14-day EBA regimen trial (TB Alliance Trial NC-001-(B-M-Pa-Z)) evaluated bedaquiline 
administered as monotherapy at 400 mg/d or in combination at that dose with either 
pretomanid administered at 200 mg/d or weight-adjusted pyrazinamide, to participants with 
pulmonary TB at 2 clinical sites in South Africa. The results indicate that over 14 days, the 
mean logCFU decreased by 1.3 from baseline in the 15 participants given bedaquiline 400 
mg/d after a 2-day loading dose. In the cohort of 15 participants given bedaquiline 400 mg/d 
after a loading dose plus weight-adjusted daily doses of pyrazinamide (Z), the mean logCFU 
decreased by 2.0 logs from baseline, indicating that Z potentiates the early bactericidal effect 
of bedaquiline. In the cohort with 15 participants given bedaquiline 400 mg/d after a loading 
dose plus 200 mg/d pretomanid, the mean logCFU decreased by 1.9. While it appeared that 
the addition of pretomanid potentiated the anti-tuberculosis activity of bedaquiline, the mean 
logCFU decrease of the combination was similar to that of two previous EBA studies using 
pretomanid monotherapy at 200 mg/day. 
The second 14-day EBA combination trial (NC-003) included a number of bedaquiline-
containing arms: bedaquiline, pyrazinamide and clofazimine (B-Z-C), bedaquiline, pretomanid 
and clofazimine (B-Pa-C), bedaquiline, pretomanid, and pyrazinamide (B-Pa-Z) and 
bedaquiline, pretomanid, pyrazinamide and clofazimine (B-Pa-Z-C). Among these, B-Pa-Z had 
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the best activity which was at least as good as the HRZE control (Daily Log CFU – 0.167 vs 
0.151, respectively). 
The long-term efficacy of bedaquiline in participants with MDR-TB has been studied in a 
placebo-controlled, randomized Phase 2b trial (C208) and an open-label, uncontrolled, Phase 
2b trial (C209). In the Phase 2b placebo-controlled trial, C208, the addition of bedaquiline to a 
5-drug MDR-TB regimen resulted in significantly faster time to culture conversion compared to 
placebo. During the 8-week treatment in Stage 1, 47.6% of participants in the bedaquiline group 
became MGIT culture negative compared to 8.7% of participants in the placebo group. At Week 
24 in Stage 1, after 8 weeks of investigational treatment and 24 weeks of background 
treatment, 81.0% of participants in the bedaquiline group and 65.2% of participants in the 
placebo group showed treatment success, (i.e., completed week 24 and were liquid culture 
negative, at this time point). 
For C208 Stage 2, in the interim analysis as well as in the primary efficacy analysis, a 
statistically significant difference in time to culture conversion between the treatment groups (p 
< 0.0001) in favour of bedaquiline was shown. In both analyses, an identical number of 
participants with culture conversion at week 24 (i.e., 24-week responders [missing = failure]) 
was observed: 78.8% in the bedaquiline group and 57.6% in the placebo group, which was 
statistically significantly different (p =   0.008) based on a logistic regression model with only 
treatment as covariate. Microbiological response at Week 24 was durable in C208 Stage 2: the 
percentage of responders (missing = failure) at week 72 was 71.2% in the bedaquiline group 
and 56.1% in the placebo group. 
In the Phase 2b uncontrolled trial, C209, treatment with bedaquiline in combination with an 
individualized MDR- TB treatment regimen was effective against pulmonary MDR-TB both in 
newly diagnosed and in non-newly diagnosed participants. Culture conversion rates after 
2 weeks of treatment with bedaquiline as part of an individualized anti-tuberculosis regimen 
were higher in participants with lower extent of resistance of the M. Tb strain and in participants 
with no lung cavitation compared to participants with cavitations (in one or both lungs). 
2.5.1.3 
Bedaquiline Clinical Safety 
In the clinical trials conducted to date, a total of approximately 645 participants (including 
265 healthy volunteers) have been exposed to bedaquiline in the Phase 1 and 2 clinical trials 
conducted as a part of the development program for the treatment of MDR-TB. An additional 
60 participants received bedaquiline in a monotherapy EBA trial of 14 days (trial TMC207-
CL001) 45 participants received bedaquiline, either as monotherapy (B) or in combination with 
other agents (B-Pa or B-Z) in trial NC-001 and 45 more in trial NC- 003 (B-Pa-Z, B-Pa-C, B-
Pa-Z-C). In these trials, bedaquiline has been shown to be an effective treatment for 
participants with both DS and MDR-TB. Specifically, the regimen B-Pa-Z was demonstrated 
to have efficacy at least as good as the HRZE control in trial NC-003. Furthermore, bedaquiline 
is a novel agent with no pre-existing resistance and, based on mouse model data, may result 
in shortened treatment durations when included in novel regimens to treat both DS- and MDR-
TB. Based on the combined experience in these clinical trials, the following known and 
potential risks have been identified. 
Adverse Drug Reactions for bedaquiline 
During the Investigational Treatment phase in the controlled trials, the most frequently reported 
Adverse Drug Reactions in the any bedaquiline group (> 10.0% of participants) were nausea, 
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arthralgia, headache, vomiting, and dizziness. Details of Adverse Events, none of which were 
Serious, that were considered Adverse Drug Reactions are in the table below: 
Table 1.  Bedaquiline Adverse Drug Reactions 
 
 
 
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Mortality 
Overall, there was an imbalance in the number of deaths in the pooled Stage 1 and Stage 2 
C208 trial. In the pooled analysis (Stage 1 and Stage 2), 12 participants in the Any bedaquiline 
group and 5 participants in the Any Placebo group experienced a SAE leading to death; 
causes of death were varied with only death due to TB reported more than once, and none of 
these participants had a treatment-emergent QTcF ≥ 500 ms. The imbalance in deaths is 
primarily driven by the C208 Stage 2 results in which the imbalance was 10 bedaquiline 
participants (12.7%) compared to 3 placebo participants (3.7%). Based on the pooled results 
(Stage 1 and 2) while being followed in the placebo- controlled trial, 7 participants in the Any 
bedaquiline group and 1 Participant in the Any Placebo group died. Of these deaths, 1 
occurred during the Investigational Treatment phase with bedaquiline/placebo, the remaining 
deaths occurred afterwards. In the Any bedaquiline group, causes of death were myocardial 
infarction, TB (2 cases), alcohol poisoning, hepatitis and hepatic cirrhosis (1 case), septic 
shock and peritonitis (1 case), and cerebrovascular accident. In the Any Placebo group, cause 
of death was haemoptysis. The Investigator considered the SAEs leading to death not related 
to bedaquiline intake in the Any bedaquiline group and doubtfully related to investigational 
medication in the Any Placebo group. The analysis of long-term follow-up for survival 
outcomes in participants who prematurely discontinued in trial C208 (Stage 1 and 2), based 
on data collection every 24 weeks (6 months) after withdrawal (up to LSLV in the rollover arm 
[16 Oct 2012] in Stage 2), included 9 deaths. One Participant in the bedaquiline group 
(pulmonary TB) and 2 participants in the Placebo group (TB-related illness and pulmonary TB) 
in Stage 1 died, and 4 participants in the bedaquiline group (3 participants with TB-related 
illness, 1 Participant motor vehicle accident) and 2 participants in the Placebo group (both TB-
related illness) died after they discontinued Stage 2 of the trial. None of these participants had 
a treatment-emergent QTcF ≥ 500 ms. The imbalance in deaths is unexplained.  In addition, 
no discernible pattern between death and  sputum  culture  conversion,  relapse, sensitivity to 
other drugs used to treat TB, human immunodeficiency virus (HIV) status, or severity of disease 
was observed. 
In the uncontrolled Phase 2b trial, C209, the most frequently reported AEs during the 
investigational phase were hyperuricemia, arthralgia, nausea, vomiting, headache, diarrhoea, 
blood uric acid increased, hypokalaemia, pruritus, injection site pain, insomnia, and tinnitus. 
From start of the trial up to the final analysis, 12 participants died during the C209 trial due to 
SAEs that included TB (5 cases), congestive cardiac failure, renal impairment, lung infection, 
cardiac 
arrest 
(underlying 
cause 
pneumonia), 
haemoptysis, 
hypertension, 
and 
pyopneumothorax/respiratory failure. These SAEs leading to death were considered not 
related to bedaquiline by the Investigator, except for renal impairment that was judged 
doubtfully related to bedaquiline. 
The analysis of long-term follow-up for survival outcomes for participants who prematurely 
discontinued in trial C209, based on data collection every 24 weeks (6 months) after 
withdrawal, included 4 deaths (all described as TB-related). In total, since the start of the C209 
trial, 16 participants (6.9%) have died (12 participants during the trial and 4 participants during 
the survival follow-up phase after premature discontinuation). None of the fatal SAEs were 
considered related to bedaquiline by the Investigator and none of these participants has a 
treatment- emergent adverse event. 
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Cardiovascular safety 
During clinical trials with bedaquiline a prolongation of QTc interval was observed. The US 
Product Label for bedaquiline[7] notes that treatment initiation is not recommended in patients 
with: 
• 
Heart failure; 
• 
QTcF interval > 500 ms (confirmed by repeat electrocardiogram); 
• 
A personal or family history of congenital QT prolongation; 
• 
Concomitant administration of fluoroquinolone antibiotics that have a greater 
potential for significant QT prolongation (i.e., gatifloxacin, moxifloxacin and 
sparfloxacin). 
• 
Hypokalaemia 
The US Product Label recommends that bedaquiline treatment must be discontinued if the 
patient develops clinically significant ventricular arrhythmia. An additive or synergistic effect 
on QT prolongation of bedaquiline when co-administered with other medicinal products that 
prolong the QT interval cannot be excluded. Caution is recommended when using bedaquiline 
concomitantly with medicinal products with a known risk of QT prolongation. If co-
administration of such medicinal products with bedaquiline is necessary, clinical monitoring 
including frequent ECG assessment is recommended. 
Hepatic safety 
The US product label notes increases in transaminases were seen in clinical trials during 
administration of bedaquiline with the background regimen. participants should be monitored 
during treatment. Other hepatotoxic medicinal products and alcohol should be avoided while 
taking bedaquiline, especially in those participants with diminished hepatic reserve.[7]  
Additional safety information from a recently completed trial 
In a recently completed phase I trial not yet included in the bedaquiline Investigators Brochure 
that evaluated drug-drug interactions between bedaquiline and either rifampin or rifabutin, 7 
participants experienced SAEs. Of those participants, 5 experienced SAEs of 
lymphocytopenia (all received rifabutin), which did not appear to be related to the AUC or 
Cmax of TMC207 or rifabutin. One participant experienced an SAE of elevated Creatine 
Kinase (rifampicin arm) and one experienced a grade 4 Total Bilirubin SAE (rifampicin arm). 
Lymphopenia was previously noted to be an infrequent toxicity associated with rifabutin, but 
not previously seen with bedaquiline. 
The bedaquiline/rifabutin regimen demonstrated significant reversible lymphopenia, which did 
not appear to be related to the AUC or Cmax of TMC-207 or rifabutin. 
2.5.2 
Pretomanid (P) 
As detailed in the Investigator’s Brochure,[15] pretomanid is a new chemical entity and a 
member of a class of compounds known as nitroimidazo-oxazines, which possess significant 
anti-tuberculosis activity and a unique mechanism of action.[16] Pretomanid demonstrated in 
vitro activity against both DS- and MDR-TB,[17] and in vivo activity in a mouse model of 
tuberculosis.[16, 17]  
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2.5.2.1 
Pharmacology 
Key in Vitro Evaluation of Pretomanid Bactericidal Activity 
Non-clinical in vitro trials demonstrated that pretomanid was active against actively growing 
drug- sensitive and drug-resistant MTB strains as well as against non-replicating MTB. The 
minimum inhibitory concentration (MIC) of pretomanid against a variety of drug-sensitive MTB 
isolates in vitro was shown to be like the MIC of isoniazid (MIC of pretomanid, ≤0.015 to 0.25 
µg/mL; MIC of isoniazid, 0.03 to 0.06 µg/mL). Pretomanid was efficacious in vitro against drug-
resistant clinical isolates of MTB with MIC values ranging from 0.03 to 0.53 µg/mL. The 
Investigator’s Brochure contains further information on in vitro bactericidal activity.[16] 
Although not thoroughly elucidated at this time, pretomanid has a novel mechanism of action 
that appears to involve inhibition of the synthesis of cell wall lipids under aerobic conditions 
and generation of reactive nitrogen species under anaerobic conditions. Reduction of 
pretomanid by a deazaflavin (F420)-dependent nitroreductase has been shown to be 
associated with generation of reactive nitrogen species, including nitric oxide (NO),[29] although 
the exact target(s) of the reactive nitrogen species are not known. Transcriptional profiling 
trials also suggest that pretomanid affects both cell wall biosynthesis and the respiratory 
complex of MTB.[30, 31] 
2.5.2.2 
Key Non-Clinical Trials of Pretomanid 
The activity of pretomanid as a single agent or as part of a multi-drug combination regimen 
has been examined in a number of mouse trials.[13, 14, 18, 32, 33] In a mouse model of established 
TB, the activity of various doses of pretomanid (given once daily, 5 days/week, for 1 month), 
initiated 22 days after inhalation infection with H37Rv MTB is shown in Figure 2. In this model, 
the minimum effective dose (MED) for pretomanid, defined as the lowest dose able to prevent 
the development of gross lung lesions and splenomegaly, was 12.5 mg/kg/day, while the 
minimum bactericidal dose (MBD), defined as the lowest dose able to reduce lung colony 
forming units (CFU) by 99%, was 100 mg/kg/day. Moreover, in these experiments, the activity 
of pretomanid at 100 mg/kg was comparable to the activity of isoniazid at 25 mg/kg. 
Figure 2.  Log10 CFU Counts in Lungs  
After One Month of Daily Treatment with the Indicated Dose (in mg/kg) of Pretomanid 
 
Arrows denote the minimum effective dose (MED) and minimum bactericidal dose (MBD). 
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2.5.2.3 
Non-Clinical Toxicology and Safety 
Pretomanid has been evaluated in an ICH recommended battery of safety pharmacology trials, 
in repeat-dose toxicity trials in rats (2 to 26 weeks) and cynomolgus monkeys (7 days to 
9 months), in 8 genotoxicity trials, and in fertility and teratology trials in rats and rabbits.  
In the repeat-dose toxicity trials, the lowest no-observed adverse effect level (NOAELs) was 
10 mg/kg/day in a 26-week trial in rats, 50 mg/kg/day in a 13-week trial in monkeys and 
<25 mg/kg/day (based on findings of thickening of the gastrointestinal tract at all doses) in a 
9-month trial in monkeys. The major findings in safety and toxicity trials are listed below in 
Table 2 and are detailed in the Investigator’s Brochure.[15] 
Table 2.  Key findings of Pretomanid in Safety and Toxicity Trials 
Nervous system-related effects.  
Rats given single oral pretomanid doses had decreased body tone, touch responses and 
decreased grooming behaviour at ≥150 mg/kg, which resolved within 24 hours. Rats given 
repeated daily doses of pretomanid had convulsions, ataxia, hypoactivity, recumbency, 
hyperactivity and sensitivity to touch, and squinting at ≥100 mg/kg/day, and early deaths 
occurred at doses ≥500 mg/kg/day. Monkeys given repeated daily doses of pretomanid had 
hypoactivity, ataxia, tremors, and convulsions at ≥450/300 mg/kg/day. These effects were 
reversible when dosing stopped and were absent at ≤30 mg/kg/day in rats and 
≤150 mg/kg/day in monkeys. 
Testicular toxicity 
Although rat and rabbit embryonic development trials indicate no effects of pretomanid on 
foetal development, testicular atrophy in rats was observed in 3-month and 6-month repeat-
dose toxicology trials and a Segment I fertility trial. In this fertility trial, testicular atrophy was 
associated with infertility; an approximate 30% reduction in fertility was also observed at a 
lower dose not associated with testicular atrophy. A detailed trial in sexually mature male 
monkeys demonstrated no effects on testicular histology or function in adult cynomolgus 
monkeys after 3 months’ dosing.  
Cataracts 
Cataracts developed in rats with prolonged daily administration of pretomanid at doses 
≥100 mg/kg/day. In one 13-week trial in monkeys, cataracts did develop at 
450/300 mg/kg/day, but only by the end of a 13-week recovery period. In a second 13-week 
trial in monkeys that included extensive ophthalmic examinations, cataracts did not develop 
at the high-dose level of 300 mg/kg/day. 
hERG inhibition and QT prolongation 
Altered ventricular repolarisation due to inhibition of hERG-mediated potassium current and 
manifested on the ECG as a prolonged QT interval corrected for heart rate (QTc). 
Pretomanid inhibited hERG current with IC50 values of approximately 6.2 µg/mL. Following 
a single pretomanid dose of 450 mg/kg in monkeys, QTc interval prolongation ranged from 
21 to 36 msec using Fridericia’s formula (QTcF) to correct for heart rate. Co-administration 
of pretomanid with moxifloxacin in the monkey or with bedaquiline in the dog did not result 
in any greater effect on the QT interval than with either agent alone. After repeated daily 
doses, the QTc interval in the monkey was prolonged at pretomanid doses of 
≥150 mg/kg/day. 
 
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2.5.2.4 
Clinical Background Information 
Pretomanid has been evaluated in 8 single- and multi-dose Phase 1 trials with healthy adult 
male and female participants, with 163 participants receiving single oral doses ranging from 
50 to 1500 mg and multiple oral doses ranging from 50 to 1000 mg/day given for up to 7 days. 
These Phase 1 trials have evaluated the safety, tolerability, and pharmacokinetics (PK) of 
pretomanid. Two additional Phase 1 trials Sponsored by the NIH included a Thorough QT trial 
and a trial of drug interactions among pretomanid, efavirenz and ritonavir/lopinavir.  Further 
details of the trials are in the Investigator’s Brochure.[15] 
2.5.2.5 
Pharmacokinetics 
Several Phase 1 trials have evaluated the safety, tolerability, and pharmacokinetics (PK) of 
pretomanid and have demonstrated that pretomanid has a half-life of approximately 18 hours, 
which supports daily dosing, and an effect of food with the 200-mg dose that increases total 
exposure by 88%. Interaction trials with midazolam, efavirenz and ritonavir/lopinavir 
demonstrate effects that are not likely to be clinically significant. 
Drug interaction with midazolam: Trial CL-006 was an open-label, fixed-sequence drug-drug 
interaction trial to evaluate the effects of multiple-dose administration of pretomanid on the PK 
of midazolam, a sensitive probe substrate and representative compound for drugs 
metabolised by CYP3A enzymes. Dosing with pretomanid at 400 mg/day for 14 days (to 
steady state) had minimal effect on the PK of midazolam and its 1-hydroxy metabolite as 
assessed by measurement of the Day 17: Day 1 ratios of maximum concentration (Cmax, AUC0-
t, and AUC0-inf. The Cmax and AUC values for midazolam after co-administration with 
pretomanid were approximately 85% of those observed after treatment with midazolam alone. 
Furthermore, midazolam and 1-hydroxy midazolam time to maximum concentration (Tmax) and 
half-life (t1/2) values were not different in the presence or absence of pretomanid. Therefore, 
14 days’ dosing with 400 mg/day pretomanid does not appear to significantly inhibit CYP3A4 
in humans. 
Drug interaction with efavirenz, ritonavir/lopinavir, and rifampicin: The US NIH Sponsored this 
drug interaction trial with rifampicin, a known hepatic enzyme inducer, and with the 
antiretroviral drugs efavirenz and ritonavir/lopinavir (LPV/r) in healthy participants. Participants 
in Arm 1 were randomised to Sequence 1 (pretomanid 200 mg once daily for 7 days, two-
week washout period, efavirenz (EFV) 600 mg once daily for 14 days, then both drugs for 7 
days) or Sequence 2 (Treatment 1B: EFV, then EFV + pretomanid, washout, and pretomanid). 
Results indicate that comparing pretomanid given with EFV versus pretomanid alone in 16 
participants, the geometric mean ratio (GMR) for Cmax was 0.71, the GMR for AUC0-24h was 
0.65, and the GMR for Cmin was 0.54. Concentrations of EFV when given with pretomanid 
versus given alone were similar. Participants in Arm 2 were randomised to Sequence 1 
(pretomanid 200 mg once daily for 7 days, then a 2-week washout period, then LPV/r 400/100 
mg twice daily for 14 days, then LPV/r + pretomanid together for 7 days) or Sequence 2 (LPV/r, 
then LPV/r + pretomanid, washout, then pretomanid alone). Comparing pretomanid + LPV/r 
versus pretomanid- alone from 16 PK-evaluable participants, the GMR for Cmax was 0.87, for 
AUC0-24h was 0.83, and for Cmin was 0.78. In Arm 3, participants received pretomanid for 7 
days, then rifampicin 600 mg for 7 days, then pretomanid + rifampicin together for 7 days. 
Comparing pretomanid + rifampicin versus pretomanid alone from 16 PK-evaluable 
participants, the GMR for Cmax, AUC0-24h, and Cmin were 0.47, 0.34, and 0.15, respectively.  
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In conclusion, compared to pretomanid alone, plasma pretomanid values (based on geometric 
mean ratios) for Cmax, AUC0-24h, and Cmin were reduced 28%, 35%, and 46% with efavirenz; 
13%, 17%, and 21% with LPV/r; and 53%, 66%, and 85% with rifampicin, respectively. 
2.5.2.6 
Pretomanid Clinical Efficacy 
The first two Phase 2 trials to evaluate the early bactericidal effect (EBA) of pretomanid oral 
monotherapy (50 to 1200 mg/day for 14 days) examined the dose-response for pretomanid in 
participants with newly diagnosed pulmonary TB infection. The first trial (CL-007) 
demonstrated good EBA, but all doses in this trial (200 to 1200 mg/day) had the same activity. 
The second trial (CL-010) evaluated a lower dose range (50 to 200 mg/day) and the maximum 
effect on EBA was seen at a dose of 100 mg/day over 14 days (Figure 3).[34] 
Figure 3.  Mean log Colony Forming Unit Values over Time Trial CL-010 
 
CFU = colony-forming unit; PRETOMANID = pretomanid 
* Day 0 = (Day -2 + Day -1)/2 = baseline measurement 
Pretomanid has been evaluated in patients with TB as monotherapy for a maximum duration 
of 14 days, the longest considered acceptable for a TB patient to be treated in a clinical trial 
with a single drug.  Trials of pretomanid for both 14 days and for up to 6 months, in combination 
with either bedaquiline and/or linezolid, are described below.  
2.5.2.7 
Pretomanid Clinical Safety 
The pretomanid Investigator’s Brochure[15] provides detailed safety information. 
Across the 16 clinical trials with pretomanid completed to date, a total of 649 participants have 
been exposed to pretomanid, including 289 healthy participants across the 10 Phase 1 trials 
4
4.5
5
5.5
6
logCFU
0
2
4
6
8
10
12
14
Day
 PA-824 50mg
 PA-824 100mg
 PA-824 150mg
 PA-824 200mg
 Rifafour e275 
Bi-linear regression of logCFU vs day over treatment
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and 360 participants with newly diagnosed smear positive pulmonary TB across 5 Phase 2 
trials.  Among the 289 healthy participants, 174 received exposure to a single dose of 
pretomanid ranging from 50 to 1500 mg and 115 received exposures to repeated daily doses 
of pretomanid (50 to 1000 mg) for up to 14 days. The 360 participants with newly diagnosed 
smear positive pulmonary TB were exposed to pretomanid either as a single agent at daily 
doses of 50 to 1200 mg for 14 days or in combination with other anti-TB agents (bedaquiline, 
moxifloxacin, pyrazinamide, linezolid and/or clofazimine) at a dose of 100 mg or 200 mg for 
up to 26 weeks.  The overall safety profile determined from the clinical trials completed to date 
indicates pretomanid is well tolerated in healthy adults and in TB patients when administered 
alone and in combination with moxifloxacin, pyrazinamide, bedaquiline and clofazimine.   
Pretomanid is an investigational drug and there is limited experience in humans; the safety 
database is being developed and Investigators should be vigilant to any adverse events noted 
in clinical trials.  Across these trials, the most common side effects or AEs associated with 
pretomanid exposure include: 
• 
Headache 
• 
Stomach discomfort (nausea, vomiting, flatulence, and/or diarrhoea) 
• 
Skin and subcutaneous tissue disorders 
The only adverse drug reaction identified in clinical trials completed to date as likely caused 
by pretomanid is blood creatinine increased.  A trial of the effects of repeat doses of 
pretomanid in healthy volunteers determined that the drug does not adversely affect 
glomerular filtration rate, effective renal plasma flow or filtration fraction and the elevations in 
serum creatinine reverse.  
The following parameters will be followed with particular care in the Phase 3 development 
program: 
• 
Hepatic Safety – Specific guidelines are included in the protocol to assure close 
surveillance and careful management of participants who have elevations in 
aminotransferases and/or bilirubin. Serious liver injury, including death in 3 participants 
taking a combination of pretomanid, pyrazinamide and moxifloxacin, has occurred during 
clinical trials and the risk of liver injury may be higher for participants taking a combination 
of pretomanid and pyrazinamide than it is for the standard HRZE treatment. Therefore, 
close monitoring of liver function is required for participants who are administered 
pretomanid, especially when combined with pyrazinamide.  Administration of the regimen 
of PaMZ has been associated with death in 3 participants associated with hepatic injury. 
Furthermore, the HRZE control regimen, and both pyrazinamide and moxifloxacin, has 
been associated with drug induced liver injury and in rare cases hepatic necrosis.  
Consequently, hepatic safety will be under close surveillance in all clinical trials. 
• 
Ophthalmologic Evaluations – while the detailed examinations in Phase 2 have not raised 
concern for humans, ophthalmologic examinations, with slit lamp exam and grading of lens 
opacities, will continue in all human trials that involve exposure to pretomanid longer than 
14 days.  These examinations will be conducted at baseline, near the end of the dosing 
period and 3 months after the end of trial drug exposure.  These examinations are to follow 
up on the finding of cataracts in rats exposed to pretomanid in clinical trials. 
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• 
Cardiovascular Safety – All participants will have ECGs taken at baseline and at multiple 
time points during the trial.  Although the Thorough QT Trial in healthy participants found 
that pretomanid did not increase corrected QT intervals in a clinically meaningful way and 
did not add to the known effect of moxifloxacin, the ECGs will be carefully monitored during 
Phase 3.  All ECGs will be interpreted and conduction intervals will be confirmed by a 
central cardiology service. 
• 
Central Nervous System Safety –While pretomanid alone or combined in various regimens 
has been well tolerated overall, one participant in Trial NC-002 of the Pa-M-Z regimen had 
a seizure without any prior seizure history, and some animals in toxicology trials have had 
seizures at high drug exposures.  Consequently, close surveillance will be made of 
participants in the Phase 3 trial for seizures or any central nervous system adverse events 
of potential concern. 
Of note, preclinical toxicology trials found that rats, but not primates, had testicular toxicity 
when treated with pretomanid. Clinical evaluations of potential testicular toxicity in Phase 2 
trials have evaluated over 300 participants exposed to pretomanid over 2-6 months with 
evaluations of testosterone, LH, or Inhibin B (2 trials) or FSH values (3 trials) at baseline and 
after daily dosing of regimens containing pretomanid in various combinations with 
moxifloxacin, pyrazinamide and bedaquiline.  A review of data from the 3 trials by an 
independent reproductive endocrine expert concluded that, based on the hormone evaluations 
to date, there is no evidence that pretomanid is a testicular toxicant in men at the doses and 
exposure times evaluated. 
2.5.3 
Moxifloxacin (M) 
Moxifloxacin (M)[19]  is an 8-methoxyquinolone whose oral formulation (which will be used 
in this trial) has enhanced activity against Gram-positive pathogens, and anaerobes while 
retaining useful activity against Gram-negative organisms. Moxifloxacin is not metabolized by 
nor induces the cytochrome P450 system, thus the risk of clinically relevant drug interactions 
is reduced. It has a positive safety profile within the fluoroquinolone class at the approved daily 
dose of 400 mg. Moxifloxacin while not approved for TB by most regulatory authorities, it is 
regularly used in second line MDR-TB treatment. The WHO TB Treatment Guidelines place 
moxifloxacin in the category of Group 3 drugs and notes that “all patients [with MDR-TB] 
should receive a Group 3 medication if the strain of MTB is susceptible or if the agent is thought 
to have efficacy. One of the higher generation fluoroquinolones, such as levofloxacin or 
moxifloxacin, is the fluoroquinolone of choice.[5]” It is currently in late stage clinical 
development for first-line TB treatment in combination with other TB drugs, including 
pyrazinamide in two different four-month long regimens.  
2.2.3.1. 
Moxifloxacin Clinical Trials 
Moxifloxacin is commonly used as second line therapy for TB (e.g. MDR- TB), and has also 
been evaluated in several clinical studies of participants with TB, including four 8-week 
treatment period Phase 2b studies (see Table 3 below).  
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Table 3.  Summary of Phase 2b trials in which moxifloxacin were administered 
as part of a four-drug regimen during the intensive phase of treatment (total 
treatment duration: 2 months) 
Trial 
Design 
Objective 
Participants 
(N) 
Status 
Trial 27 
Randomized, 
double-blind, 
controlled 
To compare the sputum culture-
conversion rate at the end of the 4-
drug (intensive) phase of therapy 
using the standard 4-drug regimen 
HRZE with a standard regimen with M 
replacing E.  
336 
Completed 
OFLOTUB 
Trial 
Randomized, 
Open label, 
Controlled 
To compare the bactericidal activities 
of regimens where gatifloxacin, M, 
and ofloxacin were substituted for E in 
the 2-month initial phase of standard 
TB treatment with HRZE.  
 
217 
Completed 
Johns 
Hopkins 
(FDA 
orphan 
drug) Trial 
Randomized, 
double-blind, 
Controlled 
To compare the sputum culture 
conversion rate at the end of the 4-
drug (intensive) phase of therapy 
using a standard 4-drug regimen 
(HRZE) with a regimen with M 
replacing E (HRZM). 
170 
Completed 
Trial 28 
Randomized, 
double-blind, 
Controlled 
To compare the culture-conversion 
rate at the end of the 4-drug 
(intensive) phase of therapy using a 
standard 4-drug regimen (HRZE 5 
days per week) with a regimen with M 
replacing H (MRZE 5 days per week). 
 
433 
Completed 
 
2.5.3.1 
Moxifloxacin Clinical Safety 
In Trial 27,[35] the moxifloxacin-containing TB regimens (HRZM) were shown to be safe and 
well tolerated. There was no difference in SAEs between the HRZM and HRZE treatment 
arms, and most SAEs were hospitalizations thought to be unrelated to the trial treatment.  
Participants treated with the moxifloxacin-containing regimen were more likely to report 
nausea (22% vs. 9%, p = 0.002), but this was generally mild and did not lead to treatment 
discontinuation as similar proportions of participants in both groups completed trial drug 
treatment (88% HRZM-treated vs. 89% HRZE-treated).  The one death during the first 2 
months of treatment was thought to be caused by a pulmonary embolism unrelated to 
tuberculosis therapy.   
In the OFLOTUB trial,[36] AEs and SAEs occurred with equal frequency in the four treatment 
arms.  The most frequent AEs were raised amylase (in 41% of participants due to HIV 
infection), raised transaminase (10%), arthralgia (9%), anaemia (7%), hypokalaemia (6%) and 
vomiting (5%).  No Participant was withdrawn from the trial due to an adverse event.  There 
were 4 deaths in the trial: 2 in the control group, 1 each in the moxifloxacin and ofloxacin arms.  
Importantly, participants in this trial who received moxifloxacin and pyrazinamide in addition 
to isoniazid and rifampin had more rapid sputum clearance than participants on the four 
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standard first line drugs (isoniazid, rifampin, pyrazinamide and ethambutol). This difference 
was evident 14 days after initiation of treatment. 
In the JHU trial,[37] AEs did not differ by treatment group. There were 16 SAEs (8 in each 
group) in 12 participants. Only 1 event was judged related to trial drug (grade 3 cutaneous 
reaction in the ethambutol group). Eight participants died during the trial, including 1 in each 
group still receiving trial phase treatment. No death was attributed to trial treatment. Only 5 
participants discontinued treatment because of toxic effects; 2 participants in the moxifloxacin 
group stopped because of grade 2 nausea and vomiting and 1 because of grade 2 
paraesthesia’s and ataxia. Two participants in the E group stopped because of grade 2 rash 
and pruritus and 1 because of grade 3 peripheral neuropathy.  There was no change in the 
QTc interval on serial electrocardiograms taken during the trial. 
In Trial 28,[38] the proportions of participants with SAEs during the intensive phase treatment 
were similar between arms (isoniazid 3.9% vs. moxifloxacin 4.2%; P = 0.88). Three SAEs 
attributed to trial treatment during the first 2 months occurred among the moxifloxacin group 
and two in the isoniazid group.  Seven participants died during the trial including 3 participants 
receiving the moxifloxacin treatment regimen and 4 participants receiving the isoniazid 
treatment regimen. The 3 moxifloxacin participants died during the intensive phase of TB 
treatment. Two participants died from advanced pulmonary TB judged not related to trial 
treatment and 1 Participant (who developed diabetic ketoacidosis considered possibly related 
to trial treatment) died from possible acute pulmonary embolus unrelated to trial treatment. 
The 4 isoniazid deaths occurred during the continuation phase, and all 4 were considered 
unrelated to trial treatment.  Nausea was more common among participants in the moxifloxacin 
arm than in the isoniazid arm (19.6% vs. 11.7%, respectively; P = 0.03) although similar 
proportions reported vomiting.  However, the proportions of participants with hepatitis, defined 
as serum AST 3 times or greater than the upper limit of normal, were similar between treatment 
arms during intensive phase (isoniazid 3.4% vs. moxifloxacin 3.3%; P = 0.93).  Moxifloxacin 
has also been evaluated in combination with pretomanid for two weeks in participants with TB 
(Trial NC-001) and for 8 weeks in NC002 as reviewed above in Section 2.2.3 (Trial NC-001). 
For additional information on moxifloxacin, refer to the IB[39] and the manufacturer’s package 
insert.[19] 
2.5.4 
Pyrazinamide (Z) 
Pyrazinamide (Z) is a standard drug used as part of the four drug HRZE regimen used for the 
first two months of intensive therapy for drug-sensitive TB as recommended by the WHO and 
many National TB programs.  Please see the Package Insert[20] for more detail.  Z is active 
against TB in vitro and it potentiates the bactericidal and sterilizing activity of both bedaquiline 
and  pretomanid in mouse models of TB infection.[8, 15]  Pyrazinamide enhanced the 
bactericidal activity of both bedaquiline and  pretomanid in Trial NC-001-(J-M-Pa-Z) as noted 
by decreases over 14 days in the CFU counts in sputum among participants. 
The pyrazinamide product label notes that pyrazinamide is contraindicated in persons with 
severe hepatic damage, who have shown hypersensitivity to it, and with acute gout.  The most 
serious side effect is hepatotoxicity. Its frequency appears to be dose-related and thus liver 
function should be assessed before and regularly during treatment with pyrazinamide.  
Hyperuricemia commonly occurs and is occasionally accompanied by arthralgia and may lead 
to attacks of gout. Photosensitivity and skin rash have been reported less frequently. Other 
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side effects that have been reported are anorexia, nausea and vomiting, malaise, fever, 
sideroblastic anaemia and dysuria.  
Pyrazinamide may decrease the efficacy of gout therapy (e.g. allopurinol, colchicine, 
probenecid or sulphinpyrazone) and dosage adjustments of these medications may be 
necessary.  For additional information on pyrazinamide, refer to the manufacturer’s package 
insert. [20] 
2.6 
Overall Benefit/Risk Assessment 
Some participants with pulmonary TB in this trial will be given a regimen of BPaMZ. These 
drugs individually and in combination are known to have anti-tuberculosis activity and is not 
expected to have an adverse impact on the ultimate cure of TB in these participants. Based 
on NC-005 and other regimens using each of the regimen drugs in different combinations 
there is good evidence that this may be a highly effective therapy for both DS-TB and DR-TB.  
For DS-TB the potential for a shorter regimen than 6 months is expected to be successful 
based on preclinical and clinical information as listed before.  Participants in this trial will have 
their TB infection carefully characterized, with drug sensitivity profiles established, and they 
will receive treatment with trial drugs that have demonstrated activity against MTB.   
Participants will receive individualized medical attention; this will allow a continuous monitoring 
of the health conditions of each participant, any of whom can be withdrawn at any stage of the 
trial and removed from trial treatment should his/her condition suggest to the Investigator that 
this would be in his/her best interest.  Multiple blood samples will be taken for safety laboratory 
studies, and ECGs will be taken at multiple time points.  
One concern, the combination of two agents with known QT-prolonging effects (bedaquiline 
and moxifloxacin), has been addressed specifically by carefully identifying and excluding 
participants with risk factors that might predispose them to cardiac arrhythmias, screening all 
participants for evidence of existing cardiac disease and monitoring all participants with ECGs 
throughout the trial.  
The trial drugs in the proposed regimens to be tested in this trial have all demonstrated safety 
and efficacy in the treatment of pulmonary tuberculosis in non-clinical and clinical studies. 
Specifically, the regimen B-Pa-Z was generally well-tolerated and demonstrated bactericidal 
activity in a 14-day EBA trial. The potential risks associated with the trial drugs and regimens 
has been identified as outlined below and will be monitored carefully throughout the conduct 
of the trial. 
The BPaMZ regimen is a novel regimen treatment expected to be effective, safe and well-
tolerated and might even shorten the current treatment duration for patients with TB. Based 
on data from previous trial evaluations of key monitoring and safety information as outlined 
before suggests a favourable benefit-to-risk ratio trials.  
Key Monitoring and Safety Information Regarding Regimen Agents 
2.6.1 
Bedaquiline (B) 
2.6.1.1 
Adverse Drug Reactions for bedaquiline  
Participants in the Any bedaquiline group compared to the Any Placebo group (difference > 
5.0%) had headache (23.5% versus 11.4%, respectively), nausea (35.3% versus 25.7%, 
respectively), arthralgia (29.4% versus 20.0%, respectively), and transaminases increased 
(6.9% versus 1.0%, respectively).and diarrhoea (11.4% versus 5.9%, respectively). 
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2.6.1.2 
Cardiovascular safety 
During clinical studies with bedaquiline a prolongation of QTc interval was observed. An ECG 
should be obtained prior to and after initiation of therapy with bedaquiline to monitor the QTc 
interval. 
Bedaquiline treatment initiation is not recommended in patients with: 
• 
Heart failure 
• 
QTcF interval > 450 ms (confirmed by repeat electrocardiogram) 
• 
A personal or family history of congenital QT prolongation 
• 
Concomitant administration of fluoroquinolone antibiotics that have a greater potential 
for significant QT prolongation (i.e., gatifloxacin, moxifloxacin and sparfloxacin) 
• 
Hypokalemia 
 
Bedaquiline treatment must be discontinued if the patient develops clinically significant 
ventricular arrhythmia. An additive or synergistic effect on QT prolongation of bedaquiline 
when co-administered with other medicinal products that prolong the QT interval cannot be 
excluded. Caution is recommended when using bedaquiline concomitantly with medicinal 
products with a known risk of QT prolongation. If co-administration of such medicinal products 
with bedaquiline is necessary, clinical monitoring including frequent ECG assessment is 
recommended. 
In the DR-TB treatment arm of the present trial, moxifloxacin will be co-administered with 
bedaquiline. This is to prevent the development of resistance to the other drugs in the regimen 
in case the participant’s strain of MTB is resistant to pyrazinamide. ECG assessments will be 
performed on all participants at screening, baseline, and at treatment visits specified in the 
flow chart.   
2.6.1.3 
Hepatic safety 
Increases in transaminases were seen in clinical studies during administration of bedaquiline 
with the background regimen. Participants should be monitored during treatment. 
Other hepatotoxic medicinal products and alcohol should be avoided while taking bedaquiline, 
especially in participants with diminished hepatic reserve. 
2.6.2 
Pretomanid (P) 
The most common side effects or AEs associated with pretomanid exposure include: 
• 
Headache 
• 
Benign, isolated and reversible elevations of serum creatinine 
• 
Stomach discomfort (nausea, vomiting, flatulence, and/or diarrhoea) 
• 
Skin and subcutaneous tissue disorders 
2.6.2.1 
Hepatic Safety 
Hepatic enzyme increases have been seen in participants treated with pretomanid in 
combinations with various other medications during the clinical development program. It is 
difficult to assign specific causality to any one drug within a regimen; nonetheless, the NC-008 
trial will include specific monitoring of hepatic enzymes. 
For additional information refer to  pretomanid IB.[15] 
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2.6.3 
Moxifloxacin (M) 
In the usual daily doses of 400 mg/day, moxifloxacin is well tolerated.  As stated in the Package 
Insert[19]  the most frequent individual drug related AEs observed in clinical trials with 400 mg 
oral moxifloxacin therapy were nausea (7.5%) and diarrhoea (5.8%).  Fluoroquinolones, 
including moxifloxacin, are associated with an increased risk of tendinitis and tendon rupture 
in all ages.   
A known but rare side effect of fluoroquinolones, including moxifloxacin is exacerbation of 
myasthenia gravis. In addition, moxifloxacin has been shown to prolong the QT interval of the 
electrocardiogram in some participants.  It should be used with caution in participants being 
treated concomitantly with other drugs where an additive effect on the QT interval cannot be 
excluded.  
Serious and sometimes fatal hypersensitivity reactions, including anaphylactic reactions, as 
well as peripheral neuropathy may occur after the first or subsequent doses of moxifloxacin. 
For additional information, refer to the moxifloxacin package insert.[19] 
2.6.4 
Pyrazinamide (Z) 
The dose of pyrazinamide that will be used in this trial is an approved dosage for the treatment 
of TB. The most serious side-effect of pyrazinamide is hepatotoxicity and its frequency 
appears to be dose-related. Hyperuricemia commonly occurs, occasionally accompanied by 
arthralgia and may lead to attacks of gout.  Photosensitivity and skin rash have been reported 
less frequently.  Other side-effects that have been reported are anorexia, nausea and 
vomiting, malaise, fever, sideroblastic anaemia and dysuria.  Pyrazinamide may decrease the 
efficacy of gout therapy (e.g. allopurinol, colchicine, probenecid or sulphinpyrazone) and 
dosage adjustments of these medications may be necessary.  For additional information on 
pyrazinamide, refer to the manufacturer’s package insert.[20] 
2.6.5 
HRZE/HR Control 
The HRZE (isoniazid 75 mg plus rifampicin 150 mg plus pyrazinamide 400 mg plus ethambutol 
275 mg combination tablets) combination will be given the first 8 weeks and the HR (isoniazid 
75 mg plus rifampicin 150 mg combination tablets) combination will be given from Weeks 9 to 
26. 
Participants with DS-TB that are randomized to the HRZE/HR control arm in this trial will be 
given standard weight-adjusted doses of HRZE.   
Please see the HRZE and HR Package Inserts[22, 40] for known and potential risks and benefits. 
3.0 
Trial Objectives 
3.1 
Primary Endpoint 
To evaluate the time to culture negativity over 8 weeks from the start of the treatment regimens 
in participants with: 
• 
Drug Sensitive TB (DS-TB) 
• 
Drug Resistant TB (DR-TB)  
 
DR-TB are defined as participants with: 
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1. mono-resistance to rifampicin or isoniazid, OR 
2. resistance to both rifampicin and isoniazid (DR-TB) 
3.2 
Secondary Endpoints 
Efficacy: 
 
• 
Incidence of bacteriologic failure or relapse or clinical failure at 52 weeks (12 months) and 
104 weeks (or 24 months) weeks from the start of therapy.  
• 
Proportion of participants with sputum culture conversion to negative status in liquid culture 
(MGIT) at 4, 6, 12 and 17 weeks to be explored as a potential biomarker of outcome at 52 
weeks from start of therapy. 
• 
Change from baseline in weight. 
• 
Change from baseline in TB symptoms. 
• 
Change from baseline in Participant Reported Health Status. 
 
Safety and Tolerability: 
 
• 
Incidence of Treatment Emergent Adverse Events (TEAEs) presented by incidence, 
severity, drug relatedness, seriousness, leading to early withdrawal, and leading to death.  
 
Quantitative and qualitative clinical safety laboratory measurements, including 
observed and change from baseline. 
 
Quantitative and qualitative ECG results (heart rate, RR interval, PR interval, QRS 
interval, QT interval and QTc interval), including observed. QT/QTc intervals, change 
from baseline, will be categorized as these will be centrally read. 
• 
Changes in male reproductive hormones. 
• 
Changes in lens opacities. 
 
These data will be presented as descriptive analyses, and no inferential tests will be carried 
out. 
Pharmacokinetics (PK) and Pharmacokinetics/Pharmacodynamics (PK/PD): 
 
Plasma concentrations from sparse sampling will be used to update existing population PK 
models and derive exposure metrics (e.g., minimum plasma concentration [Cmin], maximum 
plasma concentration [Cmax], area under curve over a dosing interval [AUC]) for bedaquiline 
and its M2 metabolite, pretomanid, moxifloxacin, and pyrazinamide. Effects of baseline 
covariates on exposure will be assessed; so too, will the effects of concomitant medications, 
including antiretroviral therapy (ART), where feasible.  
Data from other trials may be included to enhance the model-based analysis. Relationships 
will be explored between drug exposure and efficacy and safety endpoints. These exploratory 
PK/PD analyses may include HIV status as a covariate. 
3.3 
Exploratory Objectives 
• 
Evaluate whether any of the secondary endpoints predicts relapse free cure. 
• 
Subgroup analysis of populations by HIV status.  
 
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4.0 
Trial Design 
4.1 
Summary of Trial Design 
This is a Phase 2c, multi-centre, open-label, partially randomized clinical trial conducted in 3 
treatment groups.  Participants, trial Investigators and staff, including laboratory staff, will not 
be blinded to treatment randomization and allocation during the treatment phase of the trial. 
The trial will be performed globally at multiple centres located throughout the world.    
A total of 300 DS-TB participants (150 per treatment arm) will be randomized and stratified for 
co-infection with HIV and cavitation, with a target of 50% of the participants being HIV positive.  
Up to 150 DR-TB participants will be enrolled and assigned to the treatment arm described in 
Table 4 below. 
Refer to Section 3.0 Trial Objectives above and Section 9.3 Interim Analysis for details of the 
planned interim analysis and potential updates to the trial objectives and sample size.   
Participants with Drug Sensitive TB (DS-TB): 
 
Participants with DS-TB will be randomized to one of two treatment arms. These participants 
will receive either BPaMZ daily for 17 Weeks, or HRZE/HR combination tablets daily for 26 
Weeks.  Participants will be stratified for co-infection with human immunodeficiency virus (HIV) 
and cavitation. 
 
Participants with Drug Resistant TB (DR-TB): 
 
Participants with DR-TB will be assigned to receive BPaMZ daily for 26 weeks (6 months). 
Eligible participants who meet all the inclusion criteria and none of the exclusion criteria, aged 
18 and over, male or female will be assigned to one of the 3 treatment groups with a target of 
50% of the participants being HIV positive.  
DR participants will be treated with 6 months of BPaMZ. DS participants will be randomized 
using an interactive web response system (IWRS) stratifying for cavitation and HIV status to 
allocate participants evenly across the arms after they have given written, informed consent 
during the Screening Visit (Days -9 to -1).  
 
4.2 
Treatment Plan: Schedule of Assessments 
• 
Screening Period (Day -9 to Day -1) 
• 
Treatment Period (Day 1 to Week 17 / Week 26)  
• 
Follow-Up Period (Week 39 to Week 104) 
 
Refer to: 
• 
Synopsis Flow Chart and Procedures (Section 1.2) for the timing of all procedures and 
laboratory samples to done at each visit.   
• 
Trial Procedures (Section 7.0, Trial Variables and Procedures) for details regarding 
specific procedures or laboratory tests. 
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Each participant will receive up to 26 weeks of treatment.  The trial IMP regimens may require 
interruptions/pauses due to toxicities. All dose interruptions/pauses should be discussed with 
the Sponsor’s Medical Monitor prior to implementation unless an interruption/pause is required 
urgently for a safety concern.  
 
All participants will enter post-treatment follow-up which continues until Week 104 after start 
of treatment / randomisation. 
 
Participants will receive daily dosing, orally. They will be randomized to one of the following 
arms: 
Table 4: Treatment Groups 
 
Treatment Group 
Treatment 
Duration 
No of 
Participants 
1 Bedaquiline 200 mg daily for 8 weeks  
then 100 mg daily for 9 weeks, together with pretomanid 
200 mg + moxifloxacin 400 mg + pyrazinamide 1500 mg 
daily 
17 weeks 
(4 months) 
150 DS-TB 
2 HRZE Tablets (Weeks 1-8): (isoniazid 75 mg plus 
rifampicin 150 mg plus pyrazinamide 400 mg plus 
ethambutol 275 mg combination tablets).  
 
Followed by 
 
HR Tablets (Weeks 9-26): (isoniazid 75 mg plus 
rifampicin 150 mg combination tablets).   
First 8 weeks  
(2 months) 
 
 
then 
 
17 weeks  
(4 months) 
 
Total 6 months 
150 DS-TB 
3 Bedaquiline 200 mg daily for 8 weeks  
then 100 mg daily for 18 weeks, together with pretomanid 
200 mg + moxifloxacin 400 mg + pyrazinamide 1500 mg 
daily. 
26 weeks 
(6 months) 
Up to 150 
DR-TB 
5.0 
Trial Population 
The participant must meet all inclusion and no exclusion criteria within the screening period.  
Retesting for any laboratory or ECG parameters is allowed within the screening period.  
Sponsor may consider replacement of late exclusions. It is the intent of the protocol that the 
participants are hospitalized according to local practices and at the judgment of the treating 
physician / investigator. 
5.1 
Inclusion Criteria 
Participants are required to meet all the following inclusion criteria during the screening period 
to be randomized. 
1. Signed written consent prior to undertaking any trial-related procedures. 
2. Male or female, aged 18 years or over. 
3. Body weight (in light clothing and no shoes) ≥ 30 kg. 
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4. Sputum positive for tubercule bacilli (at least 1+ on the International Union Against 
Tuberculosis and Lung Disease [IUATLD]/WHO scale (Appendix 1) on smear microscopy) 
at the trial laboratory. 
5. Disease Characteristics - Participants with one of the following pulmonary TB conditions: 
DS-TB treatment arm participants should be: 
a. sensitive to rifampicin, isoniazid and fluoroquinolones by rapid sputum-based 
test AND 
b. either newly diagnosed for TB or have a history of being untreated for at least 
3 years after cure from a previous episode of TB. 
DR-TB treatment arm participants should be: 
a. Resistant to rifampicin and/or isoniazid; but sensitive to fluoroquinolones by 
rapid sputum-based test AND  
b. Should not have had previous treatment for DR-TB/MDR-TB, although may 
have been on a DR-TB/MDR-TB treatment regimen for no longer than 3 days 
at start of screening. 
c. Participants with resistance to injectables by rapid sputum-based test are 
allowed in the trial. 
When Phenotypic DST and whole genome sequencing (WGS) results on baseline 
samples become available, any results that are discordant with the screening 
molecular test results used to qualify a participant’s eligibility for the trial will be 
reviewed by the Sponsor Medical Monitor in consultation with the Investigator to 
determine whether that participant is unlikely to respond to treatment and should 
therefore be removed from the trial and given alternative treatment. If a participant is 
removed from the trial for such a reason, they will be classified as a late exclusion.  
6. A chest x-ray, within 6 months prior to or during the Screening visit, which in the opinion 
of the Investigator is compatible with pulmonary TB.  
7. Contraception: 
 
Be of non-childbearing potential or using effective methods of birth control, as defined 
 
below: 
Non-childbearing potential: 
a. Participant - not heterosexually active or practice sexual abstinence; or  
b. Female participant or male participants female sexual partner - bilateral 
oophorectomy, bilateral tubal ligation and/or hysterectomy or has been 
postmenopausal with a history of no menses for at least 12 consecutive months; 
or  
c. Male participant or female participants male sexual partner - vasectomised or has 
had a bilateral orchidectomy at least three months prior to screening; 
 
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Effective birth control methods: 
a. Double barrier method which can include a male condom, diaphragm, cervical cap, 
or female condom; or  
b. Female participant: Barrier method combined with hormone-based contraceptives 
or an intra-uterine device. 
c. Male participants’ female sexual partner: Barrier method combined with hormone-
based contraceptives or an intra-uterine device.  
Both male and female participants must be willing to continue practicing birth control 
methods and are not planning to conceive throughout treatment and for 6 months after 
the last dose of trial IMP or discontinuation from trial IMP in case of premature 
discontinuation.  
Note: Hormone-based contraception alone may not be reliable when taking IMP; therefore, 
hormone-based contraceptives alone cannot be used by female participants to prevent 
pregnancy. 
 
5.2 
Exclusion Criteria 
Participants will be excluded from participation if they meet any of the following criteria: 
Medical History and Concurrent Conditions: 
1. Any non-TB related condition where participation in the trial, as judged by the 
Investigator, could compromise the well-being of the participant or prevent, limit or 
confound protocol specified assessments. 
2. Abuse of alcohol or illegal drugs that in the opinion of the Investigator would 
compromise the participants’ safety or ability to follow through with all protocol-
specified restrictions, visits and evaluations. 
3. Historical and or current use of local traditional medications/herbs which in the opinion 
of the Investigator would compromise the participants’ safety or ability to follow through 
with all protocol-specified restrictions, visits and evaluations.  
4. Being, or about to be, treated for malaria. 
5. Is critically ill and, in the judgment of the Investigator, has a diagnosis likely to result in 
death during the trial or the follow-up period. 
6. TB meningitis or other forms of extrapulmonary tuberculosis with high risk of a poor 
outcome, or likely to require a longer course of therapy (such as TB of the bone or 
joint), as judged by the Investigator. 
7. History of allergy or hypersensitivity to any of the trial IMP or related substances, 
including known allergy to any fluoroquinolone antibiotic, history of tendinopathy 
associated with quinolones or suspected hypersensitivity to any rifampicin antibiotics. 
8. For HIV infected participants any of the following: 
 
a. CD4+ count <100 cells/µL  
b. Karnofsky score <60% (Appendix 5)   
c. Received intravenous antifungal medication within the last 90 days 
d. WHO Clinical Stage 4 HIV disease (Appendix 3) 
 
9. Participants who recently started or expected to need to start ART within 1 month after 
randomization. Participants who have been on ARTs for more than 30 days prior to 
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start of the Screening visit or expected to start ART greater than 30 days after 
randomization may be included.  
 
10. Having participated in other clinical trials with investigational agents within 8 weeks 
prior to start of trial medication or currently enrolled in an investigational trial. 
11. Participants with any of the following at the Screening visit (per measurements and 
reading done by ECG): 
 
a. QTcF interval on ECG >500 msec.  Participants with QTcF > 450 must be 
discussed with the Sponsor Medical Monitor before enrolment. 
b. Heart failure 
c. A personal or family history of congenital QT prolongation 
d. A history of or known, untreated, ongoing hypothyroidism 
e. A history of or ongoing bradyarrhythmia 
f. 
A history of Torsade de Pointe 
 
12. Unstable Diabetes Mellitus which required hospitalization for hyper- or hypo-glycaemia 
within the past year prior to start of screening. 
13. Females who have a positive pregnancy test at the Screening visit or already known 
to be pregnant, breast-feeding, or planning to conceive a child during the trial or within 
6 months of stopping treatment.  Males planning to conceive a child during the trial or 
within 6 months of stopping treatment.  
14. Participants with lactose intolerance, lactase deficiency and/or glucose-galactose 
malabsorption. 
 
Previous and Concomitant Therapy 
15. Previous treatment for TB which includes: 
 
• 
For DS-TB participants: Previous treatment for tuberculosis within 3 years prior to 
the Screening visit. Participants who have previously received isoniazid 
prophylactically may be included in the trial if that treatment is/was discontinued at 
least 7 days at the start of the Screening visit. 
• 
For the DR-TB participants: Previous treatment for DR-TB/MDR-TB, although may 
have been on a DR-TB/MDR-TB treatment regimen for no longer than 3 days at 
the start of the Screening visit. 
16. Any diseases or conditions in which the use of the standard TB drugs or any of their 
components is contra-indicated, including but not limited to drug allergy. 
17. Use of any drug within 30 days prior to randomisation known to prolong QTc interval 
(including, but not limited to, amiodarone, amitriptyline, bepridil, chloroquine, 
chlorpromazine, cisapride, clarithromycin, disopyramide dofetilide, domperidone, 
droperidol, 
erythromycin, 
halofantrine, 
haloperidol, 
ibutilide, 
levomethadyl, 
mesoridazine, methadone, pentamidine, pimozide, procainamide, quinacrine, 
quinidine, sotalol, sparfloxacin, thioridazine). 
18. Use of systemic glucocorticoids within one year of the start of the Screening visit 
(topical, inhaled or intranasal glucocorticoids are allowed), as they can lead to visual 
opacities or cataracts. 
19. For HIV infected participants: 
 
a. The following antiretroviral therapy (ART) should not be used with either 
(BPaMZ and HRZE/HR) trial regimen: 
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1. Stavudine  
2. Didanosine  
3. Triple NRTI regimen is not considered optimal for HIV treatment (poor 
efficacy) 
 
b. In the case where participants are randomised to HRZE arm, rilpivirine and 
etravirine cannot be given with rifampicin due to drug-drug interactions. A 
standard NRTI backbone may be used in combination with one of the 
following: 
 
1. Efavirenz requires no dose adjustment  
2. Dolutegravir dose adjustment is required – double dose when co-
prescribed with rifampicin. 
3. Raltegravir requires no dose adjustment 
4. Lopinavir/r dose adjustment is required – double dose when co-
prescribed with rifampicin 
5. Nevirapine requires no dose adjustment, however please note that 
nevirapine based regimens are associated with higher ART failure in 
participants having or known to have a previous viral load more than 
or equal to 100,000/ mL 
 
c. In the case where participants are randomized to the BPaMZ trial regimen, a 
standard NRTI backbone may be combined with the following:  
 
1. Rilpivirine 
2. Dolutegravir  
3. Raltegravir 
4. Nevirapine  
5. Lopinavir/r  
6. Participants who are on efavirenz, atazanavir/r or darunavir/r at the 
time of screening and have an undetectable viral load, should have 
their ART switched to one of the agents listed above (1-5). It would be 
preferable to switch to another permissible ARV within the same class 
accompanied by the same nucleoside backbone. 
 
d. ART regimen choice should be discussed with the Sponsor Medical Monitors 
if there are any concerns. 
 
Confirmed plans to use Isoniazid prophylaxis for HIV positive participants during the 
treatment and follow up period is not permitted. 
Diagnostic and Laboratory Abnormalities 
20. Participants with the following toxicities at screening as defined by the enhanced 
Division of Microbiology and Infectious Disease (DMID) adult toxicity table (Draft 
November 2007) (Appendix 2) where applicable: 
 
a. platelets <75,000/mm3 
b. creatinine 1.5 times upper limit of normal [ULN])  
c. eGFR ≤ 60 mL/min/ 
d. haemoglobin <8.0 g/dL 
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e. serum potassium less than the lower limit of normal for the laboratory. This may 
be repeated once 
f. GGT: greater than 3 x ULN 
g. AST: 
• 
≥3.0 x ULN to be excluded; 
• 
results between 1.5 x ULN and 3 x ULN must be discussed with and 
approved by the Sponsor Medical Monitor 
h. ALT: 
• 
≥3.0 x ULN to be excluded 
• 
greater than ULN must be discussed with and approved by the Sponsor 
Medical Monitor 
i. 
 ALP: 
• 
≥3.0 x ULN to be excluded 
• 
2.0 – <3.0 x ULN must be discussed with and approved by the Sponsor 
Medical Monitor 
j. 
Total bilirubin: 
• 
>1.5 x ULN to be excluded; 
• 
Greater than 1 – 1.5 x ULN must be discussed with and approved by 
the Sponsor Medical Monitor 
k. Direct bilirubin: 
• 
greater than 1x ULN to be excluded 
All the inclusion and none of the exclusion criteria must be met. If no single variable/value is 
outside of the ranges of acceptability, but when multiple values are close to the limits and/or 
whenever the Investigator has reason to suspect that there might be a health problem (other 
than TB), enrolment should only be considered after discussing the case with the Sponsor 
Medical monitor. 
 No protocol waivers will be granted by the TB Alliance. 
 
5.3 
Restrictions 
Concomitant medications should be kept to a minimum during the trial. However, if 
concomitant medications are necessary for the participant’s welfare, they may be given at the 
discretion of the Investigator. For any concomitant medications given as a treatment for a new 
condition or a worsening of an existing condition occurring after signing of the informed 
consent form, the condition must be documented on the Adverse Event pages of the electronic 
Case Report Form (eCRF). 
The prescribing information for all concomitant medication should be reviewed carefully. The 
determinations listed in the respective contraindicated, warning, and precaution sections must 
be respected to prevent any potentially serious and/or life-threatening drug interactions. 
The following recommendations should be followed with regards to concomitant medication to 
avoid possible drug interaction with the IMP: 
Participants on a moxifloxacin containing treatment arm: The IMP should be taken either 
4 hours before or 8 hours after taking the following products: 
• 
An antacid, multivitamin, or other product that has magnesium, aluminium, iron 
or zinc 
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• 
Sucralfate 
• 
Didanosine 
Participants on the HRZE/HR treatment arm: 
• 
Any aluminium-containing antacids should be taken at least one hour after the IMP 
dose. 
The following medicinal products are prohibited from the Screening visit and during the 
treatment period: 
• 
Quinolone antimalarial (e.g., chloroquine and quinacrine). Participants who have 
malaria at screening are to be excluded. However, if a participant develops malaria 
during the trial, the Investigator is advised to consult the Malaria Treatment 
Guidance document regarding the interaction between moxifloxacin and 
bedaquiline with anti-malarial drugs. Investigators may also contact the Sponsor 
Medical Monitor for further guidance. 
• 
Chronic systemic glucocorticoids (topical, inhaled or intranasal glucocorticoids are 
allowed) due to their potential to cause visual opacities. Short term systemic 
glucocorticoids are allowed for emergency situations (e.g. for treatment of 
pulmonary exacerbation when inhaled glucocorticoids is inadequate). 
• 
Medicinal products used to treat pulmonary TB: including but not limited to 
gatifloxacin, amikacin, cycloserine, rifabutin, kanamycin, para-aminosalicylic acid, 
rifapentine, thioacetazone, capreomycin, other quinolones, thioamides, and 
metronidazole. 
The following medicinal products should be avoided from Day 1 (Baseline visit) and during the 
treatment period as much as possible (unless this is required for emergency management of 
the participant). Investigators may also contact the Sponsor Medical Monitor for further 
guidance. 
• 
Any drug known to prolong QTc interval (including but not limited to amiodarone, 
bepridil, chloroquine, chlorpromazine, cisapride, clarithromycin, disopyramide 
dofetilide, domperidone, droperidol, erythromycin, halofantrine, haloperidol, 
ibutilide, levomethadyl, mesoridazine, methadone, pentamidine, pimozide, 
procainamide, quinidine, sotalol, sparfloxacin, thioridazine). The exception is 
moxifloxacin and bedaquiline administered as part of the trial IMP, with ECG 
monitoring, to help ensure participant safety. 
• 
Any 
drug 
known 
to 
be 
hepatotoxic 
(including 
but 
not 
limited 
to 
acetaminophen/paracetamol, 
acetazolamide, 
allopurinol, 
amiodarone, 
amitriptyline, amoxicillin, amprenavir, atorvastatin, augmentin/co-amoxiclav, 
azathioprine, baclofen, bumetanide, captopril, carbamazepine, celecoxib, 
chlorpromazine, 
chlorpromazine, 
clindamycin, 
clopidogrel, 
co-trimoxazole, 
darunavir, delavirdine, diclofenac, doxycycline, enalapril, fluconazole, fluoxetine, 
fosamprenavir, furosemide, gliclazide, glimeperide, glipizide, ibuprofen, irbesartan, 
ketoconazole, 
lisinopril, 
loperamide, 
losartan, methotrexate, 
metolazone, 
mirtazepine, nitrofurantoin, omeprazole, other non-steroidal anti-inflammatory 
drugs, paroxetine, phenobarbital, phenothiazines, phenytoin, pravastatin, 
probenecid, prochlorperazine, risperidone, rosuvastatin, sertraline, simeprevir, 
simvastatin, sodium valproate, sotalol, sulfasalazine, sumatriptan, tamsulosin, 
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terbinafine, tetracycline, theophyllin/uniphyllin, tipranavir, tolazamide, tolbutamide, 
topiramate, trazodone, tricyclic antidepressants, trimethoprim, verapamil).  
 
5.4 
Treatment Discontinuation and/or Early Withdrawal  
Any participant for whom the Investigator decides to temporarily discontinue their IMP is to be 
discussed with the Sponsor Medical Monitor and, if applicable, be restarted on IMP as soon 
as possible.  
A participant must be prematurely withdrawn from the trial (during the trial treatment or follow-
up periods) because of the following: 
• 
Withdrawal of informed consent 
• 
Investigator considers that for safety reasons it is in the best interest of the participant 
that he/she be withdrawn, including a concern that the participant has symptomatic TB 
and/or bacteriological failure/relapse and requires a change in TB treatment 
• 
Pregnancy 
• 
At the specific request of the Sponsor or termination of the trial by the Sponsor 
• 
Lost to follow-up 
• 
When Phenotypic DST and whole genome sequencing (WGS) results on baseline 
samples become available, any results that are discordant with the screening molecular 
test results used to qualify a participant’s eligibility for the trial will be reviewed by the 
Sponsor Medical Monitor in consultation with the Investigator to determine whether that 
participant is unlikely to respond to treatment and should therefore be removed from the 
trial and given alternative treatment.  If a participant is removed from the trial for such a 
reason, they will be classified as a late exclusion. 
A participant may withdraw from the trial at any time at his/her request (withdrawal of consent), 
or may be withdrawn at any time at the discretion of the Investigator for safety, behavioural, 
compliance or administrative issues.  
When a participant withdraws consent from the trial, no additional follow-up visits will be 
performed. 
Participants who withdraw from the trial after having received IMP will not be replaced.  
All participants withdrawn from trial and who received at least one dose of IMP will be 
requested to return for an Early Withdrawal visit and the applicable safety Follow-Up visits, as 
per the Synopsis Flow Chart and Procedures (Section 1.2 footnote c), as well as Table 5. 
5.4.1 
Early Withdrawal 
In case of early withdrawal during the treatment or follow-up period, all efforts shall be made 
to complete the Early Withdrawal assessments.  At the Early Withdrawal visit the following 
information will be collected and procedures performed: 
• 
Sputum sample collection x 2 (one EMS brought from home and one spot at the research 
site under the coaching and observation of the trial staff).  If no EMS was provided by the 
participant, 2 spot samples may be collected at the site, at least 30 minutes apart. 
• 
Urine pregnancy test (women of child bearing potential, whether they are sexually active 
or not) 
• 
Laboratory safety sampling (including male reproductive hormone tests); 
• 
Single 12-lead ECG 
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• 
TB Symptoms Profile 
• 
Patient Reported Health Status Questionnaire 
• 
Vital signs 
• 
Full physical examination, including weight 
• 
Ophthalmology examination, if required as described in Table 5 
• 
IMP compliance check (if participant on IMP) 
• 
Concomitant medications 
• 
Adverse events 
Once a participant has been withdrawn early from the trial, they will be requested to attend 
follow-up visits as described in Table 5: 
Table 5: Follow-up Visits Required for Early Withdrawal Participants 
Treatment 
Duration at 
EWD visit 
Ophthalmology 
Examination at 
EWDa 
Ophthalmology 
Examination  
 
Visit 3 months 
after EWD Visita 
Week 52  
(Month12) 
Follow-up 
Visit 
Week 104 
(Month 24) 
Follow-up 
Visit 
≤ 14 days 
Not required 
Not required 
Required 
Required 
15 days to      
≤ 12 weeks 
Not required 
Required 
Required 
Required 
> 12 weeks  
Required 
Required 
Required, if 
not already 
performed 
Required 
a. If an additional visit is required for an ophthalmology examination after EWD, only the 
ophthalmology examination will be performed at this visit, and it will occur 3 months after 
the EWD visit date. 
The Weeks 52 and 104 visits will be performed to collect SAE information (including 
verification of survival) and participant reported TB outcome information.  This visit may be 
telephonic, a home or a site visit at Weeks 52 and/or Week 104 after the participants’ start of 
treatment date. 
5.4.2 
Unscheduled Visits 
Any visit which is conducted in addition to those required by the Synopsis Flow Chart and 
Procedures (Section 1.2), should be considered unscheduled regardless of the reason for the 
visit. The assessments which are undertaken as part of an Unscheduled visit should be as 
clinically indicated.  
The following situation/s would require an unscheduled visit/s: 
• 
For any medical reason, as determined by the investigator or participant. 
• 
If both sputum samples (EMS and spot) at Week 8 or later are contaminated, the 
participant should return for an unscheduled visit/s to give additional sputum samples 
or to document that the participant is not able to produce sputum. 
• 
If after having converted to culture negative, the participant has a MTB confirmed 
positive culture at or after the last visit of the treatment period (Week 17 or Week 26), 
the participant should return for an unscheduled visit/s to provide additional sputum 
samples, at a minimum of 7 days apart, or to document that the participant is not able 
to produce sputum sample.  
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Determination of the participant’s primary outcome status requires sputum culture results at 
the following time-points during the trial:  
o End of Follow-up Period (Week 52 and 104) 
o Early Withdrawal, if applicable 
 
At least one of the following criteria should be met at these time-points to confirm a 
participant’s primary outcome status: 
 
o two sequential negative sputum culture results; or  
o two sequential positive sputum culture results; or  
o has been unable to produce sputum after documentation of two negative 
sputum cultures with no intervening positive and the participant is clinically 
asymptomatic 
Should the participant’s primary outcome not meet any of the above criteria, the Investigator 
should continue to recall the participant for a Unscheduled visit to collect sputum samples until 
the criteria is met and the primary outcome can be determined. 
Additional sputum samples: Two samples at each visit – ideally, one EMS and one spot 
sputum at the research site under the coaching and observation of the trial staff. If no EMS 
was provided by the participant, 2 spot sputum samples may be collected on site, at least 30 
minutes apart. Additional sputum samples should be collected at least 7 days after the 
previous sample.  
Table 
6: 
Summary 
of 
Scenarios 
Requiring 
Unscheduled 
Visits 
for 
Mycobacteriology Testing 
Time-point 
Scenario 
Unscheduled 
Visit/s 
Required? 
Comment 
Week 8 or later 
Both sputum cultures are 
contaminated 
Yes 
Provide additional samples 
until a positive or negative 
result is reported, or it is 
confirmed that the participant 
is unable to produce sputum 
At or after the last 
treatment visit 
(Week 17 or Week 
26) 
Previously converted to 
culture negative but now 
has an MTB-positive 
culture 
Yes 
Provide additional samples at 
least 7 days after the 
previous sample until the 
result is confirmed, or it is 
confirmed that the participant 
is unable to produce sputum.  
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End of Follow-up 
Period (Week 52 
and 104)  
Early 
Withdrawal, if 
applicable 
Participant’s primary 
outcome status cannot be 
confirmed by: 
Two sequential negative 
sputum culture results; or   
two sequential positive 
sputum culture results; 
or has been unable to 
produce sputum after 
documentation of two 
negative sputum cultures 
with no intervening positive 
and are clinically 
asymptomatic 
Yes 
Provide additional samples at 
least 7 days after the 
previous sample until one of 
the criteria is met and the 
primary outcome status can 
be determined.  
 
If the Investigator is unsure of the outcome in any of the above scenarios the Investigator 
should contact the Sponsor Medical Monitor to discuss and agree on how the participant is to 
be managed. 
5.4.3 
Lost-to-Follow-up 
Every reasonable attempt must be made to minimise Lost-to-Follow-up (LTFU) participants.  
A minimum of three contact attempts (telephonic/home visit) will be made for participants who 
do not arrive for their scheduled trial visits. If these attempts are unsuccessful the participant 
will be considered LTFU.  All attempts to contact the participant must be clearly documented 
in the participant’s source documents. 
5.4.4 
Early Withdrawal due to TB 
Ultimately it is the Investigator’s decision whether a participant requires early withdrawal from 
the trial due to a concern that the participant has symptomatic worsening of TB and/or 
bacteriological failure/relapse.  
Early withdrawal is usually not indicated for a single positive culture.  Should a participant have 
a single positive culture result after being culture negative, the Investigator is to evaluate 
whether the participant has signs and symptoms suggestive of active inadequately treated TB 
and whether it is in the participants best interest that he/she be withdrawn. Prior to early 
withdrawal of a participant due to TB, the Investigator must discuss the participant with the 
Sponsor Medical Monitor, unless the Investigator cannot contact the Sponsor Medical Monitor 
and considers that early withdrawal must occur immediately due to immediate safety concerns 
with respect to the participant. 
If the Investigator decides to withdraw a participant due to TB, additional sputum samples may 
need to be collected to ensure the participant’s outcome status as determined in Section 5.5. 
All early withdrawn participants who are confirmed sputum positive (two sequential sputum 
positive cultures) and/or have symptomatic TB will require further TB treatment. These 
participants will be referred to their applicable DS/DR local community TB clinics for standard 
anti-tuberculosis chemotherapy according to National TB Treatment Guidelines.  
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The participants will be provided with a referral letter from the Investigator to take with them 
to their National Treatment Program (NTP) clinic and the referral letter, at a minimum, should 
include 
all 
treatment 
received 
by 
the 
participant 
and 
information 
about 
any 
suspected/confirmed adverse event/reaction related to any of the trial IMP’s and or 
concomitant medications.  A follow-up call should be made by the trial site staff to the clinic to 
ensure the participant attended the NTP clinic.  
5.5 
Participant Progress Definitions 
Table 7: Participant Progress Definitions 
Status 
Treatment 
Follow-Up 
Screen Failure 
Participants from whom informed consent is obtained and is 
documented in writing (i.e., participant signs an informed consent form) 
but who are not randomized 
Completed 
Treatment / 
Completed 
Follow-Up* 
Participants who complete 
the full course of IMP 
Participants who complete all follow-up 
visits 
Completed 
Treatment / 
Discontinued 
Follow-Up 
Participants who complete 
the full course of IMP 
Participants who do not complete all 
applicable follow-up visits, regardless of 
the reason (excluding LTFU) 
Completed 
Treatment / Lost 
to Follow-Up 
Participants who complete 
the full course of IMP 
Participants who are unable to be 
contacted on or before their final visit 
Discontinued 
Treatment / 
Completed FU 
Participants who discontinue 
IMP prior to completion of 
the protocol-defined 
treatment course 
Participants who complete all applicable 
follow-up visits 
Discontinued 
Treatment / 
Discontinued 
Follow-Up** 
Participants who discontinue 
IMP prior to completion of 
the protocol-defined 
treatment course 
Participants who do not complete all 
applicable follow-up visits, regardless of 
the reason (excluding LTFU) 
Lost to Follow-Up 
Participants who are unable to be contacted on or before their final 
treatment visit and it cannot be confirmed whether treatment was 
completed 
* 
Note that this includes treatment failures who complete all applicable follow-up visits 
** 
Early Withdrawal 
5.6 
Trial Stopping Rules 
There are no trial specific stopping rules.  
The trial or parts of the trial can be stopped by the Sponsor on advice from the Data Safety 
and Monitoring Committee (DSMC) after their review of applicable trial data.  In addition, the 
Sponsor has the right to stop the trial or a specific trial site at any time, although this should 
only occur after consultation between the involved parties.  Should this occur, the local and 
central Ethics Committee/Institutional Review Board (EC/IRB) and Regulatory Authorities will 
be informed.   
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Should a trial site be closed prematurely, all trial materials (except source documentation that 
must remain at the site) will be returned to the Sponsor or applicable vendor.   The Investigator 
will retain all other documents until notification given by the Sponsor for destruction.  
Participants currently on trial IMP will receive an appropriate regimen and all participants will 
be referred to their applicable DS-TB/DR-TB NTP clinic. 
6.0 
Treatment 
6.1 
IMP Administration  
6.1.1 
Instructions for Dosing of Test Regimen (BPaMZ):  
• 
Treatment will be orally administered once daily, to be taken during breakfast, with a 
full glass of water (approximately 240 ml), for 17 weeks (4 months) or 26 weeks (6 
months). 
 
6.1.2 
Instructions for Dosing Control Treatment Regimen (HRZE/HR): 
• 
To be taken with a glass of water (approximately 240 ml). 
• 
HRZE or HR should not be taken with a meal (generally, no closer to meals than 1 
hour before or 2 hours after a meal) in the following dosing schemes. 
HRZE/HR treatment will be administered orally once daily to DS-TB participants as follows: 
Weight Band 
Weight Range 
Number of tablets 
per weight band 
1 
30-39 kg 
2 
2 
40-54 kg 
3 
3 
55-70 kg 
4 
4 
≥ 71 kg 
5 
 
The participant’s weight at the Screening (HRZE) and Week 8 (HR) visits will be used to 
determine which weight band and dose to administer. 
 
A daily supplement of Vitamin B6 will be provided by the trial site to participants randomised 
to the HRZE/HR treatment arm, per each country’s National TB Treatment Guideline.   
6.2 
Participant Compliance 
During site clinic visits, the IMP will be administered by the Investigator(s)/designated site 
personnel and when possible, the check for IMP compliance via the hand-and-mouth 
procedure (both the hand and the mouth of the participant will be checked to ensure that the 
participant has swallowed the IMP). During the trial, sites will be responsible for ensuring 
participants are taking IMP correctly and are fully trained on how the IMP is to be taken, as 
well as to check the IMP cards for unused tablets in the containers at each visit during the 
treatment phase.  
6.3 
Treatment Modification(s) 
The importance of adherence to the treatment schedule will be reinforced at each visit.  Non-
adherence should prompt the Investigator to identify and address the cause(s) (e.g. side 
effects).  
 
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Participants that do not take: 
 
• 
Up to 7 consecutive doses of IMP doses: restart IMP, no extension of IMP required. 
• 
If more than 7 to ≤ 35 consecutive doses of IMP: restart IMP and extend the IMP 
treatment by the number of consecutive doses missed. The final treatment visit 
should also be pushed out to the date of last dose. It is not necessary to have an 
unscheduled visit at the time when the end of treatment visit would have been.   
• 
If more than 35 consecutive doses of IMP, discontinue IMP and withdraw participant 
from the trial. 
• 
If the participant misses a total (sum) of 56 cumulative missed doses, discontinue the 
IMP and withdraw the participant from the trial. 
• 
If more than 7 to ≤ 35 consecutive doses are missed, these must be made up with 
the same treatment combination or dose that was missed. 
Any participant for whom the trial IMP is discontinued (including for non-adherence) will be 
discussed with the Sponsor Medical Monitor and, if applicable, the participant will be restarted 
on trial IMP as soon as possible.  
6.4 
IMP Packaging and Labelling 
The complete formulations of the IMP, bedaquiline and pretomanid, are found in the respective 
Investigator Brochures.[8, 15] The complete formulations of moxifloxacin, pyrazinamide, 
HRZE/HR are found in the Package Inserts.[19, 20, 22, 40]  
The IMP will be packaged in weekly or bi-weekly cards as follows: 
Week 1 to 8 Cards: Dispensed Weekly 
IMP 
Strength 
Number of tablets 
Abbreviation 
Bedaquiline 
100 mg 
14 
B 
Pretomanid 
200 mg 
7 
Pa 
Moxifloxacin 
400 mg 
7 
M 
Pyrazinamide 
500 mg 
21 
Z 
 
Week 9 to 17/26 Cards: Dispensed Weekly 
IMP 
Strength 
Number of tablets 
Abbreviation 
Bedaquiline 
100 mg 
7 
B 
Pretomanid 
200 mg 
7 
Pa 
Moxifloxacin 
400 mg 
7 
M 
Pyrazinamide 
500 mg 
21 
Z 
 
Control (HRZE/HR) Group: Dispensed Bi-weekly 
Weight Band 
Weight Range 
Number of tablets 
per weight band 
Number of tablets 
in each card 
1 
30-39 kg 
2 
28 
2 
40-54 kg 
3 
42 
3 
55-70 kg 
4 
56 
4 
≥71 kg 
5 
70 
 
A daily supplement of Vitamin B6 will be provided by the trial site to participants randomised 
to the HRZE/HR treatment arm, per each country’s National TB Treatment Guideline. 
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The packaging of each weekly and biweekly cards will be labelled with, at a minimum, the 
following information: 
• 
Name of Sponsor 
• 
Name of medication 
• 
Dosage, quantity and method of administration  
• 
Reference/lot number 
• 
The statement “For Clinical Trial Use Only” 
• 
Space for completion of name of Investigator and site number 
• 
MedID: medication identification number 
• 
Storage conditions 
• 
Period of use 
• 
The statement “Keep out of reach of children” 
• 
Expiry date 
• 
Directions for use 
• 
Space for completion of participant number and visit/date dispensed 
6.5 
Blinding and Procedures for Breaking the Blind 
As this is an open label trial there is no need for blinding or procedures to break the blind. The 
trial participants, the site staff, Sponsor, and CROs will not be blinded to treatment assignment.  
6.6 
Handling, Storage and Accountability  
The Investigator or designee must confirm that the appropriate temperature conditions as per 
details on IMP labelling, have been maintained during transit for all trial IMP received and any 
discrepancies are reported and resolved before use of the trial IMP. 
Only participants randomised in the trial may receive trial IMP and only authorized site staff 
may supply or administer trial IMP. All trial IMP’s must be stored in a secure, environmentally 
controlled, and monitored (manual or automated) area in accordance with the labelled storage 
conditions with access limited to the Investigator and authorized site staff. 
The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for trial IMP accountability, reconciliation, and record maintenance (i.e., receipt, 
reconciliation, and final disposition records).  Upon completion or termination of the trial, all 
unused and/or partially used IMPs must either be returned to Sponsor (or designated vendor: 
who will arrange for destruction) or destroyed at site as agreed by the Sponsor, after final 
accountability has been confirmed. 
The Investigator/designee will immediately inform the Sponsor of any quality issues arising 
with respect to the trial IMP. The Sponsor will take whatever action is required should such a 
situation arise. 
Further guidance and information for the handling, storage, accountability and final disposition 
of unused trial IMPs are provided in the Pharmacy Manual. 
7.0 
Trial Variables and Procedures 
The Synopsis Flowchart and Procedures in (Section 1.2) should be referenced for timing, 
sequence of assessments, and specific procedures. 
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7.1 
Demographic and Background Variables and Procedures 
The following demographic and background variables will be collected: 
• 
Written Informed Consent 
• 
Visit dates 
• 
Participant disposition 
• 
Demography (date of birth, race and gender) 
• 
Inclusion and exclusion criteria 
• 
Clinically significant medical and TB treatment history (including past and current TB 
diagnosis, smoking and alcohol use) 
• 
Screening coached spot sputum samples: 
 
o Smear microscopy for acid-fast bacilli 
o Rapid molecular tests for isoniazid, rifampicin, fluoroquinolones resistance (Hain 
MTBDRplus and HainMTBRsl) 
o Liquid Culture (MGIT) for Mycobacterium tuberculosis (MTB), followed by a 
speciation test to detect presence or absence of MTB and obtain time to positivity 
(TTP) when positive. 
 
• 
Urine pregnancy test: women of childbearing potential only, whether they are sexually 
active or not (non-childbearing potential for a female participant is defined as having 
bilateral oophorectomy, bilateral tubal ligation and/or hysterectomy or has been 
postmenopausal with a history of no menses for at least 12 consecutive months). 
• 
Serology: HIV and CD4 count.  Where required by regulatory authorities or ethics 
committees, a separate (EC/IRB approved) HIV informed consent form will be obtained 
from participants: 
 
o Prior to HIV testing and on receipt of the results, participants will be counselled on 
HIV by trained counsellors if they have indicated as such on the HIV consent form. If 
requested by the participant, HIV counselling that is provided to the participant by 
the trial site should be clearly documented in the participant’s medical 
records/source.  Participants have the right to decline to know or receive their HIV 
test results. This decision should be clearly documented in the participant’s medical 
records/source.   
• 
Karnofsky Score (Appendix 5). Only for HIV positive participants. 
• 
Chest X-Ray: A chest X-ray digital image within 6 months prior to or during the 
Screening visit, will be obtained and read locally by the Investigator or designee.  Digital 
images will be provided to the Sponsor; this process will be documented in the Chest X-
Ray / Radiology Manual.  The investigator is responsible for review and analysis of the 
chest X-ray for participant’s inclusion. 
• 
Method of birth control: male and female participants and their sexual partners 
• 
IMP details: randomization 
• 
IMP compliance and actual dosing 
• 
Concomitant medications 
7.2 
Efficacy Variables and Procedures 
Two spot sputum samples are collected, one EMS brought from home or collected in the 
hospital ward (only if the participant is hospitalised) and one spot sputum sample collected at 
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the research site under the coaching and observation of the trial staff or, if no EMS sample 
was provided by the participant, 2 samples may be collected on site at least 30 minutes apart. 
The mycobacteriology sampling methodology and requirements will be described in a 
separate document, the Mycobacteriology Laboratory Manual, which will be provided prior to 
the trial start. Sputum samples may not be obtained by induction. 
The following analyses will be performed: 
• 
Liquid culture (MGIT), to detect presence or absence of MTB and obtain the TTP 
followed by a speciation test when applicable, to confirm MTB. 
 
Using these observed variables, the following derived variables will be assessed for evaluation 
of the efficacy endpoints: 
• 
Bacteriologic failure/relapse 
• 
Time to sputum culture conversion 
• 
Number of participants with sputum culture conversion 
 
Every effort must be made to collect sputum samples. However, in general, the inability to 
produce sputum is treated as being equivalent to having a negative culture (favourable) result.  
A participant who never achieves culture negative status due to the inability to produce 
sputum, but has completed Week 17 or Week 26 and post treatment completion follow-up 
(Weeks 39 to 104) and is without clinical or biological evidence of relapse, will be considered 
to have a favourable outcome. 
TB Symptoms Profile:  
• 
The TB Symptoms Profile will record participants’ ratings of the severity of common TB 
symptoms.  
 
Patient Reported Health Status Variables and Procedures:  
• 
The Patient Reported Health Status variables will be collected at the time points 
described in the Synopsis Flow Chart and Procedures (Section 1.2). Patient Reported 
Health Status will be collected using the EQ-5D-5L Health Questionnaire (Appendix 7). 
This descriptive system consists of five health-related quality of life dimensions, each of 
which will be recorded using five levels of severity.  
 
Methodology: The Patient Reported Health Status methodology and requirements will be 
described in a separate trial Participant Questionnaires Guideline which will be provided 
prior to the trial start. 
7.3 
Safety and Tolerability Assessments 
The following safety and tolerability variables will be collected at the time points described in 
the Synopsis Flow Chart and Procedures (Section 1.2) and assessed for evaluation of the 
safety endpoints: 
• 
The safety laboratory sampling methodology and requirements will be described in a 
separate document, the Safety Laboratory Manual, which will be provided prior to the 
trial start. The following analyses will be performed: 
 
o Full Blood Count (haemoglobin, haematocrit, red blood cell count, white blood 
cell count with differential, platelet count) 
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o Clinical Chemistry (albumin, serum urea, creatinine, direct, indirect and total 
bilirubin, uric acid, total protein, ALP, AST, ALT, lipase, phosphate, sodium, 
potassium, calcium (corrected for albumin), chloride, magnesium, glucose, 
bicarbonate/CO2, creatine phosphokinase (CPK). GGT is only routinely included 
at the Screening visit (Day -9 to -1).  
o When managing participants with elevated liver enzymes at an Unscheduled visit, 
the investigator can request additional tests, in addition to the repeat LFT [e.g. 
Gamma Glutamyl Transferase (GGT), screening for Hepatitis A, B, C; to assist in 
ruling out other causes of a dysfunctional liver test (e.g. alcohol induced hepatic 
cell injury, hepatobiliary disease, hepatic viral infection)]. 
o Urinalysis (pH, specific gravity, protein, glucose, micro-albumin, ketones, 
bilirubin, creatinine, nitrite, sodium, urobilinogen, blood, leukocytes). Microscopy 
will be completed as follow up to abnormal urinalysis per discretion of Investigator 
• 
12-lead ECG: 
o Investigator assessment: normal or abnormal 
o Central cardiologist assessment: heart rate, PR interval, RR interval, QT, corrected 
QT Interval (QTc) (QTcB and QTcF), QRS. 
o Methodology: 
 
Timing (Synopsis Flow Chart and Procedures, Section 1.2) and registration 
technique for ECGs will be standardized for all participants and will be described 
in a separate document which will be provided prior to the trial start 
 
ECGs are to be recorded for 10 seconds 
 
ECGs are to be performed during a single visit 
 
ECGs should be done before any phlebotomy when both included in a visit 
 
For each participant, the ECGs should, to every extent possible, be collected at 
approximately the same time of day (+/- 1 hours) and in the same fed/fast state 
throughout the trial (e.g. 4 hours after lunch) 
o ECGs to be performed prior to pre- and post-dose PK sampling as described below: 
• 
Day 1: pre-dose (within 2 hours prior to dosing) 
• 
Week 2: pre-dose (within 2 hours prior to dosing), 1.5–3 hours post-dose and 4-6 
hours post-dose 
• 
Week 8: pre-dose (within 2 hours prior to dosing), 1.5–3 hours post-dose and 4-6 
hours post-dose 
• 
Week 12: pre-dose (within 2 hours prior to dosing)  
• 
Week 17 or at early withdrawal if prior to week 17: pre-dose (within 2 hours prior 
to dosing) and 1.5–3 hours post-dose 
• 
Vital signs: 
o Vital signs (should be done before any phlebotomy in light clothing and with no 
shoes) 
o Systolic and diastolic blood pressure (mmHg) to be measured in a supine position 
(after 5 minutes of rest) using an appropriately sized cuff, and using the same type of 
sphygmomanometer, if possible by the same observer, at each relevant visit 
o Heart rate (beats per minute) 
o Respiratory rate (breaths per minute)  
o Axillary body temperature (°C) 
• 
Physical Examination:  
o Height (m) is measured at the screening visit only 
o Full (complete) and limited (gross neurological, pulmonary, cardiovascular and 
abdominal) examinations will be performed and any clinically significant findings will 
be recorded 
o Weight (kg) (in light clothing and with no shoes) 
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o Using the variables of weight and height, the body mass index (BMI) will be 
calculated 
• 
Ophthalmology Slit Lamp Examination: 
o To be done by an Ophthalmologist trained on Age-Related Eye Disease Scale 2 
(AREDS2) assessment. The ophthalmology slit lamp methodology and requirements 
will be described in a separate document, the Ophthalmology Guideline. The 
following analyses will be performed: AREDS2 opacity typing and grading. 
• 
Adverse events 
• 
Investigator assessment:  
o The Investigator will review the participant status at specified visits in the Synopsis 
Flow Chart and Procedures (Section 1.2), including any time the Investigator 
determines that the participant fulfils the criteria for the primary outcome of treatment 
failure. The Investigator will assess whether TB treatment is considered a “success” 
or “failure”.  If it is considered a failure, the Investigator should specify if the 
assessment is based on bacteriology and/or clinical deterioration and/or radiological 
deterioration. 
7.4 
PK Variables and Procedures 
Plasma concentrations from sparse sampling (Synopsis Flow Chart and Procedures, Section 
1.2) will be used to update population PK models for bedaquiline and its M2 metabolite, 
pretomanid, moxifloxacin and pyrazinamide to further evaluate the effects of covariates on 
model parameters in this trial population. 
 
PK data from the current trial may be combined with prior data to enhance this population PK 
analysis. The models will be used to estimate individual exposure metrics (e.g., Cmin, Cmax, 
AUCτ, Cmean, and time above minimum inhibitory concentration) for subsequent analyses 
exploring relationships between drug exposure and efficacy and safety endpoints. 
 
If IMP is not administered during Week 2, 8 and or 17, then only a single PK sample is 
required to be obtained at any time during the visit assessment. 
7.5 
Mycobacteriology Characterization Variable and Procedures 
 
• 
Day 1 (Baseline) sputum sample (or any positive sample from Screening to Week 4, if 
the baseline cultures are contaminated or negative); 
• 
MTB confirmed positive cultures (after the participant has previously converted to 
negative) at or after the last visit of the treatment period (Week 17 or Week 26) or visits 
with positive cultures, during the post-treatment follow-up period. 
• 
Refer to the Mycobacteriology Laboratory Manual for full details. 
 
Mycobacterial Characterization - MTB isolates (from the first MTB positive culture) will be 
processed for: 
 
• 
Rapid molecular tests for fluoroquinolones, injectables, isoniazid and rifampicin 
resistance (only on MTB positive cultures in the follow-up period); 
• 
Minimum Inhibitory Concentration (MIC) against bedaquiline, pretomanid and 
moxifloxacin  
• 
Drug Susceptibility Testing for streptomycin, rifampicin, isoniazid, ethambutol, 
moxifloxacin and pyrazinamide in liquid culture; 
• 
Extraction of organismal (MTB) DNA for whole genome sequencing (WGS), and the 
comparison of sequences from baseline and relapse isolates. 
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If the participant’s culture converts to negative and has a MTB positive culture at or after the 
last visit of the treatment period (Week 17 and Week 26), the MTB cultures will be tested at 
the trial mycobacteriology laboratories using Hain MTBDRplus and HainMTBRsl to detect 
resistance to isoniazid, rifampicin, fluoroquinolones and injectables. 
 
All MTB isolates must be stored be stored at the local mycobacteriology laboratories, until trial 
closure. In addition, MTB isolates as well as extracted MTB DNA from the applicable baseline 
and follow-up cultures will be stored at the central mycobacteriology laboratory for potential 
further work to advance new assay tools and understanding of MTB as a pathogen for a 
maximum of 5 years after trial closure.  
 
8.0 
Adverse Events 
8.1 
Definitions 
8.1.1 
Adverse Event (AE) 
Any untoward medical occurrence in a clinical investigation participant, temporally associated 
with the use of a trial treatment whether or not considered related to trial treatment. An AE can 
therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease (new or exacerbated) temporally associated with the use of a trial 
treatment, whether or not related to the trial treatment. 
8.1.2 
Serious Adverse Event (SAE) 
Any untoward medical occurrence that at any dose: 
• 
Results in death 
• 
Is life threatening (any event in which the participant was at risk of death at the time of 
the event; it does not refer to an event, which hypothetically might have caused death 
if it were more severe) 
• 
Requires inpatient hospitalisation or prolongation of existing hospitalisation; In general, 
hospitalisation signifies that the participant has been detained (usually involving at 
least an overnight stay) at the hospital or emergency ward for observation and/or 
treatment that would not have been appropriate in the physician’s office or outpatient 
setting. Complications that occur during hospitalisation are AEs. If a complication 
prolongs hospitalisation or fulfils any other serious criteria, the event is serious. When 
in doubt as to whether “hospitalisation” occurred, or was necessary, the AE should be 
considered serious. Hospitalisation for elective treatment of a pre-existing condition 
that did not worsen from baseline is not considered an AE. 
• 
Results in persistent or significant disability/incapacity; the term disability means a 
substantial disruption of a person’s ability to conduct normal life functions. This 
definition is not intended to include experiences of relatively minor medical significance 
such as uncomplicated headache, nausea, vomiting, diarrhoea, influenza, and 
accidental trauma (e.g., sprained ankle) which may interfere with or prevent everyday 
life functions but do not constitute a substantial disruption. 
• 
Is a congenital anomaly/birth defect; or 
• 
Is a medically important event 
Note:  Medical and scientific judgment should be exercised in deciding which is a medically 
important event that may not be immediately life-threatening or result in death or 
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hospitalisation but may jeopardize the participant or may require medical or surgical 
intervention to prevent one of the outcomes listed above.   
Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias or convulsions that do not result in hospitalisation, or the 
development of drug dependency or drug abuse. A “suspected transmission of infectious 
agent by a medicinal product” is also considered a serious adverse event under the SAE 
criterion “Other medically important condition”.     
8.1.3 
Attribution/Causality 
• 
The Investigator is obligated to assess the relationship between trial treatment and 
each occurrence of each AE/SAE 
• 
The Investigator will use clinical judgment to determine the relationship 
• 
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to trial IMP administration will 
be considered and investigated 
• 
The Investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment 
• 
For each AE/SAE, the Investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality 
• 
There may be situations in which an SAE has occurred and the Investigator has 
minimal information to include in the initial report to the Sponsor/designee. However, 
it is very important that the Investigator always assesses causality for every event 
before the initial transmission of the SAE data to the Sponsor/designee. 
• 
The Investigator may change his/her opinion of causality in light of follow-up 
information and send a SAE follow-up report with the updated causality assessment 
Table 8: Adverse Events Attribution/Causality Ratings 
Relatedness Rating 
Definition 
Not Related 
An AE, which is not related to the use of the drug. 
Unlikely 
An AE for which an alternative explanation is more likely, e.g., 
concomitant drug(s) or concomitant disease(s), and/or the 
relationship in time suggests that a causal relationship is unlikely. 
Possible 
An AE, which might be due to the use of the drug.  An alternative 
explanation, e.g., concomitant drug(s) or concomitant disease(s), is 
inconclusive.  The relationship in time is reasonable; therefore, the 
causal relationship cannot be excluded. 
Probable 
An AE, which might be due to the use of the drug.  The relationship 
in time is suggestive, e.g., confirmed by de-challenge.  An alternative 
explanation is less likely, e.g., concomitant drug(s) or concomitant 
disease(s). 
Certain 
An AE, which is listed as a possible adverse reaction and cannot be 
reasonably explained by an alternative explanation, e.g., concomitant 
drug(s) or concomitant disease(s).   
 
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8.1.4 
Severity 
Table 9: Definitions for Adverse Event Severity Gradings 
Grade 
Severity Rating 
Definition 
GRADE 1 
Mild 
Transient or mild discomfort (< 48 hours); no medical 
intervention/therapy required. 
GRADE 2 
Moderate 
Mild to moderate limitation in activity - some assistance 
may be needed; no or minimal medical intervention/therapy 
required. 
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. 
 
See Appendix 2 for full DMID Toxicity Tables. Above ratings should be used to estimate the 
grade for abnormalities NOT found elsewhere in the Toxicity Tables. 
8.2 
Reporting 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about AE 
occurrences. 
All AEs will be collected by the Investigator from the time a participant signs the Informed 
Consent Form through to their Week 104 follow-up visit. The exception to this is early 
withdrawal participants who will only have SAEs collected from their time of early withdrawal 
to their Week 104 follow-up visit at the timepoints specified in the Synopsis Flow Chart and 
Procedures (Section 1.2) and recorded in the CRF.   
Medical occurrences that begin after obtaining informed consent will be recorded as AEs. If 
an AE started before signing of the informed consent, but is ongoing at trial start, it should be 
recorded as medical history.  If the pre-existing medical occurrence worsens during the trial, 
an AE will be recorded. 
All SAEs will be recorded and reported to the Sponsor or designee within 24 hours of the 
information becoming known to the Investigator, as noted in the SAE reporting guidelines. The 
Investigator will submit any updated SAE data to the Sponsor within 24 hours of information 
becoming known to the Investigator.  
The Sponsor/Investigator/designee will inform Regulatory Authorities and/or EC/IRB of all 
SAEs in accordance with local requirements and ICH guidelines for GCP. 
The Sponsor/designee will forward Safety Notification letters to the Investigator for submission 
to the EC/IRB. 
Investigators are not obligated to actively seek AE or SAE information in former trial 
participants. However, if the Investigator learns of any SAE, including a death, at any time 
after a participant has been discharged from the trial, and he/she considers the event to be 
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reasonably related to the trial IMP or trial participation, the Investigator must promptly notify 
the Sponsor, EC/IRB and regulatory authorities in an expedited basis, in accordance with local 
requirements and ICH GCP Guidelines. 
8.2.1 
Follow up of Adverse Events 
All AEs will be followed until: 
• 
Satisfactory clinical resolution or stabilization; or 
• 
The end of the follow-up period; and  
• 
All queries on these AEs have been resolved.   
Certain long-term AEs cannot be followed until resolution within the setting of this protocol. In 
these cases, follow-up will be the responsibility of the Investigator.  However, this will have to 
be agreed upon with the Sponsor Medical Monitor. 
The Investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor or 
representative to elucidate the nature and/or causality of the AE or SAE as fully as possible. 
This may include additional laboratory tests or investigations, histopathological examinations, 
or consultation with other health care professionals.  The Investigator should contact the 
Sponsor/designee to discuss appropriate medical follow-up if consultation is required.  
If a participant dies during participation in the trial or during a recognized follow-up period, the 
Investigator will provide the Sponsor/representative with a copy of any post-mortem findings, 
including histopathology. 
New or updated SAE information will be recorded in the originally completed CRF and 
submitted to the Sponsor within 24 hours of receipt, per the eCRF completion guidelines. 
8.2.2 
Clinical Laboratory Adverse Events 
Changes in the results of the clinical laboratory assessment results and which the Investigator 
determines are clinically significant will be reported as AEs.  It is the Investigators’ 
responsibility to review the results of all laboratory tests as they become available.  This review 
must be documented by the Investigators’ dated signature on the laboratory report.  For each 
abnormal laboratory test result, the Investigator needs to ascertain and document if this is a 
clinically significant change from baseline for that individual participant.  This determination, 
however, does not necessarily need to be made the first time an abnormal value is observed.  
The Investigator may repeat the laboratory test or request additional tests to verify the results 
of the original laboratory tests.  If this laboratory value is determined by the Investigator to be 
a clinically significant change from baseline for that participant, it is considered to be an AE. 
8.2.3 
Disease Symptoms During Trial 
Symptoms of the disease under trial (Tuberculosis) experienced by the participant while on 
the trial will be assessed by the Investigator.  If the symptom has: 
o worsened while the participant is in the trial; and  
o the Investigator assesses it as clinically significant; 
it will be recorded as an adverse event. If there is: 
o no change; and  
o the Investigator assesses the symptom as due to the participant’s TB; and  
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o not clinically significant; 
it will not be recorded as an AE and this will be noted in the participant’s source documentation. 
All TB related symptoms that meet SAE criteria will be recorded and reported as a SAE. 
8.2.4 
Overdose 
Overdose of the IMP experienced by the participant while on the trial, will be assessed by the 
Investigator to determine whether the overdose led to an adverse event, including if the taking 
of the suspected medicine led to suicidal intention and subsequent overdose of the suspected 
medicine, or other medication. In this case it will be recorded as an adverse event. If it does 
not lead to an adverse event, it will not be recorded as an AE and this will be noted in the 
participant’s source documentation. 
8.2.5 
Drug Interaction 
If the Investigator becomes aware that the participant has experienced a drug interaction 
which has resulted in an adverse event, it will be recorded as an adverse event. 
8.2.6 
Pregnancy 
The Investigator will immediately notify the Sponsor of any pregnancy that is discovered during 
IMP administration or which started during IMP administration.  Pregnancy forms will be 
completed for all pregnancies reported during the clinical trial, as defined below. In addition, 
the Investigator will report to the Sponsor any follow up information regarding the outcome of 
the pregnancy, including perinatal and neonatal outcome.  Infants will be followed-up for 6 
months.   
All women of childbearing potential will be instructed to contact the investigator immediately if 
they suspect they might be pregnant (for example, missed or late menses) at any time during 
the trial. 
If a pregnancy is suspected while the participant is receiving IMP, the IMP will be withheld 
immediately until the result of the pregnancy test is known.  If pregnancy is confirmed, the IMP 
will be permanently discontinued in an appropriate manner and the participant withdrawn from 
the trial and referred to the NTP for further management.  
Protocol-required procedures for trial discontinuation and follow-up will be performed unless 
contraindicated by the pregnancy. 
Pregnancy reporting will follow the same timelines for a SAE (see above). Instructions and 
forms will be provided separately. SAE reporting will also occur if the pregnancy outcome is a 
congenital anomaly.  This will follow the reporting procedures described above for SAE 
reporting. 
8.3 
Monitoring for Specific Toxicities  
Monitoring for specific toxicities is based upon target organs as defined in the preclinical 
toxicity studies of the Investigator’s Brochures[8, 15] and Package Inserts.[19, 20, 22, 40] 
AEs still ongoing at the end of the treatment period in the trial will be followed until satisfactory 
clinical resolution or stabilization, or until the end of the follow-up period and until all queries 
on these AEs have been resolved.   
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Grade 3 and Grade 4 laboratory abnormalities, and laboratory abnormalities considered 
clinically significant should be followed until satisfactory resolution or stabilization. 
Note: For Grade 3 or 4 laboratory toxicities, participants should have a confirmatory 
measurement within 48 hours, where possible. The recommendations for managing 
participants below assumes that the laboratory abnormalities of concern have been 
confirmed. 
 
8.3.1 
ALT, AST and Bilirubin Elevations 
The Investigator should refer to the Hepatotoxicity Management Guideline, to appropriately 
monitor significant elevations of AST, ALT or Bilirubin. A separate Hepatoxicity Management 
Guideline document has been developed to aid investigators in the management of 
participants. 
When managing participants with elevated liver enzymes at an Unscheduled visit, the 
investigator can request additional tests, in addition to the repeat LFT [e.g. Gamma Glutamyl 
Transferase (GGT), screening for Hepatitis A, B, C; to assist in ruling out other causes of a 
dysfunctional liver test (e.g. alcohol induced hepatic cell injury, hepatobiliary disease, hepatic 
viral infection)]. 
8.3.2 
Lipase 
Grade 3 (> 2.0 to ≤ 5.0 x ULN) or Grade 4 (> 5.0 x ULN): 
• 
Contact the Sponsor Medical Monitor to review. Participants with confirmed Grade 3 
or 4 elevations of lipase, the Investigator should consider pausing the full regimen, 
pending further evaluation. 
8.3.3 
Musculoskeletal System and Cardiac Muscle Myalgia 
Grade 2 (muscle tenderness at a site other than sites of injection and/or venepuncture or with 
moderate impairment of activity) or Grade 3 (severe muscle tenderness with marked 
impairment of activity) or Grade 4 (frank myonecrosis): 
• 
Participants with Grade 2 signs and symptoms should be followed closely. Participants 
with Grade 3 or 4 signs and symptoms should be discussed with the Sponsor Medical 
Monitor to consider pausing trial IMP, pending further evaluation. 
8.3.4 
Cardiac Rhythm Disturbances 
Cardiac rhythm disturbances that are Grade 3 (recurrent, persistent, symptomatic arrhythmia 
requiring treatment) or Grade 4 (unstable dysrhythmia requiring treatment): 
• 
Participants should be monitored closely.  The Investigator should discuss with the 
Sponsor Medical Monitor to consider pausing the full regimen, pending further 
evaluation. 
QTc prolongation  
If QTcF is equal to or greater than 500 msec, the ECG should be repeated and serum 
electrolytes should be evaluated. If the second ECG also has a QTcF of > 500 msec, the 
Sponsor Medical Monitor should be consulted to consider pausing the full regimen, pending 
further evaluation. 
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New left bundle branch block (LBBB) or Mobitz type 2 or complete heart block. Recordings 
with artifacts that interfere with the interpretation of the ECG should be repeated to confirm 
the findings. If the finding is from the centralized ECG machine reading the result is to be 
checked and confirmed by the Investigator.  If this is confirmed by the Investigator, dosing is 
to be paused until the reading has been confirmed by the central cardiologist and the 
participant is to be treated per the Investigator’s clinical judgment. If it is confirmed by the 
central cardiologist, the participant is to be withdrawn from the full regimen.  Contact Sponsor 
Medical Monitor to review.  
8.4 
Safety Monitoring by Data Monitoring Committee 
A Data Safety Monitoring Committee (DSMC) will be appointed for the trial. The primary 
responsibility of the DSMC will be to act in an advisory capacity to the Sponsor to safeguard 
the interests of trial participants by monitoring participant safety, assess participant risk versus 
benefit, and assess data quality and general evaluation of the trial progress. Its activities will 
be delineated in a DSMC Charter that will define the membership, responsibilities and the 
scope and frequency of data reviews.  
The DSMC will operate on a conflict-free basis independently of the Sponsor and the trial 
team. It will comprise at least 3 voting members that include at least 2 clinicians and one 
statistician.   
The DSMC may have an organizational meeting prior to commencement of the trial. The 
DSMC will have meetings where it will review unblinded data during a closed session. These 
meetings will be planned at regular intervals.  
The Sponsor or the DSMC may convene ad hoc meetings based on rates of SAEs and/or to 
review results of the futility analysis, or if safety concerns arise during the trial.  After its 
assessment, the DSMC will recommend to the Sponsor continuation, modification or 
termination of the clinical trial.  
9.0 
Statistical Analysis 
The statistical analysis plan (SAP), which will contain details of the analyses specified in this 
section, will be written and signed off prior to the interim analysis. 
There will be 3 data analyses and trial reports generated for this trial:  
 
1. When all participants have completed 8 weeks (2 months) of treatment from 
baseline.  
2. When all participants have completed 52 weeks (12 months) follow-up from start of 
therapy. 
3. When all participants have completed 104 weeks (24 months) follow-up from start of 
therapy.  
9.1 
Analysis Populations 
There will be three main analyses of the primary efficacy endpoint: An intent to treat (ITT) 
analysis; a modified intent to treat (mITT) analysis and a per protocol (PP) analysis 
• 
The ITT population is defined as all randomized participants excluding late screening 
failures. Late screening failures are participants withdrawn from treatment because 
they were found to be ineligible (late exclusions from the trial), based on data collected 
prior to randomization. 
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• 
The mITT population is defined as the ITT population with extra exclusions (described 
in the SAP). 
• 
The PP population is defined as the mITT population with extra exclusions (described 
in the SAP). 
• 
The mITT analysis will be considered primary, with consistent findings required from 
the other main analysis populations to support the primary conclusion. 
9.2 
Sample Size 
For the primary endpoint, time-to-culture conversion at 8 weeks,150 participants per arm (DS-
TB participants) will provide at more than 90% power (5% 2-sided significance) to detect a 
hazard ratio (HR) of at least 2 assuming 50% of control participants are culture negative by 8 
weeks. If only 25% of the control arm remain culture positive at 8 weeks, then this sample size 
will still retain more than 90% power to detect a HR of least 2.  This sample size also allows 
for one planned interim analysis of the primary endpoint (See Section 9.4.1) 
For the key secondary endpoint of clinical outcome at 12 months from randomization, 150 
patients per arm will provide 74% power based on assumptions using data from the largest 
most recent and completed phase 3 TB treatment trial which used the same control arm.[41]  
That is, assuming 16% unfavourable (see Section 9.4.2) in the control arm and 13% 
unassessable (see Section 9.6) at 52 weeks post randomization. A 12% margin of non-
inferiority was chosen to preserve at least 75% of the estimated control arm effect against 
placebo (estimated to be 54%)[41, 42] which is considered an acceptable proportion on which to 
declare non-inferiority of the test regimen. 
9.3 
Interim Analyses 
There is one planned interim efficacy analysis which will occur after approximately 60 
assessable participants have been randomised to the control arm and have reached the 8-
week primary endpoint. Time to culture negative status in liquid media up to 8 weeks will be 
analysed using a Cox regression model, censoring for death and lost to follow up/withdrawal 
to estimate the hazard ratio (HR). Following a review of these interim findings, the following 
considerations will be given to modify the trial objectives and sample size: 
If the observed HR (time to culture negativity, experimental arm vs. HRZE control arm) is >2, 
the sample size may be increased to adequately power the trial on the key secondary efficacy 
endpoint (clinical and microbiological outcome at 52 weeks from randomization), which will 
then become the primary efficacy endpoint. The trial efficacy objectives will be updated as 
follows: 
- 
Primary Objective 
To determine the incidence of bacteriologic failure or relapse or clinical failure at 52 
weeks from the start of treatment / randomisation.  
- 
Secondary Objectives 
To evaluate the time to culture negativity over 8 weeks, from the start of treatment / 
randomisation. 
All other trial objectives will remain unchanged. 
To achieve 90% power and overall 5% 2-sided significance after adjusting for the 
interim analysis, this will mean increasing the sample size to 225 participants per randomised 
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arm, i.e., to a total of 450 DS-TB participants (and up to 225 DR-TB participants). This 
adaptation is based on the Multi-arm Multi-stage (MAMS) framework [46,47,48] and full details 
are provided in the Statistical Analysis Plan.  
9.4 
Primary and Secondary Efficacy Endpoint Analysis 
9.4.1 
Primary Efficacy Endpoint, Time to Culture Conversion at 8 Weeks 
The primary analysis will be conducted using culture results from liquid culture (MGIT) media. 
Participants will be classified as being culture positive, culture negative, dead or unassessable 
at 8 weeks.  The proportion culture negative will be those classified as being culture negative 
divided by the total considered culture negative, culture positive or have died. This proportion 
will be estimated from the Kaplan Meier estimates from the time to culture conversion to 
negative status analysis and groups compared using a hazard ratio and 95% confidence 
interval. 
Non-inferiority of the key secondary endpoint of clinical outcome will be assessed using the 
upper bound of the one-sided 97.5% confidence interval for the difference between the 
proportion of participants who are classified as having an unfavourable status on the 
intervention less the control regimen.  If the upper bound of the one-sided 97.5% confidence 
limit for this difference in proportions is less than 12% (the margin of inferiority) the intervention 
will be non-inferior to the control arm. 
9.4.2 
Key Secondary Efficacy Endpoint, Clinical Outcome at 52 Weeks from 
Randomization  
For the key secondary endpoint of clinical outcome (bacteriologic failure or relapse or clinical 
failure), participants will be classified as having a favourable, unfavourable or unassessable 
outcome status which will be defined in detail in the SAP.  In general, participants achieving 
and maintaining culture negative status without any additional treatment will be considered 
favourable; participants who fail on treatment or relapse in follow-up will be considered 
unfavourable and participants who are not assessable (and who have not already been 
declared as unfavourable) will be considered unassessable and excluded from the analysis. 
9.4.3 
Other Secondary Efficacy Endpoints 
The secondary efficacy endpoints and analyses are as follows are: 
• 
Clinical outcome (bacteriologic failure or relapse or clinical failure) at 104 weeks from the 
start of therapy.  
• 
Proportion of participants with sputum culture conversion to negative status in liquid culture 
(MGIT) at 4, 6, 12 and 17 weeks to be explored as a potential biomarker of outcome at 
52 weeks from start of therapy. 
• 
Change from baseline in weight will be summarised and presented. 
• 
Proportion of participants experiencing a change from baseline in TB symptoms. 
• 
Change from baseline in Patient Reported Health Status will be summarised and 
presented. 
9.5 
Safety and Tolerability Assessments 
The incidence of all-cause mortality will be summarized. All adverse events will be coded using 
the Medical Dictionary for Regulatory Activities (MedDRA) and will be presented by Preferred 
Term within each MedDRA System Organ Class (SOC). 
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Treatment-emergent adverse events (TEAEs) are defined as AEs which started at or after the 
first administration of IMP and includes those events started prior to the first administration of 
IMP but which worsened after the first intake.  Adverse events starting after the last 
administration of IMP until the last scheduled visit/assessment/measurement will be regarded 
as treatment-emergent. 
The incidence of the following events will be summarized for further medical analysis: 
o Incidence of TEAEs; 
o Incidence of TEAEs by Severity; 
o Incidence of TEAEs by DMID toxicity grade; 
o Incidence of Drug-Related TEAEs; 
o Incidence of Serious TEAEs; 
o Incidence of TEAEs Leading to Early Withdrawal; 
o Incidence of TEAEs leading to Death. 
9.6 
Pharmacokinetics 
For each analyte and each scheduled sampling time/window, the plasma concentration will 
be summarized by descriptive statistics including the mean, SD, coefficient of variation (CV), 
median, minimum, maximum, geometric mean and geometric CV (%). 
In addition, mean and/or median concentration-versus-time graphs will be provided, with error 
bars and/or scatter plots as appropriate. 
Plasma concentrations from sparse sampling will be used to update existing population PK 
models and derive exposure metrics (e.g., Cmin, Cmax, AUC) for bedaquiline and its M2 
metabolite, pretomanid, moxifloxacin, and pyrazinamide. Effects of baseline covariates on 
exposure will be assessed; so, too, will the effects of concomitant medications including ART, 
as feasible. Data from other trials may be included to enhance the model-based analysis.  
Detailed plans for the PopPK analysis will be outlined in a separate modelling plan, and results 
will be reported in separate modelling report. 
9.7 
Pharmacokinetics/Pharmacodynamics 
Relationships will be explored between drug exposure and efficacy and safety endpoints. 
These exploratory PK/PD analyses may include HIV status as a covariate. Planning details 
and results will be included in the separate modelling plan and report. 
10.0 Records Management 
10.1 Data Collection 
All relevant CRF/eCRF pages will be completed for each participant who receives any amount 
of IMP, depending on visits attended.  For screening failure participants, specific eCRF pages 
will be completed as described in the eCRF Completion Guidelines. For participants who are 
prematurely withdrawn, all the visits the participant attended including withdrawal and follow-
up visits need to be completed. 
10.2 Source Documents 
Source documents are defined as all information in original records and certified copies of 
original records of clinical findings, observations, or other activities in a clinical trial necessary 
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for the reconstruction and evaluation of the trial.  Source documents will include, but are not 
limited to, progress notes, in-patient hospital records, electronic data, screening logs, and 
recorded data from automated instruments. 
All source documents pertaining to this trial will be maintained by the Investigators.  The 
Investigator 
must 
permit 
trial 
related 
monitoring, 
audits, 
Independent 
Ethics 
Committee/Institutional Review Board (EC/IRB) review and regulatory inspections providing 
authorized personnel direct access to source documents, including documents required to 
confirm inclusion/exclusion and relevant in-patient records while participants are on trial 
treatment. 
10.3 File Management at the Trial Centre 
It is the responsibility of the Investigators to ensure that the trial centre files are maintained in 
accordance with International Good Clinical Practice Guidelines and the ethical principles that 
have their origin in the Declaration of Helsinki. 
10.4 Records Retention at the Trial Centre 
The Investigator is obliged to retain records and data from the trial for safety reasons and for 
audit and inspection after trial completion.  The essential documents should be retained for 
not less than 2 years after the last approval of a marketing application and until there are no 
pending or contemplated marketing applications or at least 2 years have elapsed since the 
formal discontinuation of clinical development of the IMP.  Investigator should notify the 
Sponsor/designees prior to destroying any records pertaining to the trial. 
 
11.0 Quality Control and Assurance  
11.1 Site Procedures 
The Investigator undertakes to perform the clinical trial in accordance with this protocol, local 
regulations, International GCP, and the ethical principles that have their origin in the 
Declaration of Helsinki. 
The Investigator undertakes to complete the CRFs according to the Sponsor’s requirements, 
in a timely, accurate and legible manner. CRF entries will be verifiable to source 
documentation other than the CRF. 
Site Standard Operating Procedures (SOPs), where available, will be adhered to for all clinical 
and bioanalytical activities relevant to the quality of the trial.  Participant compliance will be 
monitored throughout the trial. 
The Investigator will sign and date any analysis results (e.g., laboratory, ECG, etc.) to verify 
that the results have been reviewed. 
The Investigator may appoint other sub-Investigators to assist with the trial. However, the 
Investigator maintains responsibility for the trial and will supervise the sub-Investigators. 
Written EC/IRB approval of the trial will be obtained prior to involvement in the trial. 
The Investigator will ensure that all site personnel are adequately trained in GCP, local 
regulations, the protocol, IBs/package inserts and all trial procedures and requirements. 
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11.2 Monitoring 
The Investigator is responsible for the validity of all data collected at the clinical site and must 
accept the various monitoring procedures employed by the Sponsor.  The purpose of 
monitoring is to verify that the rights and well-being of human participants are protected; that 
trial data are accurate, complete and verifiable with source data; and that the trial is conducted 
in compliance with the protocol, International GCP, the ethical principles that have their origin 
in the Declaration of Helsinki and the applicable regulatory requirements.  
Monitors assigned by the Sponsor will conduct regular site visits before, during and after the 
trial for monitoring various aspects of the trial, and to assure appropriate conduct of the trial in 
accordance with ICH GCP.  Visits will take place usually within a predetermined interval, but 
this may vary during the trial.  The Investigator and site staff will allow the trial monitor and 
authorized representatives of the Sponsor to (1) inspect all CRFs, written informed consent 
documents and corresponding source documents (e.g., original medical records), patient 
records and laboratory raw data, site SOPs, training records, facilities and other trial related 
systems/processes, and (2) access clinical supplies, dispensing and storage areas.  The 
Investigator and site staff should also (1) agree to assist with monitoring activities if requested 
and (2) provide adequate time and space for monitoring visits.  
The monitor will query any missing, confusing, spurious, or otherwise ambiguous data with 
the Investigator.  All queries should be resolved in a timely manner.  A monitoring log will be 
maintained recording each visit, the reason for the visit, the monitor’s signature and 
Investigator or designee’s confirmation signature. 
11.3 Protocol Deviations 
A protocol deviation is any noncompliance with the clinical trial protocol and GCP 
requirements. The noncompliance may be either on the part of the participant, the Investigator, 
or the trial site staff. Because of deviations, corrective actions are to be developed by the site 
and implemented promptly.  
It is the responsibility of the site to use continuous vigilance to identify and report deviations. 
All deviations must be addressed in trial source documents and reported to Sponsor/designee. 
Protocol deviations must be sent to the local IRB per their guidelines. The site PI/trial staff is 
responsible for knowing and adhering to their IRB requirements. 
11.4 Auditing 
For compliance with International GCP and regulatory agency guidelines, it may be necessary 
for Sponsor-authorized Quality Assurance personnel and/or authorized personnel from an 
external regulatory agency to conduct an audit or inspection of the investigational site.  The 
purpose of an audit is to assess the quality of data about accuracy, adequacy and consistency, 
and to assure that trials are in accordance with the guidelines.  Having the highest quality data 
from trials is an essential aspect of drug development.  
The Investigator and site staff will be given sufficient notice to prepare for such visits, which 
will usually last between one and two days and may be conducted at any stage during the 
trial.  The audit will involve the review of all trial-related documentation required by GCP to be 
maintained by each site; drug storage, dispensing and return; all trial-related supplies; and 
source documents against the CRFs to assure the adequacy and accuracy of the information 
which has been recorded, including the verification of any AEs which have occurred. The 
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auditors or inspectors may also review site SOPs, training records, site facilities and other trial 
related systems/processes. 
In the event of the site being notified of a Regulatory Inspection, the Sponsor will help with 
preparation.  It is essential that the Sponsor be notified of the inspection as soon as possible. 
 
12.0 Ethics and Regulatory 
12.1 Basic Principles 
This research will be carried out in accordance with International GCP, the ethical principles 
that have their origin in the Declaration of Helsinki and the applicable regulatory requirements. 
12.2 Independent Ethics Committee/Institutional Review Board (EC/IRB) 
Review 
The protocol and required trial related documents will be reviewed by the sites respective 
EC/IRB.  The trial will not start until the EC/IRB has approved the protocol, written informed 
consent, any written information to be provided to the participant or any modification thereof, 
plus any other trial related documents required for review.  The EC/IRB shall be constituted 
and shall operate in accordance with International GCP, the ethical principles that have their 
origin in the Declaration of Helsinki. The Investigator will maintain an accurate and complete 
record of all submissions made to, and responses from the IRB/EC.  The records should be 
filed in the Investigator’s Trial File, and copies will be sent to the Sponsor. 
12.3 Regulatory Authorities 
The Regulatory Authorities will receive the protocol, amendments, reports on SAEs, and the 
Integrated Clinical Trial Report according to national regulations.  As required by local 
legislation, written approval will be obtained from the Regulatory Authorities prior to 
commencement of the trial and implementation of e.g. amendments as applicable. 
12.4 Informed Consent 
Written informed consent will be obtained from all participants (or legally acceptable 
representative) before any trial-related procedures (including any screening or pre-treatment 
procedures) are performed.  Investigators may discuss the availability of the trial and the 
opportunity for entry with a potential participant without first obtaining consent.  However, 
informed consent must be obtained and documented prior to initiation of any procedures that 
are performed solely for determining eligibility for research, including withdrawal from current 
medication(s).  When this is done in anticipation of, or in preparation for, the research, it is 
part of the research. 
The Investigators have both ethical and legal responsibility to ensure that each participant 
being considered for inclusion in this trial is given a full explanation of the protocol.  Participants 
must be informed that their participation is voluntary.  The Investigator or his/her 
representative will explain the nature of the trial to the participant or his/her legally authorized 
representative and answer all questions regarding the trial. This shall be documented on a 
written informed consent form that shall be approved by the same EC/IRB responsible for 
approval of this protocol.  Each informed consent form shall include the elements required by 
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the international GCP and must adhere to the ethical principles that have their origin in the 
Declaration of Helsinki.  
The trial will be included and updated in the appropriate Country registry and referenced in 
the informed consent forms (ICF). 
Once the appropriate essential information has been provided to the participant and fully 
explained by the Investigators (or qualified designees) and it is felt that the participant 
understands the implications of participating, the EC/IRB approved written ICF will be signed 
and dated by both the participant and the person obtaining consent (Investigators or 
designees), and by any other parties required by the EC/IRB. Ongoing participants must be 
re-consented to the most current version of the ICF(s) during their participation in the trial. 
The original signed ICFs will be kept with the trial records and a copy of ICF will be provided 
to the participant or the participant’s legally authorized representative.  Another copy of the 
signed ICF and a source document identifying the trial and recording the dates of participation 
will be placed in the participant’s medical record. 
The monitor will inspect the original completed ICFs for all participants. 
12.5 Confidentiality 
All site staff, the Sponsor, and any Sponsor representatives will preserve the confidentiality of 
all participants taking part in the trial, in accordance with International GCP, applicable local 
legislation/regulations.  Subject to the requirement for source data verification by the trial 
personnel by reference to the participant’s notes, confidentiality of all participant identities will 
be maintained.  Unique identifiers will be used on the CRF and in all trial correspondence, as 
permitted.  No material bearing a participant’s name will be kept on file by the Sponsor. The 
written informed consent will contain a clause granting permission for review of the 
participants’ source data by the Sponsor or designees. 
 
13.0 Publication Policy 
The definition of publication for this purpose is any public presentation of the data emerging 
from this trial.  
All unpublished information given to the Investigator by the Sponsor shall not be published or 
disclosed to a third party, other than to the responsible EC/IRB, within the understanding of 
the confidentiality of their nature, without the prior written consent of the Sponsor. 
Results of this research will be submitted for publication as soon as feasible upon completion 
of the trial in the form of a joint publication(s) between Sponsor and Investigator(s), including 
site clinical and laboratory Investigators, as appropriate. Publication and authorship will be in 
accord with the International Association of Journal Editors.[43]  
Because the trial is funded, in whole or in part, by the Bill and Melinda Gates Foundation (the 
“Foundation”), all peer-reviewed published research relating to the Trial must comply with the 
Foundation’s 
Open 
Access 
Policy 
as 
described 
from 
time 
to 
time 
at 
http://www.gatesfoundation.org/How-We-Work/General-Information/Open-Access-Policy 
. 
Specifically, (a) all peer-reviewed published research relating to the trial must be submitted for 
publication by TB Alliance through the Chronos Open Access Publishing Service established 
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by the Foundation to ensure the immediate and unrestricted access and reuse of all peer-
reviewed published research funded, in whole or in part, by the Foundation without any 
embargo period, and (b) all data underlying the peer-reviewed published research results must 
be immediately made accessible and open to the public in accordance with the Foundation’s 
Open Access Policy. 
 
14.0 Protocol Amendment Policy 
Any change to the protocol will be affected by means of a protocol amendment.  Any changes 
which affect participant safety or welfare will be submitted to the EC/IRB and Regulatory 
Authorities prior to implementation.  The Investigator, EC/IRB, and Sponsor must agree on all 
amendments.  No amendment will be implemented until approved by the relevant authorities 
and/or EC/IRB and signed by all required parties.  Exceptions to this are when the Investigator 
considers that the participant’s safety is compromised.  
Protocol amendments detailing minor administrative changes should be submitted by the 
Investigator to the EC/IRB and Regulatory Authorities, either for notification purposes or 
approval as appropriate. 
 
15.0 Sponsor, Financial Aspects, Insurance and Indemnity 
The trial Sponsor is the TB Alliance (TBA).  The TB Alliance is a not for profit, product 
development partnership accelerating the discovery and development of new TB drugs that 
will shorten treatment, be effective against susceptible and resistant strains, be compatible 
with antiretroviral therapies for those HIV-TB participants currently on such therapies and 
improve treatment of latent infection. 
The TB Alliance works with public and private partners worldwide.  It is committed to ensuring 
that approved new regimens are affordable, adopted and available to those who need them. 
The TB Alliance operates with funding mainly from the Bill & Melinda Gates Foundation, the 
Netherlands Ministry of Foreign Affairs (DGIS), the United Kingdom Department for 
International Development (DFID), and the United States Agency for International 
Development (USAID). 
The participants will not receive any incentives for their involvement in the trial.  The Sponsor 
has made provision to reimburse the participants for out-of-pocket expenses such as travelling 
to and from the trial site and other miscellaneous costs as a result of their trial participation. 
The Sponsor certifies that it has liability insurance coverage for itself and will provide an 
associated certificate upon request.  The insurance does not relieve the Investigators of the 
obligation to maintain their own liability insurance as required by applicable law. The Sponsor 
does not assume any obligation for the medical treatment of other injuries and illnesses.
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Page 83 of 98 
16.0 References 
1. 
Maggi N, Pasqualucci CR, Ballotta R, Sensi P. Rifampicin: a new orally active 
rifamycin. Chemotherapy. 1966;11(5):285-292. 
2. 
Jindani A, Aber VR, Edwards EA, Mitchison DA. The early bactericidal activity of drugs 
in patients with pulmonary tuberculosis. Am Rev Respir Dis. 1980;121(6):939-949. 
3. 
Dietze R, Teixeira L, Rocha LM, Palaci M, Johnson JL, Wells C, et al. Safety and 
bactericidal activity of rifalazil in patients with pulmonary tuberculosis. Antimicrob 
Agents Chemother. 2001;45(7):1972-1976. 
4. 
Donald PR, Sirgel FA, Venter A, Parkin DP, Seifart HI, van de Wal BW, et al. Early 
bactericidal activity of antituberculosis agents. Expert Rev Anti Infect Ther. 
2003;1(1):141-155. 
5. 
Johnson JL, Hadad DJ, Boom WH, Daley CL, Peloquin CA, Eisenach KD, et al. Early 
and extended early bactericidal activity of levofloxacin, gatifloxacin and moxifloxacin 
in pulmonary tuberculosis. Int J Tuberc Lung Dis. 2006;10(6):605-612. 
6. 
Rustomjee R, Diacon AH, Allen J, Venter A, Reddy C, Patientia RF, et al. Early 
bactericidal activity and pharmacokinetics of the diarylquinoline TMC207 in treatment 
of pulmonary tuberculosis. Antimicrob Agents Chemother. 2008;52(8):2831-2835. 
7. 
Package insert: Sirturo.  Janssen Therapeutics, September 2014 Available at: 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/204384s000lbl.pdf. 
8. 
Investigator’s Brochure: TMC207 (bedaquiline).  Edition 10. Janssen Research and 
Development, 02 Dec 2016. 
9. 
Koul A, Dendouga N, Vergauwen K, Molenberghs B, Vranckx L, Willebrords R, et al. 
Diarylquinolines target subunit c of mycobacterial ATP synthase. Nat Chem Biol. 
2007;3(6):323-324. 
10. 
Andries K, Verhasselt P, Guillemont J, Gohlmann HW, Neefs JM, Winkler H, et al. A 
diarylquinoline drug active on the ATP synthase of Mycobacterium tuberculosis. 
Science. 2005;307(5707):223-227. 
11. 
Huitric E, Verhasselt P, Andries K, Hoffner SE. In vitro antimycobacterial spectrum of 
a 
diarylquinoline 
ATP 
synthase 
inhibitor. 
Antimicrob 
Agents 
Chemother. 
2007;51(11):4202-4204. 
12. 
Koul A, Vranckx L, Dendouga N, Balemans W, Van den Wyngaert I, Vergauwen K, et 
al. Diarylquinolines are bactericidal for dormant mycobacteria as a result of disturbed 
ATP homeostasis. J Biol Chem. 2008;283(37):25273-25280. 
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Page 84 of 98 
13. 
Nuermberger E, Rosenthal I, Tyagi S, Williams KN, Almeida D, Peloquin CA, et al. 
Combination chemotherapy with the nitroimidazopyran PA-824 and first-line drugs in 
a murine model of tuberculosis. Antimicrob Agents Chemother. 2006;50(8):2621-2625. 
14. 
Nuermberger E, Tyagi S, Tasneen R, Williams KN, Almeida D, Rosenthal I, et al. 
Powerful bactericidal and sterilizing activity of a regimen containing PA-824, 
moxifloxacin, and pyrazinamide in a murine model of tuberculosis. Antimicrob Agents 
Chemother. 2008;52(4):1522-1524. 
15. 
Investigator's Brochure: Pretomanid (PA-824).  Global Alliance for TB Drug 
Development, 22 December 2016. 
16. 
Stover CK, Warrener P, VanDevanter DR, Sherman DR, Arain TM, Langhorne MH, et 
al. A small-molecule nitroimidazopyran drug candidate for the treatment of 
tuberculosis. Nature. 2000;405(6789):962-966. 
17. 
Lenaerts AJ, Gruppo V, Marietta KS, Johnson CM, Driscoll DK, Tompkins NM, et al. 
Preclinical testing of the nitroimidazopyran PA-824 for activity against Mycobacterium 
tuberculosis in a series of in vitro and in vivo models. Antimicrob Agents Chemother. 
2005;49(6):2294-2301. 
18. 
Tyagi S, Nuermberger E, Yoshimatsu T, Williams K, Rosenthal I, Lounis N, et al. 
Bactericidal activity of the nitroimidazopyran PA-824 in a murine model of tuberculosis. 
Antimicrob Agents Chemother. 2005;49(6):2289-2293. 
19. 
Package insert: Moxifloxacin.  MacLeods Pharmaceuticals Ltd., January 2014. 
20. 
Package insert: Pyrazinamide.  MacLeods Pharmaceuticals Ltd., November 2012. 
21. 
Zhang Y, Mitchison D. The curious characteristics of pyrazinamide: a review. Int J 
Tuberc Lung Dis. 2003;7(1):6-21. 
22. 
Package insert: HRZE Combination Tablets.  MacLeods Pharmaceuticals Ltd., 
September 2011. 
23. 
World Health Organization. Global tuberculosis report 2012.  2015. WHO Press, 
Geneva, Switzerland. 
24. 
Pym AS, Diacon AH, Tang S-J, Conradie F, Danilovits M, Chuchottaworn C, et al. 
Bedaquiline safety data in a broad patient population treated for drug-resistant TB 
including XDR-TB (C209 trial). Tuberculosis. 2016;47:394-402. 
25. 
Lee M, Lee J, Carroll MW, Choi H, Min S, Song T, et al. Linezolid for treatment of 
chronic extensively drug-resistant tuberculosis. N Engl J Med. 2012;367(16):1508-
1518. 
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26. 
A Phase 3 Trial Assessing the Safety and Efficacy of Bedaquiline Plus PA-824 Plus 
Linezolid in Subjects With Drug Resistant Pulmonary Tuberculosis. ClinicalTrials.gov,  
Available at: https://www.clinicaltrials.gov/ct2/show/NCT02333799, Updated 28 
February 2017. 
27. 
Mdluli K, Nuermberger E. Pre-Clinical Drug Combination Trials to Identify Novel 
Regimens for TB.  2009. in Recent Advances in TB Drug Development Symposium. 
40th Union World Conference, International Union Against TB and Lung Disease. 
Cancun, Mexico. 
28. 
Tasneen R, Li SY, Peloquin CA, Taylor D, Williams KN, Andries K, et al. Sterilizing 
activity of novel TMC207- and PA-824-containing regimens in a murine model of 
tuberculosis. Antimicrob Agents Chemother. 2011;55(12):5485-5492. 
29. 
Singh R, Manjunatha U, Boshoff HI, Ha YH, Niyomrattanakit P, Ledwidge R, et al. PA-
824 kills nonreplicating Mycobacterium tuberculosis by intracellular NO release. 
Science. 2008;322(5906):1392-1395. 
30. 
Manjunatha U, Boshoff HI, Barry CE. The mechanism of action of PA-824: Novel 
insights from transcriptional profiling. Commun Integr Biol. 2009;2(3):215-218. 
31. 
Manjunatha UH, Boshoff H, Dowd CS, Zhang L, Albert TJ, Norton JE, et al. 
Identification of a nitroimidazo-oxazine-specific protein involved in PA-824 resistance 
in Mycobacterium tuberculosis. Proc Natl Acad Sci U S A. 2006;103(2):431-436. 
32. 
Nuermberger E, Tyagi S, Williams KN, Rosenthal I, Bishai WR, Grosset JH. 
Rifapentine, moxifloxacin, or DNA vaccine improves treatment of latent tuberculosis in 
a mouse model. Am J Respir Crit Care Med. 2005;172(11):1452-1456. 
33. 
Tasneen R, Betoudji F, Tyagi S, Li SY, Williams K, Converse PJ, et al. Contribution of 
Oxazolidinones to the Efficacy of Novel Regimens Containing Bedaquiline and 
Pretomanid in a Mouse Model of Tuberculosis. Antimicrob Agents Chemother. 
2015;60(1):270-277. 
34. 
Diacon AH, Dawson R, du Bois J, Narunsky K, Venter A, Donald PR, et al. Phase II 
dose-ranging trial of the early bactericidal activity of PA-824. Antimicrob Agents 
Chemother. 2012;56(6):3027-3031. 
35. 
Burman WJ, Goldberg S, Johnson JL, Muzanye G, Engle M, Mosher AW, et al. 
Moxifloxacin versus ethambutol in the first 2 months of treatment for pulmonary 
tuberculosis. Am J Respir Crit Care Med. 2006;174(3):331-338. 
36. 
Rustomjee R, Lienhardt C, Kanyok T, Davies GR, Levin J, Mthiyane T, et al. A Phase 
II trial of the sterilising activities of ofloxacin, gatifloxacin and moxifloxacin in pulmonary 
tuberculosis. Int J Tuberc Lung Dis. 2008;12(2):128-138. 
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37. 
Conde MB, Efron A, Loredo C, De Souza GR, Graca NP, Cezar MC, et al. Moxifloxacin 
versus ethambutol in the initial treatment of tuberculosis: a double-blind, randomised, 
controlled phase II trial. Lancet. 2009;373(9670):1183-1189. 
38. 
Dorman SE, Johnson JL, Goldberg S, Muzanye G, Padayatchi N, Bozeman L, et al. 
Substitution of moxifloxacin for isoniazid during intensive phase treatment of 
pulmonary tuberculosis. Am J Respir Crit Care Med. 2009;180(3):273-280. 
39. 
Investigator's Brochure: Bayer HealthCare AG, moxifloxacin.  01 October 2011. 
40. 
Package insert: HR Combination Tablets.  MacLeods Pharmaceuticals Ltd., 
September 2011. 
41. 
Gillespie SH, Crook AM, McHugh TD, Mendel CM, Meredith SK, Murray SR, et al. 
Four-month moxifloxacin-based regimens for drug-sensitive tuberculosis. N Engl J 
Med. 2014;371(17):1577-1587. 
42. 
Tiemersma EW, van der Werf MJ, Borgdorff MW, Williams BG, Nagelkerke NJ. Natural 
history of tuberculosis: duration and fatality of untreated pulmonary tuberculosis in HIV 
negative patients: a systematic review. PLoS One. 2011;6(4):e17601. 
43. 
Recommendations for the Conduct, Reporting, Editing, and Publication of Scholarly 
work 
in 
Medical 
Journals. 
 
Available 
at: 
http://www.icmje.org/icmje-
recommendations.pdf, Updated December 2016. 
44.  
Reuben A (2004). “Hy’s Law”. Landmarks in Hepatology 39(2): 574-578. 
45. 
Temple 
RJ 
(2006). 
“Hy’s 
Law: 
predicting 
serious 
hepatotoxicity”. 
Pharmacoepidemoiology and Drug Safety 15: 241-243. 
46. 
Parmar, M.K., et al., Testing many treatments within a single protocol over 10 years at 
MRC Clinical Trials Unit at UCL: Multi-arm, multi-stage platform, umbrella and basket 
protocols. Clin Trials, 2017. 14(5): p. 451-461. 
47. 
Bratton, D.J., P.P. Phillips, and M.K. Parmar, A multi-arm multi-stage clinical trial 
design for binary outcomes with application to tuberculosis. BMC Med Res Methodol, 
2013. 13: p. 139. 
48. 
Royston, P., et al., Designs for clinical trials with time-to-event outcomes based on 
stopping guidelines for lack of benefit. Trials, 2011. 12: p. 81. 
 
 
 
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Appendices 
Appendix 1: The IUATLD Scale 
The IUATLD scale proposes five groups for reporting the results of reading smears for acid 
fast bacilli. They should be recorded as follows: 
FINDING 
RECORDING 
No acid-fast bacilli found in at least 100 fields 
negative 
1 to 9 acid-fast bacilli per 100 fields 
scanty positive 
10 to 99 acid-fast bacilli per 100 fields 
+ 
1 to 10 acid-fast bacilli per field in at least 50 
fields 
++ 
More than 10 acid-fast bacilli per field in at least 
20 fields 
+++ 
Reference: The Public Health Service National Tuberculosis Reference Laboratory and the 
National Laboratory Network. Minimum Requirements, Role and Operation in a Low-Income 
Country. International Union Against Tuberculosis and Lung Disease 1998. 
 
 
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Appendix 2: Division of Microbiology and Infectious Disease (DMID) Toxicity 
Table 
Source:  U.S. National Institute of Allergy and Infectious Diseases, DMID, November 2007 
(Draft) 
ABBREVIATIONS:  Abbreviations utilized in the Table: 
ULN = Upper Limit of Normal 
LLN = Lower Limit of Normal 
Rx = Therapy 
Req = Required 
Mod = Moderate 
IV  = Intravenous 
ADL = Activities of Daily Living 
Dec = Decreased 
 
ESTIMATING SEVERITY GRADE 
For abnormalities NOT found elsewhere in the Toxicity Tables use the scale below to estimate 
grade of severity: 
Grade 
Severity Rating 
Definition 
GRADE 1 
Mild 
Transient or mild discomfort (< 48 hours); no medical 
intervention/therapy required. 
GRADE 2 
Moderate 
Mild to moderate limitation in activity - some assistance may be 
needed; no or minimal medical intervention/therapy required. 
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. 
 
SERIOUS OR LIFE-THREATENING AEs 
ANY clinical event deemed by the clinician to be serious or life-threatening should be 
considered a grade 4 event. Clinical events considered to be serious or life-threatening 
include, but are not limited to: seizures, coma, tetany, diabetic ketoacidosis, disseminated 
intravascular coagulation, diffuse petechiae, paralysis, acute psychosis, severe depression. 
COMMENTS REGARDING THE USE OF THESE TABLES 
• 
Standardized and commonly used toxicity tables (Division of Acquired Immune Deficiency 
Syndrome (AIDS), NCI’s Common Toxicity Criteria (CTC), and World Health Organization 
(WHO)) have been adapted for use by the DMID and modified to better meet the needs of 
participants in DMID trials. 
• 
For parameters not included in the following Toxicity Tables, sites should refer to the 
“Guide For Estimating Severity Grade” located above. 
• 
Criteria are generally grouped by body system. 
• 
Some protocols may have additional protocol specific grading criteria, which will 
supersede the use of these tables for specified criteria. 
 
 
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HEMATOLOGY 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Hemoglobin 
9.5 - 10.5 gm/dL 
8.0  - 9.4gm/dL 
6.5 - 7.9 gm/dL 
< 6.5 gm/dL 
Absolute Neutrophil 
Count 
1000-1500/mm3 
750-999/mm3 
500-749/mm3 
<500/mm3 
Platelets 
75,000- 
99,999/mm3 
50,000- 
74,999/mm3 
20,000- 
49,999/mm3 
<20,000/mm3 
WBCs 
11,000-13,000/ 
mm3 
13,000-15,000 
/mm3 
15,000- 
30,000/mm3 
>30,000 or <1,000 
/mm3 
% Polymorphonuclear 
Leucocytes + Band 
Cells 
 
> 80% 
 
90 – 95% 
 
>95% 
 
---------- 
 
 
Abnormal Fibrinogen 
Low: 
100-200 mg/dL 
High: 
400-600 mg/dL 
Low: 
<100 mg/dL 
High: 
>600 mg/dL 
Low: 
< 50 mg/dL 
 
---------- 
Fibrinogen 
associated with 
gross bleeding or 
with disseminated 
coagulation 
Fibrin Split Product 
20-40 mcg/ml 
41-50 mcg/ml 
51-60 mcg/ml 
> 60 mcg/ml 
Prothrombin Time (PT) 
1.01 - 1.25 x ULN 
1.26-1.5 x ULN 
1.51 -3.0 x ULN 
>3 x ULN 
Activated 
Partial 
Thromboplastin (APPT) 
1.01 -1.66 x ULN 
1.67 - 2.33 x ULN 
2.34 - 3 x ULN 
> 3 x ULN 
Methemoglobin 
5.0 - 9.9 % 
10.0 - 14.9 % 
15.0 - 19.9% 
> 20.0 % 
 
CHEMISTRIES 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
 
Hyponatremia 
 
130-135 mEq/L 
 
123-129 mEq/L 
 
116-122 mEq/L 
< 116 mEq/L or abnormal 
sodium with mental status 
changes or seizures 
 
Hypernatremia 
 
146-150 mEq/L 
 
151-157 mEq/L 
 
158-165 mEq/L 
> 165 mEq/L or abnormal 
sodium with mental status 
changes or seizures 
 
 
Hypokalemia 
 
 
3.0 - 3.4 mEq/L 
 
 
2.5 - 2.9 mEq/L 
2.0 - 2.4 mEq/L or 
intensive 
replacement 
therapy or 
hospitalization 
required 
 
< 2.0 mEq/L or abnormal 
potassium with paresis, ileus 
or life-threatening arrhythmia 
 
Hyperkalemia 
 
5.6 - 6.0 mEq/L 
 
6.1 - 6.5 mEq/L 
 
6.6 - 7.0 mEq/l 
> 7.0 mEq/L or abnormal 
potassium with life- 
threatening arrhythmia 
 
Hypoglycemia 
 
55-64 mg/dL 
 
40-54 mg/dL 
 
30-39 mg/dL 
<30 mg/dL or abnormal 
glucose with mental status 
changes or coma 
Hyperglycemia 
(non-fasting and no 
prior diabetes) 
 
116 - 160 mg/dL 
 
161- 250 mg/dL 
 
251 - 500 mg/dL 
> 500 mg/dL or abnormal 
glucose with ketoacidosis or 
seizures 
 
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Hypocalcemia 
(corrected 
for 
albumin) 
 
8.4 - 7.8 mg/dL 
 
7.7 - 7.0 mg/dL 
 
6.9 - 6.1 mg/dL 
< 6.1 mg/dL or abnormal 
calcium with life threatening 
arrhythmia or tetany 
Hypercalcemia 
(correct for albumin) 
 
10.6 - 11.5 mg/dL 
11.6 - 12.5 
mg/dL 
 
12.6 - 13.5 mg/dL 
> 13.5 mg/dL or abnormal 
calcium with life threatening 
arrhythmia 
 
Hypomagnesemia 
 
1.4 - 1.2 mEq/L 
 
1.1 - 0.9 mEq/L 
 
0.8 - 0.6 mEq/L 
< 0.6 mEq/L or abnormal 
magnesium with life- 
threatening arrhythmia 
 
Hypophosphatemia 
 
2.0 - 2.4 mg/dL 
1.5 -1.9 mg/dL 
or replacement 
Rx required 
1.0 -1.4 mg/dL 
intensive therapy or 
hospitalization 
required 
< 1.0 mg/dL or abnormal 
phosphate with life- 
threatening arrhythmia 
Hyperbilirubinemia 
(when accompanied 
by any increase in 
other liver function 
test) 
 
 
1.1 - <1.25 x ULN 
 
1.25 - <1.5 x 
ULN 
 
 
1.5 – 1.75 x ULN 
 
 
> 1.75 x ULN 
Hyperbilirubinemia 
(when 
other 
liver 
function are in the 
normal range) 
 
1.1 - <1.5 x ULN 
 
1.5 - <2.0 x ULN 
 
2.0 – 3.0 x ULN 
 
> 3.0 x ULN 
BUN 
1.25 - 2.5 x ULN 
2.6 - 5 x ULN 
5.1 - 10 x ULN 
> 10 x ULN 
Hyperuricemia (uric 
acid) 
7.5 – 10.0 mg/dL 
10.1 – 12.0 
mg/dL 
12.1 – 15.0 mg/dL 
>15.0 mg/dL 
Creatinine 
1.1 - 1.5 x ULN 
1.6 - 3.0 x ULN 
3.1 - 6 x ULN 
> 6 x ULN or dialysis 
required 
 
ENZYMES 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
AST (SGOT) 
1.1 - <2.0 x ULN 
2.0 – <3.0 x ULN 
3.0 – 8.0 x ULN 
> 8 x ULN 
ALT (SGPT) 
1.1 - <2.0 x ULN 
2.0 – <3.0 x ULN 
3.0 – 8.0 x ULN 
> 8 x ULN 
GGT 
1.1 - <2.0 x ULN 
2.0 – <3.0 x ULN 
3.0 – 8.0 x ULN 
> 8 x ULN 
Alkaline Phosphatase 
1.1 - <2.0 x ULN 
2.0 – <3.0 x ULN 
3.0 – 8.0 x ULN 
> 8 x ULN 
Amylase 
1.1 - 1.5 x ULN 
1.6 - 2.0 x ULN 
2.1 - 5.0 x ULN 
> 5.1 x ULN 
Lipase 
1.1 - 1.5 x ULN 
1.6 - 2.0 x ULN 
2.1 - 5.0 x ULN 
> 5.1 x ULN 
 
 
URINALYSIS 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
 
Proteinuria 
1+ or 200 mg - 1 
gm loss/day 
2-3+ or 1- 2 gm 
loss/day 
4+ or 2-3.5 gm 
loss/day 
nephrotic 
syndrome or > 3.5 
gm loss/day 
 
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Hematuria 
 
microscopic only 
<10 rbc/hpf 
 
gross, no clots >10 
rbc/hpf 
gross, with or 
without clots, OR 
red blood cell 
casts 
obstructive or 
required 
transfusion 
 
CARDIOVASCULAR 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Cardiac Rhythm 
 
asymptomatic, 
transient signs, no 
Rx required 
recurrent/persistent 
; symptomatic Rx 
required 
unstable 
dysrythmia; 
hospitalization and 
treatment required 
Hypertension 
transient increase 
> 20 mm/Hg; no 
treatment 
recurrent, chronic 
increase 
> 
20mm/Hg. 
/treatment required 
acute 
treatment 
required; 
outpatienttreatm 
ent 
or 
hospitalization 
possible 
end organ damage 
or 
hospitalization 
required 
Hypotension 
transient 
orthostatic 
hypotension with 
heart 
rate 
increased by <20 
beat/min 
or 
decreased by <10 
mm Hg systolic 
BP, No treatment 
required 
symptoms due to 
orthostatic 
hypotension or BP 
decreased by <20 
mm 
Hg 
systolic; 
correctable with oral 
fluid treatment 
requires IV fluids; 
no hospitalization 
required 
mean 
arterial 
pressure <60mm/ 
Hg or end organ 
damage or shock; 
requires 
hospitalization and 
vasopressor 
treatment 
Pericarditis 
minimal effusion 
mild/moderate 
asymptomatic 
effusion, 
no 
treatment 
symptomatic 
effusion; pain; EKG 
changes 
tamponade; 
pericardiocentesis 
or surgery required 
Hemorrhage, Blood 
Loss 
microscopic/occult 
mild, no transfusion 
gross blood loss; 
1-2 
units 
transfused 
massive blood 
loss; > 3 units 
transfused 
 
RESPIRATORY 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
 
Cough 
Transient - no 
treatment 
persistent 
cough; 
treatment responsive 
Paroxysmal cough; 
uncontrolled with 
treatment 
 
-------------------- 
 
Bronchospasm, 
Acute 
transient; no 
treatment; 70% - 
80% FEV1 of peak 
flow 
requires treatment; 
normalizes with 
bronchodilator; FEV1 
50% - 70% (of peak 
flow) 
no normalization with 
bronchodilator;FEV1 
25% - 50% of peak 
flow; or retractions 
present 
cyanosis: FEV1 < 
25% of peak flow 
or intubation 
necessary 
Dyspnea 
dyspnea on exertion 
dyspnea with normal 
activity 
dyspnea at rest 
dyspnea requiring 
Oxygen therapy 
 
GASTROINTESTINAL 
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CONFIDENTIAL 
Page 92 of 98 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Nausea 
mild or transient; 
maintains 
reasonable intake 
moderate 
discomfort; intake 
decreased 
significantly; some 
activity limited 
no 
significant 
intake; requires IV 
fluids 
hospitalization 
required; 
Vomiting 
1 episode in 24 
hours 
2-5 episodes in 24 
hours 
>6 episodes in 24 
hours or needing 
IV fluids 
physiologic 
consequences 
requiring 
hospitalization 
or 
requiring 
parenteral nutrition 
Constipation 
requiring 
stool 
softener or dietary 
modification 
requiring laxatives 
obstipation 
requiring manual 
evacuation 
or 
enema 
obstruction or toxic 
megacolon 
Diarrhea 
mild or transient; 3- 
4 loose stools/day 
or 
mild 
diarrhea 
last < 1 week 
moderate 
or 
persistent; 5-7 loose 
stools/day 
or 
diarrhea lasting >1 
week 
>7 loose stools/day 
or bloody diarrhea; 
or 
orthostatic 
hypotension 
or 
electrolyte 
imbalance or >2L 
IV fluids required 
hypotensive shock 
or 
physiologic 
consequences 
requiring 
hospitalization 
Oral 
Discomfort/Dysphagia 
mild discomfort; no 
difficulty 
swallowing 
some limits on 
eating/drinking 
eating/talking very 
limited; unable to 
swallow solid foods 
unable to drink 
fluids; requires IV 
fluids 
 
NEUROLOGICAL 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Neuro-Cerebellar 
slight 
incoordination 
dysdiadochokinesis 
intention 
tremor, 
dysmetria, slurred 
speech; nystagmus 
locomotor ataxia 
incapacitated 
Psychiatric 
mild anxiety or 
depression 
moderate anxiety or 
depression; therapy 
required; change in 
normal routine 
severe 
mood 
changes requiring 
therapy; or suicidal 
ideation; 
or 
aggressive ideation 
acute 
psychosis 
requiring 
hospitalization;  or 
suicidal 
gesture/attempt or 
hallucinations 
Muscle Strength 
Subjective 
weakness 
no 
objective 
symptoms/ signs 
mild 
objective 
signs/symptoms no 
decrease in function 
objective 
weakness function 
limited 
paralysis 
Paresthesia (burning, 
tingling, etc.) 
mild discomfort; no 
treatment required 
moderate 
discomfort; 
non- 
narcotic analgesia 
required 
severe discomfort; 
or 
narcotic 
analgesia required 
with symptomatic 
improvement 
incapacitating; or 
not responsive to 
narcotic analgesia 
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SimpliciTB 
 
CONFIDENTIAL 
Page 93 of 98 
Neuro-sensory 
mild impairment in 
sensation 
(decreased 
sensation, 
e.g., 
vibratory, pinprick, 
hot/cold in great 
toes) in focal area 
or 
symmetrical 
distribution; 
or 
change in 
taste, 
smell, vision and/or 
hearing 
moderate 
impairment 
(mod 
decreased 
sensation, 
e.g., 
vibratory, pinprick, 
hot/cold to ankles) 
and/or joint position 
or mild impairment 
that 
is 
not 
symmetrical 
severe impairment 
(decreased or loss 
of 
sensation 
to 
knees or wrists) or 
loss of sensation of 
at 
least 
mod 
degree in multiple 
different 
body 
areas (i.e., upper 
and 
lower 
extremities) 
sensory 
loss 
involves limbs and 
trunk; paralysis; or 
seizures 
 
MUSCULOSKELETAL 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Arthralgia (joint pain) 
mild pain not 
interfering with 
function 
moderate 
pain, 
analgesics 
and/or 
pain interfering with 
function but not with 
activities 
of 
daily 
living 
severe pain; pain 
and/or analgesics 
interfering 
with 
activities of daily 
living 
disabling pain 
Arthritis 
mild 
pain 
with 
inflammation, 
erythema or joint 
swelling – but not 
interfering 
with 
function 
moderate pain with 
inflammation, 
erythema 
or 
joint 
swelling – interfering 
with function, but not 
with 
activities 
of 
daily living 
severe pain with 
inflammation, 
erythema or joint 
swelling 
–and 
interfering 
with 
activities of daily 
living 
permanent and/or 
disabling 
joint 
destruction 
Myalgia 
myalgia 
with 
no 
limitation of activity 
muscle tenderness 
(at 
other 
than 
injection site) or with 
moderate 
impairment 
of 
activity 
severe 
muscle 
tenderness 
with 
marked impairment 
of activity 
frank 
myonecrosis 
 
SKIN 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Mucocutaneous 
erythema; pruritus 
diffuse, 
maculo 
papular rash, dry 
desquamation 
vesiculation or moist 
desquamation 
or 
ulceration 
exfoliative 
dermatitis, mucous 
membrane 
involvement 
or 
erythema, 
multiforme 
or 
suspected Stevens- 
Johnson or necrosis 
requiring surgery 
Induration 
< 15mm 
15-30 mm 
>30mm 
 
Erythema 
< 15mm 
15-30 mm 
>30mm 
 
Edema 
< 15mm 
15-30 mm 
>30mm 
 
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CONFIDENTIAL 
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Rash at Injection 
Site 
< 15mm 
15-30 mm 
>30mm 
 
Pruritus 
slight itching at 
injection site 
moderate itching at 
injection extremity 
itching over entire 
body 
 
 
SYSTEMIC 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
 
Allergic Reaction 
 
pruritus without rash 
 
localized urticaria 
generalized 
urticaria; 
angioedema 
 
anaphylaxis 
 
Headache 
mild, no treatment 
required 
transient, moderate; 
treatment required 
severe; responds to 
initial 
narcotic 
therapy 
intractable; requires 
repeated 
narcotic 
therapy 
Fever: oral 
37.7 - 38.5 C or 
100.0 - 101.5 F 
38.6 - 39.5 C or 
101.6 - 102.9 F 
39.6 - 40.5 C or 103 
- 105 F 
> 40 C or > 105 F 
 
Fatigue 
normal 
activity 
reduced < 48 hours 
normal 
activity 
decreased 25- 50% 
> 48 hours 
normal 
activity 
decreased > 50% 
can’t work 
unable to care for 
self 
 
 
 
 
 
 
 
 
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CONFIDENTIAL 
Page 95 of 98 
Appendix 3: Who Clinical Staging of HIV/AIDS for Adults and Adolescents  
Primary HIV Infection 
Asymptomatic 
Acute retroviral syndrome 
Clinical Stage 1 
Asymptomatic 
Persistent generalized lymphadenopathy 
Clinical Stage 2 
Moderate unexplained weight loss (<10% of presumed or measured body weight) 
Recurrent respiratory infections (sinusitis, tonsillitis, otitis media, and pharyngitis) 
Herpes zoster 
Angular cheilitis 
Recurrent oral ulceration 
Papular pruritic eruptions 
Seborrheic dermatitis 
Fungal nail infections 
Clinical Stage 3 
Unexplained severe weight loss (>10% of presumed or measured body weight) 
Unexplained chronic diarrhea for >1 month 
Unexplained persistent fever for >1 month (>37.6ºC, intermittent or constant) 
Persistent oral candidiasis (thrush) 
Oral hairy leukoplakia 
Pulmonary tuberculosis (current) 
Severe presumed bacterial infections (e.g., pneumonia, empyema, pyomyositis, 
bone or joint infection, meningitis, bacteremia) 
Acute necrotizing ulcerative stomatitis, gingivitis, or periodontitis 
Unexplained anemia (hemoglobin <8 g/dL) 
Neutropenia (neutrophils <500 cells/µL) 
Chronic thrombocytopenia (platelets <50,000 cells/µL) 
Clinical Stage 4 
HIV wasting syndrome 
Pneumocystis pneumonia 
Recurrent severe bacterial pneumonia 
Chronic herpes simplex infection (orolabial, genital, or anorectal site for >1 month or 
visceral herpes at any site) 
Esophageal candidiasis (or candidiasis of trachea, bronchi, or lungs) 
Extrapulmonary tuberculosis 
Kaposi sarcoma 
Cytomegalovirus infection (retinitis or infection of other organs) 
Central nervous system toxoplasmosis 
HIV encephalopathy 
Cryptococcosis, extrapulmonary (including meningitis) 
Disseminated nontuberculosis mycobacteria infection 
Progressive multifocal leukoencephalopathy 
Candida of the trachea, bronchi, or lungs 
Chronic cryptosporidiosis (with diarrhea) 
Chronic isosporiasis 
Disseminated mycosis (e.g., histoplasmosis, coccidioidomycosis, penicilliosis) 
Recurrent nontyphoidal Salmonella bacteremia 
Lymphoma (cerebral or B-cell non-Hodgkin) 
Invasive cervical carcinoma 
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CONFIDENTIAL 
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Atypical disseminated leishmaniasis 
Symptomatic HIV-associated nephropathy 
Symptomatic HIV-associated cardiomyopathy 
Reactivation of American trypanosomiasis (meningoencephalitis or myocarditis) 
 
REF: World Health Organization. WHO Case Definitions of HIV for Surveillance and Revised Clinical Staging and Immunological 
Classification of HIV-Related Disease in Adults and Children; 2007 
Vital Signs 
The following abnormalities will be defined for vital signs: 
Abnormality Code 
Vital Signs Parameter 
 
Pulse 
DBP 
SBP 
RR 
Abnormalities on actual values 
“Abnormally low” 
≤ 50 bpm 
≤ 50 mmHg 
≤ 90 mm Hg 
<12 
Breaths per minute 
“Grade 1 or mild” 
- 
> 
90 
mmHg-
<100 mmHg 
> 140 mmHg-
<160 mmHg 
17-20 
Breaths per minute 
“Grade 2 or moderate” 
- 
≥ 100 mmHg-
<110 mmHg 
≥ 160 mmHg-
<180 mmHg 
21-25 
Breaths per minute 
“Grade 3 or severe” 
- 
≥ 110 mmHg 
≥ 180 mmHg 
>25 
Breaths per minute 
“Abnormally high or Grade 
4” 
≥ 120 bpm 
- 
- 
Intubation 
 
 
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Protocol Version: Russia V2.0 / 25 Jan 2019, Incorporating Protocol V3.0 / 14 Jan 2019 
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CONFIDENTIAL 
Page 97 of 98 
Appendix 4: Cardiovascular Safety 
CARDIOVASCULAR 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Cardiac 
Rhythm 
 
asymptomatic, 
transient signs, 
no Rx required 
recurrent/persiste
nt; symptomatic 
Rx required 
unstable 
dysrythmia; 
hospitalization and 
treatment required 
Hypertension 
transient increase > 
20 mm/Hg; no 
treatment 
recurrent, 
chronic increase 
> 20mm/Hg. 
/treatment 
required 
acute treatment 
required; 
outpatient 
treatment or 
hospitalization 
possible 
end organ damage 
or hospitalization 
required 
Hypotension 
transient orthostatic 
hypotension with 
heart rate increased 
by <20 beat/min or 
decreased by <10 
mm Hg systolic BP, 
no treatment 
required. 
symptoms due to 
orthostatic 
hypotension or 
BP decreased by 
<20 mm Hg 
systolic; 
correctable with 
oral fluid 
treatment 
requires IV fluids; 
no hospitalization 
required 
mean arterial 
pressure <60mm/ 
Hg or end organ 
damage or shock; 
requires 
hospitalization and 
vasopressor 
treatment 
Pericarditis 
minimal effusion 
mild/moderate 
asymptomatic 
effusion, no 
treatment 
symptomatic 
effusion; pain; 
EKG changes 
tamponade; 
pericardiocentesis 
or surgery required 
Hemorrhage, 
Blood Loss 
microscopic/occult 
mild, no 
transfusion 
gross blood loss; 
1-2 units 
transfused 
massive blood loss; 
> 3 units transfused 
All-important abnormalities from the ECG readings will be reported. 
The percentage of participants with increases in QTc of <30, 30-60, or > 60 ms from baseline 
will also be tabulated at each time point. 
Abnormality Code 
ECG parameter 
 
HR 
PR 
QRS 
QTcorrected 
Abnormalities on actual values 
“Abnormally low” 
≤ 50 bpm 
NAP 
≤ 50 ms 
- 
“Abnormally high” 
≥ 120 bpm 
≥ 210 ms 
≥ 120 ms 
- 
“]450 ms, 480 ms] 
- 
- 
- 
450 ms < QTc ≤ 480 ms 
“]480 ms, 500 ms] 
- 
- 
- 
480 ms < QTc ≤ 500 ms 
“More than 500 ms 
- 
- 
- 
QTc > 500 ms 
Abnormalities on changes from baseline 
“[30; 60] ms” 
- 
- 
- 
[30; 60] ms 
“> 60 ms” 
- 
- 
- 
> 60 ms 
 
 
 
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CONFIDENTIAL 
Page 98 of 98 
Appendix 5: Karnofsky Performance Status Scale Definitions Rating (%) Criteria 
Description 
% 
Able to carry on normal activity 
and to work; no special care 
needed. 
Normal no complaints; no evidence of disease. 
100 
Able to carry on normal activity; minor signs or 
symptoms of disease. 
90 
Normal activity with effort; some signs or symptoms 
of disease.  
80 
Unable to work; able to live at 
home 
and 
care 
for 
most 
personal needs; varying amount 
of assistance needed. 
Cares for self; unable to carry on normal activity or 
to do active work. 
70 
Requires occasional assistance, but is able to care 
for most of his personal needs. 
60 
Requires considerable assistance and frequent 
medical care.  
50 
Unable to care for self; requires 
equivalent of institutional or 
hospital care; disease may be 
progressing rapidly. 
Disabled; requires special care and assistance. 
40 
Severely disabled; hospital admission is indicated 
although death not imminent. 
30 
Very sick; hospital admission necessary; active 
supportive treatment necessary. 
20 
Moribund; fatal processes progressing rapidly. 
10 
Dead 
0 
 
Ref: Oxford Textbook of Palliative Medicine, Oxford University Press.  1993; 109. 
 
 
 
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Protocol Number: NC-008 
Protocol Amendment No.: Russia Amendment 1 / 25-JAN-
2019 
Protocol Name: SimpliciTB 
Protocol Amendment  
or Administrative Change 
TMP-C-SOP01-C V1.0 30-Nov-2018 
CONFIDENTIAL 
This document is proprietary and shall not be reproduced without prior written permission from TB Alliance. 
Lead Trial Number 
Trial Name
NC-008 
SimpliciTB 
x   Protocol Russia Amendment Number 1, Dated 25/JAN/2019, Incorporating Protocol V3.0/14January2019 
 Protocol Administrative Change Number _ _, Dated _ _/_ _ _/_ _ _ _ 
Summary - Protocol section changed 
Does amendment / 
administrative change 
affect any of the 
elements listed? 
YES
NO
A 
Purpose of trial 
x 
B 
Design of trial 
x 
C 
Informed consent 
x 
D 
Recruitment procedure 
x 
E 
Measures of efficacy 
x 
F 
Schedule of samples 
x 
G 
Addition or deletion of tests or measures 
x 
H 
Number of participants 
x 
I 
Age range of participants 
x 
J 
Inclusion criteria 
x 
K 
Exclusion criteria 
x 
L 
Safety monitoring 
x 
M 
Duration of exposure to the investigational medicinal product(s) 
x 
N 
Change of posology of the investigational medicinal product(s) 
x 
O 
Change of comparator 
x 
P 
Statistical analysis 
x 
1 of 48
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Protocol Number: NC-008 
Protocol Amendment No.: Russia Amendment 1 / 25-JAN-
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Protocol Name: SimpliciTB 
 
 
Protocol Amendment  
or Administrative Change 
 
TMP-C-SOP01-C V1.0 30-Nov-2018 
CONFIDENTIAL 
This document is proprietary and shall not be reproduced without prior written permission from TB Alliance. 
Reasons for Protocol Amendment or Administrative Change: 
1 
Change: All references to The Global Alliance for TB Drug Development have been changed to TB Alliance (TBA).  The correct and current TBA logo has been 
placed into the header of the protocol, on the cover page. 
2 
Delete: Lead Investigator signature filed, as there has not been in the past 
unnecessary RA and EC queries, as experienced with the review and approval cycles of the prior Protocol Versions 1.0 and 2.0. 
3 
Add: Abbreviations and Definition of Terms - DST, Drug Susceptibility Testing 
4 
Add: Abbreviations and Definition of Terms - HR, Hazard Ratio 
5 
Change: Abbreviations and Definition of Terms - LTFU, previously described as Long-Term Follow-up, changed to Lost to Follow-up in the section 
6 
Add: Abbreviations and Definition of Terms - WGS, Whole Genome Sequencing. 
7 
Delete: 1.1 Synopsis Summary, Section Trial Objective(s) - description and treatment duration from the as it is not applicable to this section. 
8 
Add:  1.1 Synopsis Summary, Statistical Methods  description of abbreviated definitions from the SAP to provide further clarity 
9 
Clarify: 1.1 Synopsis Summary and Protocol Section 6.1.2 Instructions for Dosing Control Treatment Regimen (HRZE/HR) - The participants weight at the 
Screening (HRZE) and Week 8 (HR) visits will be used to determine which weight band and HRZE and HR does to administer, to ensure optimal dosing at these
2 time-points when changing from HRZE to HR. 
10
Clarify: 1.1 Synopsis Summary and Protocol Section 6.3 Treatment Modification(s)  If more than 7 to  35 consecutive doses are missed, these must be made 
up with the same treatment combination or dose that was missed, as the Bedaquiline dose (BPaMZ treatment regime) changes from 200mg to 100 mg at Week 
9, and from HRZE to HR at Week 9 (HRZE/HR treatment regime).  
 
11
Change:  1.1 Synopsis, Statistical Methods and Protocol Section 9.0 Statistical Analysis - the Statistical Analysis Plan (SAP) will be written and signed of prior 
to the interim analysis. 
12
Change: 1.1 Synopsis, Statistical Methods and Protocol Section 9.3 Interim Analysis - There is one planned interim efficacy analysis which will occur after 
approximately 60 assessable participants have been randomised to the control arm and have reached the 8-week primary endpoint. Time to culture negative 
status in liquid media up to 8 weeks will be analysed using a Cox regression model, censoring for death and lost to follow up/withdrawal to estimate the hazard 
ratio (HR). Following a review of these interim findings, the following considerations will be given to modify the trial objectives and sample size: 
 
If the observed HR (time to culture negativity, experimental arm vs. HRZE control arm) is >2, the sample size may be increased to adequately power the study 
on the key secondary efficacy endpoint (clinical and microbiological outcome at 52 weeks from randomization), which will then become the primary efficacy 
endpoint. The study efficacy objectives will be updated as follows: 
 
- 
Primary Objective: To determine the incidence of bacteriologic failure or relapse or clinical failure at 52 weeks from the start of treatment / 
randomisation.  
- 
Secondary Objective: To evaluate the time to culture negativity over 8 weeks, from the start of treatment / randomisation. 
 
2 of 48
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TB Alliance 
Protocol Number: NC-008 
Protocol Amendment No.: Russia Amendment 1 / 25-JAN-
2019 
Protocol Name: SimpliciTB 
 
 
Protocol Amendment  
or Administrative Change 
 
TMP-C-SOP01-C V1.0 30-Nov-2018 
CONFIDENTIAL 
This document is proprietary and shall not be reproduced without prior written permission from TB Alliance. 
To achieve 90% power and overall 5% 2-sided significance after adjusting for the interim analysis, this will mean increasing the sample size to 
225 participants per randomised arm, i.e., to a total of 450 DS-TB participants (and up to 225 DR-TB participants). This adaptation is based on the Multi-arm 
Multi-stage (MAMS) framework and full details are provided in the Statistical Analysis Plan. 
13
Delete: Synopsis, Trial Duration  removed reference to 3 database locks as it is not applicable to the trial duration. 
14
Clarify: 1.2 Synopsis Flow Chart and Procedures - Week 1 occurs on Day 8 and not Day 7 (Day 7 deleted), as per Protocol Memo 1 dated 11 May 2018, to 
ensure that 7 days of IMP are administered to the participant between Day 1 / Baseline and Week 1. 
15
Change: 1.2 Synopsis and Flow Chart (foot note) General:  vital signs and blood draws (removed ECGs) are to be performed before dosing, unless otherwise 
specified.  Vital signs and or ECGs should be done before blood draws (safety and PK) on days with those assessments. 
16
Change: Synopsis and Flow Chart (foot note, a)  Screening assessments must occur during the Screening period (Day -9 to -1) before Day 1 (Baseline). This 
has been amended for clarity. 
17
Clarify: 1.2 Synopsis and Flow Chart (foot note, f) that rifampicin resistance testing includes Hain MTBDRPlus and Hain MTBRsl. 
18
Clarify: 1.2 Synopsis and Flow Chart (foot note, f) that unscheduled visits referenced in this section, are for the collection of additional sputum samples. 
19
Change: 1.2 Synopsis and Flow Chart (foot note, f) if sputum samples collected at Week 8 or later (remove reference to Weeks 17, 26, 52 and 104) are 
contaminated the participant return for an unscheduled visit. 
20
Change: 1.2 Synopsis and Flow Chart (foot note, g) Rapid molecular tests will be done for fluoroquinolones, injectables, isoniazid and rifampicin resistance 
(only on MTB positive cultures in the follow-up period) and Drug Susceptibility Testing will be done for streptomycin, rifampicin, isoniazid, ethambutol, 
moxifloxacin and pyrazinamide only, in liquid culture 
21
Add: 1.2 Synopsis and Flow Chart (foot note, n)  Additional single 12-lead ECGs to be performed prior to pre- and post-dose PK sampling to observe the 
cardiac safety profile at defined timepoints after dosing, over time, on these days (weeks 2, 8 and 17). 
22
Add: 1.2 Synopsis and Flow Chart (foot note, s) Blood draws for PK samples collected pre and post-dose must be done after the ECG is performed, as 
-dose. 
23
Add: 1.2 Synopsis and Flow Chart (foot note, s) PK samples at Weeks 39, 65, 78 and 104 are to be obtained at any time on the day of the scheduled visit, and 
only bedaquiline and M2 will be measured. 
24
Add: 1.2 Synopsis and Flow Chart (foot note, s) and Protocol Section 7.4 PK Variables and Procedures - If IMP is not administered during Week 2, 8 and or 17, 
then only a single PK sample is required to be obtained at any time during the visit assessment. 
25
Clarify: 1.2 Synopsis and Flow Chart (foot note, v) the Investigator Assessment, per the Synopsis and Flow Chart, is only performed at Week 52 and 104 or 
anytime the Investigator determines that the participant fulfills the criteria for outcome of treatment failure. 
26
Add: 1.2 Synopsis and Flow Chart (additional foot note, x) and Protocol Section 7.1 Demographic and Background Variables and Procedures - The Karnofsky 
Score is only to be performed on HIV+ participants. 
27
Clarify: Protocol Section 3.1 Primary Endpoint - To evaluate the time to culture negativity over 8 weeks from the start of the following treatment regimens in 
participants with: Drug Sensitive TB (DS-TB) and Drug Resistant TB (DR-TB). DR-TB are defined as participants with: mono-resistance to rifampicin or 
isoniazid, OR resistance to both rifampicin and isoniazid (DR-TB).  The treatment allocation descriptions have been removed as they are irrelevant to this 
section. 
3 of 48
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TB Alliance 
Protocol Number: NC-008 
Protocol Amendment No.: Russia Amendment 1 / 25-JAN-
2019 
Protocol Name: SimpliciTB 
 
 
Protocol Amendment  
or Administrative Change 
 
TMP-C-SOP01-C V1.0 30-Nov-2018 
CONFIDENTIAL 
This document is proprietary and shall not be reproduced without prior written permission from TB Alliance. 
28
Clarify: Protocol Section 3.2 Secondary Endpoints, PK and PD - Plasma concentrations from sparse sampling will be used to update existing population PK 
models and derive exposure metrics (e.g., minimum plasma concentration [Cmin], maximum plasma concentration [Cmax], area under curve over a 
dosing interval [AUC]) for bedaquiline and its M2 metabolite, pretomanid, moxifloxacin, and pyrazinamide. 
29
Clarify: Protocol Section 4.1 Summary of Trial Design - Participants, trial Investigators and staff, including laboratory staff, will not be blinded to treatment 
randomisation and allocation (as all DR-TB participants are allocated and not randomised, to only receive 6 months BPaMZ) during the treatment phase of the 
trial. 
30
Clarify: Protocol Section 4.1 has been re-written to state that DS participants will be randomized (either to HRZE/HR or 4 months BPaMZ) and all DR 
participants will be allocated and not randomized to 6 months BPaMZ. 
31
Change: Protocol Section 5.1 Inclusion Criteria #5 has been changed to the following for the DS-TB treatment arm participants: sensitive to rifampicin, isoniazid 
and fluoroquinolones by rapid sputum-based test. 
32
Change: Protocol Section 5.1 Inclusion Criteria #5 has been changed to not (late) exclude DS-TB participants who are randomized to the trial due to being 
sensitive to rifampicin and isoniazid by rapid molecular sputum-based test, however on receipt of the rifampicin and or isoniazid phenotypic resistance testing in 
liquid culture this shows they are rifampicin or isoniazid resistant. 
33
Change: Protocol Section 5.1 Inclusion Criteria #5 has been changed for the DR-TB treatment arm participants, as follows:  
 
- 
Resistant to rifampicin and/or isoniazid; but sensitive to fluoroquinolones by rapid sputum-based test AND  
- 
Should not have had previous treatment for DR-TB/MDR-TB, although may have been on a DR-TB/MDR-TB treatment regimen for no longer than 3 
days (previously, was 7 days) at start of screening. 
- 
Participants with resistance to injectables by rapid sputum-based test are allowed in the trial. 
- 
When Phenotypic DST and whole genome sequencing (WGS) results on baseline samples become available, any results that are discordant with the 
dical Monitor in consultation with 
the Investigator to determine whether that participant is unlikely to respond to treatment and should therefore be removed from the trial and given 
alternative treatment.  If a participant is removed from the trial for such a reason, they will be classified as a late exclusion. 
34
Change: Protocol Section 5.1 Inclusion Criteria #7, Contraception  Contraception has been updated to require that both the female trial participants and the 
Barrier method combined with hormone-based contraceptives or an intra-
uterine device.   
 
Both male and female participants must be willing to continue practicing birth control methods and are not planning to conceive throughout treatment and for 6 
months (previously stated in this section as 3 months) after the last dose of trial IMP or discontinuation from trial IMP in case of premature discontinuation, to 
ensure consistency throughout the protocol, as per Section 5.2 Exclusion Criteria #13 that also references a period of 6 months.  
35
Add: Protocol Section 5.2 Exclusion Criteria #3 - Historical and or current use of local traditional medications/herbs which in the opinion of the Investigator 
-specified restrictions, visits and evaluations. 
36
Delete: Protocol Section 5.2 Exclusion Criteria #9 - Resistant to fluoroquinolones (rapid, sputum-based molecular screening tests). If they are randomised into 
the trial due to being sensitive to fluoroquinolones by rapid sputum-based test, however on receipt of the moxifloxacin phenotypic resistance testing in liquid 
culture they are found to be fluoroquinolones resistant, they will be excluded as late exclusions. This criterion is already stipulated in the updated Inclusion 
Criteria #5.  
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CONFIDENTIAL 
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37
Change: Protocol Section 5.2 Exclusion Criteria #15, 16, 17 and 18, as these criteria are consolidated and described more specifically in the updated Exclusion 
Criteria #15, including an update to a limit of 3 days previous DR-TB/MDR-TB treatment regimen for the DR-TB participants. 
38
Clarify: Protocol Section 5.2 Exclusion Criteria #18 (previously #21) has been corrected, as follows:  Use of systemic glucocorticoids within one year of the start 
of the Screening visit (topical, inhaled or intranasal glucocorticoids are allowed), as they can lead to visual opacities or cataracts. 
39
Add: Protocol Section 5.2 Exclusion Criteria #19 (previously #22) has been extended to provide additional instructions wrt ART for HIV infected participants. 
40
Delete: Protocol Section 5.2 Exclusion Criteria #20 (previously #24) has been updated to remove the DMID grade for platelets, haemoglobin, AST, ALT, ALP 
and total bilirubin to provide clarity and remove ambiguity.  The actual values of these laboratory results remain unchanged. 
41
Delete: Protocol Section 5.3 Restrictions  1st paragraph, 2nd 
However, 
if concomitant medications are necessary for 
 
42
Clarify: Protocol Section 5.3 Restrictions  The section that describes medications that should be avoided has been updated to state the following:  The 
following medicinal products should be avoided from Day 1 (Baseline visit) and during the treatment period as much as possible (unless this is required for 
emergency management of the participant). Investigators may also contact the Sponsor Medical Monitor for further guidance. 
43
Delete: Protocol Section 5.3 Restrictions  
(Inclusion Criteria #7) to participate in this trial. 
44
Change:  Protocol Section 5.4 Treatment Discontinuation and/or Early Withdrawal, as the criteria for late exclusion based on phenotypic DST and whole 
genome sequencing has been amended. 
45
Delete: Protocol Section 5.4 Treatment Discontinuation and/or Early Withdrawal  the following 2 reasons for withdrawal have been removed, due to the 
updated Inclusion Criteria #5: 
- 
Participants, who have been randomised onto the trial as fluoroquinolone sensitive on the rapid sputum-based test result, who on receipt of the 
fluoroquinolone resistance testing using an indirect susceptibility test in liquid culture; this shows a fluoroquinolone resistant result. 
- 
Early withdrawal due to TB (removed as this is now detailed in the additional criteria listed in item #44 above) 
46
Clarify: Protocol Section 5.4.2 Unscheduled Visits has been updated to provide additional clarity, as follows: 
- 
Addition of the following reason: For any medical reason, as determined by the Investigator or participant. 
- 
End of Treatment Period (Week 17 or 26) has been removed from the timepoint at which sputum cultures are assessed for the primary outcome status, 
as this was incorrectly stated in the previous protocol 
- 
General rewording of this section to provide clarity to the Investigator on when Unscheduled Assessments should occur 
- 
understanding of the 
Unscheduled Assessment requirements. 
- 
should 
 
47
Clarify: Protocol Section 5.4.4 Early Withdrawal due to TB  last paragraph has been updated to ensure that the Investigator provides a referral letter and at a 
minimum should include all treatment received by the participant and information about any suspected/confirmed adverse event/reaction related to any of the 
ications.  A follow-up call should 
participant attended the NTP clinic. 
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48
Clarify: Protocol Section 7.1 Demographic and Background Variables and Procedures  The following 2 descriptions of testing as documented in Section 7.5 
Mycobacteriology Characterization Variable and Procedures: 
- 
Rapid molecular tests for isoniazid, rifampicin, fluoroquinolones resistance (Hain MTBDRplus and HainMTBRsl) 
- 
Liquid Culture (MGIT) for Mycobacterium tuberculosis (MTB), followed by a speciation test to detect presence or absence of MTB and obtain time to 
positivity (TTP) when positive. 
Delete:  Protocol Section 7.1 Demographic and Background Variables and Procedures - Gene Xpert, as this was incorrectly included in the previous version of 
the protocol. 
49
Clarify: Protocol Section 7.1 Demographic and Background Variables and Procedures  method of birth control: make and female participants and their sexual 
partners 
50
Clarify:  Protocol Section 7.5 Mycobacteriology Characterization Variable and Procedures  exact wording documented in 1.2 Synopsis and Flowchart 
(footnote, g) to ensure consistency of procedure description. 
 
Delete: Pre-screening culture that was used for the tests that qualified the participant for inclusion into the trial to be sub-cultured and sent to the central 
microbiology laboratory from the applicable local microbiology laboratory, for relevant participants / no positive cultures f
because only assessments perform from the Screening visit will be used for this trial. 
 
Change: Protocol Section 7.5 Mycobacteriology Characterization Variable and Procedures  all MTB isolates (not just those obtained at Baseline / Day 1, as 
 
51
Clarify: Protocol Section 8.2.1 Follow-up of Adverse Events  reference to the reporting requirements is now referenced as the eCRF Guidelines (incorrectly 
referenced as SAE Completion Guidelines, in the previous version of the protocol). 
52
Clarify: Protocol Section 8.2.6 Pregnancy  reporting required at any time during the trial. 
53
Delete: Protocol Section 8.3 Monitoring for Specific Toxicities  8.3.3 Neurological, has been removed, as it is not a requirement given the safety profiles of the 
BPaMZ and or HRZE/HR trial regimens. 
54
Add: (moved from the Synopsis): Protocol Section 9.0 Statistical Analysis  added the following:  There will be 3 data analyses and trial reports generated for 
this trial:  
- 
When all participants have completed 8 weeks (2 months) of treatment from baseline.  
- 
When all participants have completed 52 weeks (12 months) follow-up from start of therapy. 
- 
When all participants have completed 104 weeks (24 months) follow-up from start of therapy.  
55
Delete: Protocol Section 11.3 Protocol Deviations  reference to the Monitoring Plan has been removed as the Investigator is not provided with this plan, and 
therefore would not deviate from this plan. 
56
Delete: Removal of the following appendixes and references in the protocol, as these appendixes are now included in separate trial documents, and provided to 
the Investigator: 
- 
Appendix 6 TB Symptom Profile is 
 
- 
Appendix 7 Patient Reported Health Status is 
 
- 
Appendix 8 Liver Toxicity 
 
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57
Clarify:  Protocol Section 5.2 Exclusion Criteria  with the addition of criteria #3, deletion of #9, 15, 16 the numbering of the Exclusion Criteria has had to 
change. 
58
Change:  Tables  with the addition of Table #6, subsequent table numbering updated  
59
Change:  all references to the 2 treatment periods of Week 17 (4-month treatment arm) and Week 26 (6-month treatment arm) are stated as either Week 17 or 
Week 26, only. 
60
Change:  
 
61
Change:  
 
62
Change: all references to B-Pa-M-Z have been changed to BPaMZ. 
63
Change: all references to therapy  has been changed to treatment  for consistency. 
64
Change: all references to early morning sample or early morning sputum, has been changed to 
 
65
Change:  all references to Drug Resistant TB (DR-TB) and Drug Sensitive TB (DS-TB), are documented as either DS-
 
66
Change:  all references to trial medication and or study medication, has been ch
 
67
Delete: all references to study time points 
.  All study time points are only referenced in weeks. 
68
Administrative changes, including spelling, grammar, 
updated throughout the entire document.   
# 
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1 
Cover Page 
Global Alliance for TB Drug Development 
TB Alliance 
 
1 
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2 
Protocol 
signature page 
2 
3 
Abbreviations 
and Definitions of 
Terms 
No previous text 
DST 
Drug Susceptibility Testing 
 
3 
4 
Abbreviations 
and Definitions of 
Terms 
No previous text 
HR 
Hazard Ratio 
4 
5 
Abbreviations 
and Definitions of 
Terms 
LTFU 
Long term follow-up 
LTFU Lost to Follow-up 
5 
6 
Abbreviations 
and Definitions of 
Terms 
No previous text 
WGS
Whole Genome Sequencing
6 
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7 
1.1 Synopsis 
Summary, Trial 
Objectives 
To evaluate the efficacy, safety and tolerability at 8 weeks 
(2-months), 52 weeks (12-months), and 104 Weeks (24-
months) post the start of the following treatment regimens 
in participants with: 
 
Drug Sensitive TB (DS-TB) 
 
BPaMZ given for 17 Weeks (4 months), or 
 
Standard HRZE/HR treatment given for 26 weeks 
(6  
months) 
 
Drug Resistant TB (DR-TB)  
 
BPaMZ given for 26 Weeks (6 months) 
 
DR-TB Defined as participants with  
1. mono-resistance to rifampicin or isoniazid, OR 
2. resistance to both rifampicin and isoniazid (MDR-TB) 
To evaluate the efficacy, safety and tolerability at 8 weeks 
(2-months), 52 weeks (12-months), and 104 Weeks (24-
months) post the start of the following treatment regimens 
in participants with: 
 
Drug Sensitive TB (DS-TB) 
 
BPaMZ given for 17 Weeks (4 months), or 
 
Standard HRZE/HR treatment given for 26 weeks 
(6  
months) 
 
Drug Resistant TB (DR-TB)  
 
BPaMZ given for 26 Weeks (6 months) 
 
DR-TB Defined as participants with  
1. mono-resistance to rifampicin or isoniazid, OR 
2. resistance to both rifampicin and isoniazid (MDR-TB) 
7 
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8 
1.1 Synopsis 
Summary, 
Statistical 
Methods 
No previous text to describe the abbreviated SAP 
definitions 
Abbreviated Definitions, full definitions will be 
described in the Statistical Analysis Plan (SAP):  
 
 
Bacteriologic failure: During the treatment period, 
failure to attain or maintain culture conversion to 
negative.  
 
Bacteriologic relapse: During the follow-up 
period, failure to maintain culture conversion to 
negative status, with culture conversion to 
positive status with a strain of Mycobacterium 
tuberculosis (MTB) genetically identical to the 
infecting strain at baseline.  
 
Clinical failure: A change from protocol-specified 
TB treatment to a new regimen before end of 
protocol specified treatment due to treatment 
failure, retreatment for TB during follow up, or TB-
related death.  
 
Note:  
 
o 
Culture conversion requires at least 2 
consecutive culture negative/positive samples 
at least 7 days apart.  
o 
Participants who are documented at a visit as 
unable to produce sputum and who are 
clinically considered to be responding well to 
treatment will be considered to be culture 
negative at that visit.  
 
8 
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9 
1.1 Synopsis 
Summary, 
Positive Control 
Product, Dose 
and Mode of 
Administration 
and Protocol 
Section 6.1.2 
No previous text 
Week 8 (HR) visits will be used to determine which 
weight band and HRZE and HR dose to administer. 
 
9 
10
1.1 Synopsis 
Summary, 
Treatment 
Interruptions 
/Pauses and 
Protocol Section 
6.3 
 
Up to 7 consecutive doses of IMP doses: restart 
IMP, no extension of IMP required. 
 
restart IMP and extend the IMP treatment by the 
number of consecutive doses missed. The final 
treatment visit should also be pushed out to the 
date of last dose. It is not necessary to have an 
unscheduled visit at the time when the end of 
treatment visit would have been.   
 
Greater than 35 consecutive doses of IMP, 
discontinue IMP and withdraw participant from the 
trial. 
 
If the participant misses a total (sum) of 56 
cumulative missed doses, discontinue the IMP 
and withdraw participant from the trial. 
 
 
Up to 7 consecutive doses of IMP doses: restart 
IMP, no extension of IMP required. 
 
Greater If more 
 
missed, before the end of the treatment period 
(Week 17/26): restart IMP and extend the IMP 
treatment by the number of consecutive doses 
missed. The final treatment visit should also be 
pushed out to the date of last dose. It is not 
necessary to have an unscheduled visit at the 
time when the end of treatment visit would have 
been.   
 
Greater If more than 35 consecutive doses of 
IMP, discontinue IMP and withdraw participant 
from the trial. 
 
If the participant misses a total (sum) of 56 
cumulative missed doses, discontinue the IMP 
and withdraw the participant from the trial. 
If more than 7 to  35 consecutive doses are missed, 
these must be made up with the same treatment 
combination or dose that was missed.  
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11
1.1 Synopsis, 
Statistical 
Methods and 
Protocol Section 
9.0 Statistical 
Analysis 
A general description of the statistical methods planned to 
be used to analyse efficacy data is outlined below. 
Specific details will be provided in the statistical analysis 
plan (SAP,) which will be written and signed off prior to 
the first participant enrolled in the trial. 
 
A general description of the statistical methods planned to 
be used to analyse efficacy data is outlined below. 
Specific details will be provided in the Statistical Analysis 
Plan (SAP) which will be written and signed off prior to 
the interim analysis. 
 
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12
1.1 Synopsis, 
Statistical 
Methods and 
Protocol Sections 
2.3.1 Trial Design 
Rationale, and 
9.3 Interim 
Analysis 
No previous text 
Interim Analysis
 
There is one planned interim efficacy analysis which 
will occur after approximately 60 assessable 
participants have been randomised to the control arm 
and have reached the 8-week primary endpoint. Time 
to culture negative status in liquid media up to 8 
weeks will be analysed using a Cox regression 
model, censoring for death and lost to follow 
up/withdrawal to estimate the hazard ratio (HR). 
Following a review of these interim findings, the 
following considerations will be given to modify the 
trial objectives and sample size: 
 
If the observed HR (time to culture negativity, 
experimental arm vs. HRZE control arm) is >2, the 
sample size may be increased to adequately power 
the study on the key secondary efficacy endpoint 
(clinical and microbiological outcome at 52 weeks 
from randomization), which will then become the 
primary efficacy endpoint. The study efficacy 
objectives will be updated as follows: 
 
- 
Primary Objective 
To determine the incidence of bacteriologic failure or 
relapse or clinical failure at 52 weeks from the start of 
treatment / randomisation.  
 
- 
Secondary Objective 
To evaluate the time to culture negativity over 8 
weeks, from the start of treatment / randomisation. 
 
All other study objectives will remain unchanged. 
 
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To achieve 90% power and overall 5% 2-sided 
significance after adjusting for the interim analysis, 
this will mean increasing the sample size to 
225 participants per randomised arm, i.e., to a total of 
450 DS-TB participants (and up to 225 DR-TB 
participants). This adaptation is based on the Multi-
arm Multi-stage (MAMS) framework and full details 
are provided in the Statistical Analysis Plan.  
13
1.1 Synopsis, 
Trial Duration 
Approximately 4 years (18-month enrolment period for 
DS-TB participants, up to 26 week-treatment, and follow-
up until week 104 from start of treatment. Depending on 
the DR-TB recruitment rate, enrolment into this arm may 
continue after enrolment into the DS-TB arms is 
complete.  
 
There will be 3 database locks, data analyses and trial 
reports generated for this trial:  
 
1. When all participants have completed 8 weeks (2 
months) of treatment from baseline.  
2. When all participants have completed 52 weeks 
(12 months) follow-up from start of therapy. 
3. When all participants have completed 104 weeks 
(24 months) follow-up from start of therapy.  
 
Approximately 4 years (18-month enrolment period for 
DS-TB participants, up to 26 week-treatment, and follow-
up until week 104 from start of treatment. Depending on 
the DR-TB recruitment rate, enrolment into this arm may 
continue after enrolment into the DS-TB arms is 
complete.  
 
There will be 3 database locks, data analyses and trial 
reports generated for this trial:  
 
1. When all participants have completed 8 weeks (2 
months) of treatment from baseline.  
2. When all participants have completed 52 weeks 
(12 months) follow-up from start of therapy. 
3. When all participants have completed 104 weeks 
(24 months) follow-up from start of therapy.  
 
13 
14
1.2 Synopsis 
Flow Chart and 
Procedures 
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# 
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15
1.2 Synopsis 
Flow Chart and 
Procedures (foot 
notes), General 
GENERAL: Vital signs, ECGs and blood draws are to be 
performed pre-dosing unless otherwise specified. Vital 
signs and/or ECGs should be done prior to blood draws 
(safety and PK) on days with those assessments. 
GENERAL: Vital signs, ECGs and blood draws are to be 
performed before dosing unless otherwise specified. Vital 
signs and/or ECGs should be done before blood draws 
(safety and PK) on days with those assessments. 
15 
16
1.2 Synopsis 
Flow Chart and 
Procedures (foot 
note a) 
Screening: Screening assessments can occur on different 
days, within nine days before Day 1 dosing 
(randomisation).  
 
Screening: Screening assessments can occur on different 
days, within nine days before Day 1 dosing 
(randomisation Baseline).  
 
16 
17
1.2 Synopsis 
Flow Chart and 
Procedures (foot 
notes, f)  
Rapid molecular tests for fluoroquinolones, isoniazid and 
rifampicin resistance 
Rapid molecular tests for fluoroquinolones, isoniazid and 
rifampicin resistance (Hain MTBDRplus and Hain 
MTBRsl);  
 
17 
18
1.2 Synopsis 
Flow Chart and 
Procedures (foot 
notes, f) 
Baseline to Week 104, including any Unscheduled visits:  
 
Day 1 (Baseline) to Week 104 and including any 
Unscheduled visits for additional sputum samples:  
 
 
 
18 
19
1.2 Synopsis 
Flow Chart and 
Procedures (foot 
notes, f) 
If both sputum samples at Weeks 8, 17 (4-month 
treatment arm), 26 (6-month treatment arm), 52 or 104 
are contaminated, the participant should return for an 
unscheduled visit(s) to give additional samples or to 
document that the participant is not able to produce 
sputum. 
If both sputum samples at Weeks 8 or later, 17 (4-month 
treatment arm), 26 (6-month treatment arm), 52 or 104 
are contaminated, the participant should return for an 
unscheduled visit(s) to give additional samples or to 
document that the participant is not able to produce 
sputum. 
19 
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20
1.2 Synopsis 
Flow Chart and 
Procedures (foot 
notes, g) 
Mycobacterial Characterization - MTB isolates will be 
processed for: 
 
- Minimum Inhibitory Concentration (MIC) against 
bedaquiline, pretomanid, and moxifloxacin;  
- Drug Susceptibility Testing for streptomycin, rifampicin, 
isoniazid, ethambutol, moxifloxacin, pyrazinamide and 
second line TB drugs including, but not limited to 
fluoroquinolones, and injectables using an indirect 
susceptibility test in liquid culture;  
- Extraction of organismal (MTB) DNA for whole genome 
sequencing, and comparison of sequences from baseline 
and relapse isolates. 
 
Mycobacterial Characterization - MTB isolates (from the 
first MTB positive culture) will be processed for: 
 
- Rapid molecular tests for fluoroquinolones, 
injectables, isoniazid and rifampicin resistance (only 
on MTB positive cultures in the follow-up period); 
- Minimum Inhibitory Concentration (MIC) against 
bedaquiline, pretomanid, and moxifloxacin;  
- Drug Susceptibility Testing (DST) for streptomycin, 
rifampicin, isoniazid, ethambutol, moxifloxacin, and 
second line TB drugs including, but not limited to 
fluoroquinolones, and injectables using an indirect 
susceptibility test in pyrazinamide in liquid culture;  
- Extraction of organismal (MTB) DNA for whole genome 
sequencing (WGS), and comparison of sequences from 
baseline and relapse isolates. 
 
20 
21
1.2 Synopsis 
Flow Chart and 
Procedures (foot 
notes, n) and 
Protocol Section 
7.3 Safety and 
Tolerability 
Assessments 
Single 12-Lead ECG: To every extent possible, this 
should be performed at approximately the same time of 
day as the trial procedures (+/-1 hour).  
 
Central ECG analysis will be performed. Results from 
central reading of Day -9 to -1 (Screening) ECG must be 
used to determine eligibility.  
 
Single 12-Lead ECG: ECGs to be performed prior to 
pre- and post-dose PK sampling as described below: 
 
Day 1: pre-dose (within 2 hours prior to dosing) 
 
Week 2: pre-dose (within 2 hours prior to dosing), 
1.5 3 hours post-dose and 4-6 hours post-dose 
 
Week 8: pre-dose (within 2 hours prior to dosing), 
1.5 3 hours post-dose and 4-6 hours post-dose 
 
Week 12: pre-dose (within 2 hours prior to dosing) 
 
Week 17 or at early withdrawal if prior to week 17: 
pre-dose (within 2 hours prior to dosing) and 1.5
3 hours post-dose 
Central ECG analysis will be performed. Results from 
central reading of Day -9 to -1 (Screening) Screening 
ECG must be used to determine eligibility.  
 
21 
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Protocol Name: SimpliciTB 
 
 
Protocol Amendment  
or Administrative Change 
 
TMP-C-SOP01-C V1.0 30-Nov-2018 
CONFIDENTIAL 
This document is proprietary and shall not be reproduced without prior written permission from TB Alliance. 
# 
Section 
Previous Text 
Russia Version 1.0 dated 21-Feb-18 
 
Amended Text 
Version 2.0 dated 15-Jan-19 
Additional text - bold font. Deleted text  strike-through. 
Reason for 
Change 
Insert reason # 
from table above 
22
1.2 Synopsis 
Flow Chart and 
Procedures (foot 
notes, s) 
Pharmacokinetic (PK) Sampling: This process will be 
described in a separate document, the PK Sampling 
Manual. No PK samples will be collected for the HRZE-
HR treatment arm.  Blood draws for PK samples collected 
pre-dose must be done after the ECG is performed.   
Pharmacokinetic (PK) Sampling: This process will be 
described in a separate document, the PK Sampling 
Manual. No PK samples will be collected for the 
HRZE/HR treatment arm.  Blood draws for PK samples 
collected pre- and post-dose must be done after the 
ECG is performed.   
22 
23
1.2 Synopsis 
Flow Chart and 
Procedures (foot 
notes, s) 
Weeks 39, 65, 78 and 104: PK samples are to be 
obtained at any time on the day of the scheduled visit. 
 
Weeks 39, 65, 78 and 104: PK samples are to be 
obtained at any time on the day of the scheduled visit, 
and only bedaquiline and M2 will be measured. 
 
23 
24
1.2 Synopsis 
Flow Chart and 
Procedures (foot 
notes, s) and 
Protocol Section 
7.4 PK Variables 
and Procedures 
No previous text 
If IMP is not administered during Week 2, 8 and or 17, 
then only a single PK sample is required to be 
obtained at any time during the visit assessment. 
 
24 
25
1.2 Synopsis 
Flow Chart and 
Procedures (foot 
notes, v) 
Investigator Assessment: Investigator to review 
participant status and assess whether IMP or TB 
treatment at current 
specify if based on bacteriology and/or clinical 
deterioration and/or radiological deterioration. Investigator 
Assessment to be completed, as shown on the flowchart, 
and at any time Investigator determines that participant 
fulfils criteria for outcome of treatment failure. 
 
Investigator Assessment: Investigator to review the 
participant status and assess whether IMP or TB 
treatment at current visit Week 52 and 104 is considered 
Investigator should specify if the assessment is based on 
bacteriology and/or clinical deterioration and/or 
radiological deterioration. Investigator Assessment to be 
completed, as shown on the flowchart, at Week 52 and 
104, and at any time the Investigator determines that the 
participant fulfils the criteria for outcome of treatment 
failure. 
 
25 
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TB Alliance 
Protocol Number: NC-008 
Protocol Amendment No.: Russia Amendment 1 / 25-JAN-
2019 
Protocol Name: SimpliciTB 
 
 
Protocol Amendment  
or Administrative Change 
 
TMP-C-SOP01-C V1.0 30-Nov-2018 
CONFIDENTIAL 
This document is proprietary and shall not be reproduced without prior written permission from TB Alliance. 
# 
Section 
Previous Text 
Russia Version 1.0 dated 21-Feb-18 
 
Amended Text 
Version 2.0 dated 15-Jan-19 
Additional text - bold font. Deleted text  strike-through. 
Reason for 
Change 
Insert reason # 
from table above 
26
1.2 Synopsis 
Flow Chart and 
Procedures (foot 
notes, x), and 
Protocol section 
7.1 
No previous text 
Karnofsky Score: Only to be performed on HIV+ 
participants. 
26 
27
Protocol Section 
3.1 Primary 
Objective 
Primary Objectives 
 
To evaluate the efficacy, safety and tolerability at 8 weeks 
(2-months), 52 weeks (12-months), and 104 Weeks (24-
months) post the start of the following treatment regimens 
in participants with: 
 
Drug Sensitive TB (DS-TB) 
 
 BPaMZ given for 17 Weeks (4 months) 
 
Standard HRZE/HR treatment given for 26 weeks (6 
months) 
 
Drug Resistant TB (DR-TB)  
 
BPaMZ given for 26 Weeks (6 months) 
 
DR-TB are defined as participants with: 
 
1. 
mono-resistance to rifampicin or isoniazid, OR 
2. resistance to both rifampicin and isoniazid (DR-TB) 
 
Primary Endpoints 
 
To evaluate the time to culture negativity over 8 weeks 
from the start of the following treatment regimens in 
participants with the efficacy, safety and tolerability at 8 
weeks (2-months), 52 weeks (12-months), and 104 
Weeks (24-months) post the start of the following 
treatment regimens in participants with: 
 
- Drug Sensitive TB (DS-TB) 
 
 BPaMZ given for 17 Weeks (4 months) 
 
Standard HRZE/HR treatment given for 26 
weeks (6 months) 
- Drug Resistant TB (DR-TB)  
 
BPaMZ given for 26 Weeks (6 months) 
 
DR-TB are defined as participants with: 
 
2. 
mono-resistance to rifampicin or isoniazid, OR 
2. resistance to both rifampicin and isoniazid (DR-TB) 
 
27 
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TB Alliance 
Protocol Number: NC-008 
Protocol Amendment No.: Russia Amendment 1 / 25-JAN-
2019 
Protocol Name: SimpliciTB 
 
 
Protocol Amendment  
or Administrative Change 
 
TMP-C-SOP01-C V1.0 30-Nov-2018 
CONFIDENTIAL 
This document is proprietary and shall not be reproduced without prior written permission from TB Alliance. 
# 
Section 
Previous Text 
Russia Version 1.0 dated 21-Feb-18 
 
Amended Text 
Version 2.0 dated 15-Jan-19 
Additional text - bold font. Deleted text  strike-through. 
Reason for 
Change 
Insert reason # 
from table above 
28
Protocol Section 
3.2 Secondary 
Objectives, PK 
and PD 
Secondary Objectives 
 
Plasma concentrations from sparse sampling will be used 
to update existing population PK models and derive 
exposure metrics (e.g., Cmin, Cmax, AUC) for 
bedaquiline and its M2 metabolite, pretomanid, 
moxifloxacin, and pyrazinamide. 
Secondary Endpoints 
 
Plasma concentrations from sparse sampling will be used 
to update existing population PK models and derive 
exposure metrics (e.g., minimum plasma concentration 
[Cmin], maximum plasma concentration [Cmax], area 
under curve over a dosing interval [AUC]) for 
bedaquiline and its M2 metabolite, pretomanid, 
moxifloxacin, and pyrazinamide. 
28 
29
Protocol Section 
4.1 Summary of 
Trial Design 
Participants, trial Investigators and staff, including 
laboratory staff, will not be blinded to treatment allocation 
during the treatment phase of the trial. 
Participants, trial Investigators and staff, including 
laboratory staff, will not be blinded to treatment 
randomisation and allocation during the treatment phase 
of the trial. 
 
29 
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710 of 852


 
 
TB Alliance 
Protocol Number: NC-008 
Protocol Amendment No.: Russia Amendment 1 / 25-JAN-
2019 
Protocol Name: SimpliciTB 
 
 
Protocol Amendment  
or Administrative Change 
 
TMP-C-SOP01-C V1.0 30-Nov-2018 
CONFIDENTIAL 
This document is proprietary and shall not be reproduced without prior written permission from TB Alliance. 
# 
Section 
Previous Text 
Russia Version 1.0 dated 21-Feb-18 
 
Amended Text 
Version 2.0 dated 15-Jan-19 
Additional text - bold font. Deleted text  strike-through. 
Reason for 
Change 
Insert reason # 
from table above 
30
Protocol Section 
4.1 Summary of 
Trial Design, 6th 
paragraph 
Eligible participants who meet all the inclusion criteria and 
none of the exclusion criteria, aged 18 and over, male or 
female will be assigned to one of the 3 treatment groups 
with a target of 50% of the participants being HIV positive. 
An interactive web response system (IWRS) will be used 
which will utilize a dynamic randomization system using 
cavitation with a random element to allocate participants 
evenly across the arms by HIV status and type of TB (DS 
versus DR) after they have given written, informed 
consent during the Screening Visit (Days -9 to -1) and 
met all eligibility criteria. 
 
Eligible participants who meet all the inclusion criteria and 
none of the exclusion criteria, aged 18 and over, male or 
female will be assigned to one of the 3 treatment groups 
with a target of 50% of the participants being HIV positive. 
An interactive web response system (IWRS) will be used 
which will utilize a dynamic randomization system using 
cavitation with a random element to allocate participants 
evenly across the arms by HIV status and type of TB (DS 
versus DR) after they have given written, informed 
consent during the Screening Visit (Days -9 to -1) and 
met all eligibility criteria. 
 
DR participants will be treated with 6 months of 
BPaMZ.  DS participants will be randomised using a 
an interactive web response system (IWRS) 
stratifying for cavitation and HIV status to allocate 
participants evenly across the arms after they have 
given written, informed consent during the Screening 
Visit (Days -9 to -1). 
 
30 
31
Protocol Section 
5.1, Inclusion 
Criteria #5 
DS-TB treatment arm participants should be: sensitive to 
rifampicin and isoniazid by rapid sputum-based test 
DS-TB treatment arm participants should be: sensitive to 
rifampicin, isoniazid and fluoroquinolones by rapid 
sputum-based test. 
31 
32
Protocol Section 
5.1, Inclusion 
Criteria #5 
If they are randomised into the trial due to being sensitive 
to rifampicin and isoniazid by rapid molecular sputum- 
based test, however on receipt of the rifampicin and/or 
isoniazid phenotypic resistance testing in liquid culture 
this shows they are rifampicin or isoniazid resistant, they 
will be: 
 
 - Excluded as late exclusions; 
-  Possibly replaced as determined by the Sponsor.  
If they are randomised into the trial due to being sensitive 
to rifampicin and isoniazid by rapid molecular sputum- 
based test, however on receipt of the rifampicin and/or 
isoniazid phenotypic resistance testing in liquid culture 
this shows they are rifampicin or isoniazid resistant, they 
will be: 
 
 - Excluded as late exclusions; 
-  Possibly replaced as determined by the Sponsor.  
32 
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711 of 852


 
 
TB Alliance 
Protocol Number: NC-008 
Protocol Amendment No.: Russia Amendment 1 / 25-JAN-
2019 
Protocol Name: SimpliciTB 
 
 
Protocol Amendment  
or Administrative Change 
 
TMP-C-SOP01-C V1.0 30-Nov-2018 
CONFIDENTIAL 
This document is proprietary and shall not be reproduced without prior written permission from TB Alliance. 
# 
Section 
Previous Text 
Russia Version 1.0 dated 21-Feb-18 
 
Amended Text 
Version 2.0 dated 15-Jan-19 
Additional text - bold font. Deleted text  strike-through. 
Reason for 
Change 
Insert reason # 
from table above 
33
Protocol Section 
5.1, Inclusion 
Criteria #5 
DR-TB treatment arm participants should be: 
a. Resistant to rifampicin and/or isoniazid.  
b. Should not have had previous treatment for DR-
TB/MDR-TB, although may have been on a DR-
TB/MDR-TB treatment regimen for no longer than 
7 days at start of screening. 
 
DR-TB treatment arm participants should be: 
a. Resistant to rifampicin and/or isoniazid; but 
sensitive to fluoroquinolones by rapid sputum-
based test AND  
b. Should not have had previous treatment for DR-
TB/MDR-TB, although may have been on a DR-
TB/MDR-TB treatment regimen for no longer than 
7 3 days at start of screening. 
c. Participants with resistance to injectables by 
rapid sputum-based test are allowed in the 
trial. 
When Phenotypic DST and whole genome sequencing 
(WGS) results on baseline samples become available, 
any results that are discordant with the screening 
molecular test results used to 
eligibility for the trial will be reviewed by the Sponsor 
Medical Monitor in consultation with the Investigator 
to determine whether that participant is unlikely to 
respond to treatment and should therefore be removed 
from the trial and given alternative treatment.  If a 
participant is removed from the trial for such a reason, 
they will be classified as a late exclusion. 
33 
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712 of 852


 
 
TB Alliance 
Protocol Number: NC-008 
Protocol Amendment No.: Russia Amendment 1 / 25-JAN-
2019 
Protocol Name: SimpliciTB 
 
 
Protocol Amendment  
or Administrative Change 
 
TMP-C-SOP01-C V1.0 30-Nov-2018 
CONFIDENTIAL 
This document is proprietary and shall not be reproduced without prior written permission from TB Alliance. 
# 
Section 
Previous Text 
Russia Version 1.0 dated 21-Feb-18 
 
Amended Text 
Version 2.0 dated 15-Jan-19 
Additional text - bold font. Deleted text  strike-through. 
Reason for 
Change 
Insert reason # 
from table above 
34
Protocol Section 
5.1 Inclusion 
Criteria #7, 
Contraception 
Effective birth control methods: 
a. Double barrier method which can include a male 
condom, diaphragm, cervical cap, or female condom; 
or  
b. Female participant: Barrier method combined with 
hormone-based contraceptives or an intra-uterine 
device for the female participant.  
c. 
emale sexual partner: Double 
barrier method or hormone-based contraceptives or 
an intra-uterine device for the female partner.  
Both male and female participants must be willing to 
continue practicing birth control methods and are not 
planning to conceive throughout treatment and for 12 
weeks after the last dose of trial medication or 
discontinuation from trial medication in case of premature 
discontinuation.  
Effective birth control methods: 
a. Double barrier method which can include a male 
condom, diaphragm, cervical cap, or female condom; 
or  
b. Female participant: Barrier method combined with 
hormone-based contraceptives or an intra-uterine device 
for the female participant.  
Double 
Barrier method combined with hormone-based 
contraceptives or an intra-uterine device for the female 
partner.  
Both male and female participants must be willing to 
continue practicing birth control methods and are not 
planning to conceive throughout treatment and for 6 
months 12 weeks after the last dose of trial IMP or 
discontinuation from trial IMP in case of premature 
discontinuation.  
34 
35
Protocol Section 
5.2 Exclusion 
Criteria #3 
No previous text 
Historical and or current use of local traditional 
medications/herbs which in the opinion of the 
safety or ability to follow through with all protocol-
specified restrictions, visits and evaluations. 
35 
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TB Alliance 
Protocol Number: NC-008 
Protocol Amendment No.: Russia Amendment 1 / 25-JAN-
2019 
Protocol Name: SimpliciTB 
 
 
Protocol Amendment  
or Administrative Change 
 
TMP-C-SOP01-C V1.0 30-Nov-2018 
CONFIDENTIAL 
This document is proprietary and shall not be reproduced without prior written permission from TB Alliance. 
# 
Section 
Previous Text 
Russia Version 1.0 dated 21-Feb-18 
 
Amended Text 
Version 2.0 dated 15-Jan-19 
Additional text - bold font. Deleted text  strike-through. 
Reason for 
Change 
Insert reason # 
from table above 
36
Protocol Section 
5.2 Exclusion 
Criteria #9 
(previous 
protocol) 
Resistant to fluoroquinolones (rapid, sputum-based 
molecular screening tests)  
- If they are randomised into the trial due to being 
sensitive to fluoroquinolones by rapid sputum-based test, 
however on receipt of the moxifloxacin phenotypic 
resistance testing in liquid culture they are found to be 
fluoroquinolones resistant, they will be excluded as late 
exclusions. 
Resistant to fluoroquinolones (rapid, sputum-based 
molecular screening tests)  
- If they are randomised into the trial due to being 
sensitive to fluoroquinolones by rapid sputum-based test, 
however on receipt of the moxifloxacin phenotypic 
resistance testing in liquid culture they are found to be 
fluoroquinolones resistant, they will be excluded as late 
exclusions. 
36 
37
Protocol Section 
5.2 Exclusion 
Criteria #15, 16, 
17, 18 (previous 
protocol) 
15. Previous treatment with pretomanid or bedaquiline. 
 
16. Previous treatment for TB which includes, but is not 
limited to, gatifloxacin, amikacin, cycloserine, 
rifabutin, kanamycin, para-aminosalicylic acid, 
rifapentine, thioacetazone, capreomycin, quinolones, 
thioamides, and metronidazole. 
 
17. For DS-TB participants: Previous treatment for 
tuberculosis within 3 years prior to the Screening 
visit. Participants who have previously received 
isoniazid prophylactically may be included in the 
trial if that treatment is/was discontinued at least 7 
days prior to randomization 
 
18. For the DR-TB participants: Previous treatment for 
DR-TB/MDR-TB, although may have been on a 
DR/MDR-TB treatment regimen for no longer than 
7 days at start of screening. 
 
 
Previous treatment with pretomanid or bedaquiline. 
 
Previous treatment for TB which includes, but is not 
limited to, gatifloxacin, amikacin, cycloserine, rifabutin, 
kanamycin, para-aminosalicylic acid, rifapentine, 
thioacetazone, capreomycin, quinolones, thioamides, and 
metronidazole. 
 
15. Previous treatment for TB: 
 
For DS-TB participants: Previous treatment for 
tuberculosis within 3 years prior to the Screening visit. 
Participants who have previously received isoniazid 
prophylactically may be included in the trial if that 
treatment is/was discontinued at least 7 days at the 
start of the Screening visit. 
 
For the DR-TB participants: Previous treatment for 
DR-TB/MDR-TB, although may have been on a DR-
TB/MDR-TB treatment regimen for no longer than 3 
days at the start of the Screening visit. 
 
 
37 
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TB Alliance 
Protocol Number: NC-008 
Protocol Amendment No.: Russia Amendment 1 / 25-JAN-
2019 
Protocol Name: SimpliciTB 
 
 
Protocol Amendment  
or Administrative Change 
 
TMP-C-SOP01-C V1.0 30-Nov-2018 
CONFIDENTIAL 
This document is proprietary and shall not be reproduced without prior written permission from TB Alliance. 
# 
Section 
Previous Text 
Russia Version 1.0 dated 21-Feb-18 
 
Amended Text 
Version 2.0 dated 15-Jan-19 
Additional text - bold font. Deleted text  strike-through. 
Reason for 
Change 
Insert reason # 
from table above 
38
Protocol Section 
5.2 Exclusion 
Criteria # 18  
Use of systemic glucocorticoids within one year of the 
start of the Screening visit (topical, inhaled or intranasal 
glucocorticoids are allowed), due to visual opacities or 
cataracts. 
 
Use of systemic glucocorticoids within one year of the 
start of the Screening visit (topical, inhaled or intranasal 
glucocorticoids are allowed), due to as they can lead to 
visual opacities or cataracts. 
38 
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715 of 852


 
 
TB Alliance 
Protocol Number: NC-008 
Protocol Amendment No.: Russia Amendment 1 / 25-JAN-
2019 
Protocol Name: SimpliciTB 
 
 
Protocol Amendment  
or Administrative Change 
 
TMP-C-SOP01-C V1.0 30-Nov-2018 
CONFIDENTIAL 
This document is proprietary and shall not be reproduced without prior written permission from TB Alliance. 
39
Protocol Section 
5.2 Exclusion 
Criteria # 19 
For HIV infected participants, only the following types of 
ART are permissible:  
 
a. Lopinavir/ritonavir-based regimen consisting 
of lopinavir/ritonavir in combination with any 
two NRTI. TDF/ABC and FTC/3TC. 
b. Integrase inhibitor (e.g., dolutegravir) in 
combination with TDF/ABC and FTC/3TC. 
c. In participants who have viral load suppressed 
on efavirenz at the time of screening, their 
ART can be changed to rilpivirine in 
combination with TDF/ABC and FTC/3TC. If 
possible, the same nucleoside backbone 
should be used. 
d. Nevirapine (NVP) based regimen consisting of 
NVP in combination with any two nucleosidase 
reverse 
transcriptase 
inhibitors 
(NRTIs) 
tenofovir 
(TDF)/abacavir 
(ABC) 
and 
emtricitabine (FTC)/lamivudine (3TC). 
 
In the case where participants are randomized to a 
rifampicin containing regime: 
 
a. EFV can be used with rifampicin.  
b. LPV needs to be double dosed.  
c. Rilpivirine cannot be given with rifampicin  
 
For HIV infected participants only the following types of 
ART are permissible: 
 
a. The following antiretroviral therapy (ART) should 
not be used with either (BPaMZ and HRZE/HR) 
trial regimen: 
 
1. Stavudine  
2. Didanosine  
3. Triple NRTI regimen is not considered optimal 
for HIV treatment (poor efficacy) 
 
b. In the case where participants are randomised to 
HRZE arm, rilpivirine and etravirine cannot be 
given with rifampicin due to drug-drug 
interactions. A standard NRTI backbone may be 
used in combination with one of the following: 
 
1. Efavirenz requires no dose adjustment  
2. Dolutegravir dose adjustment is required 
 double dose when co-prescribed with 
rifampicin. 
3. Raltegravir requires no dose adjustment 
4. Lopinavir/r dose adjustment is required  
double dose when co-prescribed with 
rifampicin 
5. Nevirapine requires no dose adjustment, 
however please note that nevirapine 
based regimens are associated with 
higher ART failure in participants having 
or known to have a previous viral load 
more than or equal to 100,000/ mL 
 
c. In the case where participants are randomized to 
the BPaMZ trial regimen, a standard NRTI 
backbone may be combined with the following:  
39 
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TB Alliance 
Protocol Number: NC-008 
Protocol Amendment No.: Russia Amendment 1 / 25-JAN-
2019 
Protocol Name: SimpliciTB 
 
 
Protocol Amendment  
or Administrative Change 
 
TMP-C-SOP01-C V1.0 30-Nov-2018 
CONFIDENTIAL 
This document is proprietary and shall not be reproduced without prior written permission from TB Alliance. 
# 
Section 
Previous Text 
Russia Version 1.0 dated 21-Feb-18 
 
Amended Text 
Version 2.0 dated 15-Jan-19 
Additional text - bold font. Deleted text  strike-through. 
Reason for 
Change 
Insert reason # 
from table above 
 
1. Rilpivirine 
2. Dolutegravir  
3. Raltegravir 
4. Nevirapine  
5. Lopinavir/r  
6. Participants who are on efavirenz, 
atazanavir/r or darunavir/r at the time of 
screening and have an undetectable viral 
load, should have their ART switched to 
one of the agents listed above (1-5). It 
would be preferable to switch to another 
permissible ARV within the same class 
accompanied by the same nucleoside 
backbone. 
 
d. ART regimen choice should be discussed with the 
Sponsor Medical Monitors if there are any 
concerns. 
 
Confirmed plans to use Isoniazid prophylaxis for HIV 
positive participants during the treatment and follow 
up period is not permitted. 
 
26 of 48
717 of 852


 
 
TB Alliance 
Protocol Number: NC-008 
Protocol Amendment No.: Russia Amendment 1 / 25-JAN-
2019 
Protocol Name: SimpliciTB 
 
 
Protocol Amendment  
or Administrative Change 
 
TMP-C-SOP01-C V1.0 30-Nov-2018 
CONFIDENTIAL 
This document is proprietary and shall not be reproduced without prior written permission from TB Alliance. 
40
Protocol Section 
5.2 Exclusion 
Criteria, 
Diagnostic and 
Laboratory 
Abnormalities, 
Item #20 
(Previously #24) 
a. platelets grade 2 or greater (<100,000/mm3) 
b. creatinine grade 2 or greater (>1.5 times upper limit of 
normal [ULN])  
c. 
2 
d. haemoglobin 
 
e. serum potassium less than the lower limit of normal for 
the laboratory. This may be repeated once 
f. 
GGT: greater than 3 x ULN 
g. AST: 
 
excluded; 
 
results between 1.5 x ULN and 3 x ULN must 
be discussed with and approved by the 
Sponsor Medical Monitor 
h. ALT: 
 
 
greater than ULN must be discussed with and 
approved by the Sponsor Medical Monitor 
i. 
 ALP: 
 
 
grade 2 (2.0  <3.0 x ULN) must be discussed 
with and approved by the Sponsor Medical 
Monitor 
j. 
Total bilirubin: 
 
>1.5 x ULN to be excluded; 
 
1  1.5 x ULN must be discussed with and 
approved by the Sponsor Medical Monitor 
k. Direct bilirubin: 
 
greater than 1x ULN to be excluded 
 
a. platelets grade 2 or greater (<100<75,000/mm3) 
b. creatinine grade 2 or greater (>1.5 times upper limit of 
normal ([ULN])  
c. 
/m2 
d. haemoglobin 
<8.0 g/dL) 
e. serum potassium less than the lower limit of normal 
for the laboratory. This may be repeated once 
f. 
GGT: greater than 3 x ULN 
g. AST:  
 
grade 3 or greater (
) to be 
excluded; 
 
results between 1.5 x ULN and 3 x ULN must 
be discussed with and approved by the 
Sponsor Medical Monitor 
h. ALT: 
 
grade 3 or greater (
) to be 
excluded 
 
greater than ULN must be discussed with and 
approved by the Sponsor Medical Monitor 
i. 
ALP: 
 
grade 3 or greater (
) to be 
excluded 
 
grade 2 (2.0  <3.0 x ULN) must be 
discussed with and approved by the Sponsor 
Medical Monitor 
j. 
Total bilirubin: 
 
>1.5 x ULN to be excluded; 
 
greater than 1  1.5 x ULN must be 
discussed with and approved by the Sponsor 
Medical Monitor 
k. Direct bilirubin: 
 
greater than 1x ULN to be excluded 
 
40 
41
Protocol Section 
5.3 Restrictions 
Concomitant medications should be kept to a minimum 
during the trial. However, if concomitant medications are 
Concomitant medications should be kept to a minimum 
during the trial. However, if concomitant medications are 
and are unlikely to 
41 
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718 of 852


 
 
TB Alliance 
Protocol Number: NC-008 
Protocol Amendment No.: Russia Amendment 1 / 25-JAN-
2019 
Protocol Name: SimpliciTB 
 
 
Protocol Amendment  
or Administrative Change 
 
TMP-C-SOP01-C V1.0 30-Nov-2018 
CONFIDENTIAL 
This document is proprietary and shall not be reproduced without prior written permission from TB Alliance. 
# 
Section 
Previous Text 
Russia Version 1.0 dated 21-Feb-18 
 
Amended Text 
Version 2.0 dated 15-Jan-19 
Additional text - bold font. Deleted text  strike-through. 
Reason for 
Change 
Insert reason # 
from table above 
interfere with the IMP, they may be given at the discretion 
of the Investigator. 
interfere with the IMP, they may be given at the discretion 
of the Investigator. 
42
Protocol Section 
5.3 Restrictions 
The following medicinal products should be avoided from 
Day 1 (Baseline visit) and during the treatment period as 
much as possible unless discussed with the Sponsor 
Medical Monitor: 
 
The following medicinal products should be avoided from 
Day 1 (Baseline visit) and during the treatment period as 
much as possible (unless this is required for 
emergency management of the participant) unless 
discussed with the Sponsor Medical Monitor. 
Investigators may also contact the Sponsor Medical 
Monitor for further guidance. 
42 
43
Protocol Section 
5.3 Restrictions 
Any drug known to be hepatotoxic (including but not 
limited to acetaminophen/paracetamol, acetazolamide, 
allopurinol, amiodarone, amitriptyline, amoxicillin, 
amprenavir, atorvastatin, augmentin/co-amoxiclav, 
azathioprine, baclofen, bumetanide, captopril, 
carbamazepine, celecoxib, chlorpromazine, 
chlorpromazine, clindamycin, clopidogrel, contraceptive 
 
Any drug known to be hepatotoxic (including but not 
limited to acetaminophen/paracetamol, acetazolamide, 
allopurinol, amiodarone, amitriptyline, amoxicillin, 
amprenavir, atorvastatin, augmentin/co-amoxiclav, 
azathioprine, baclofen, bumetanide, captopril, 
carbamazepine, celecoxib, chlorpromazine, 
chlorpromazine, clindamycin, clopidogrel, contraceptive 
pill
 
43 
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719 of 852


 
 
TB Alliance 
Protocol Number: NC-008 
Protocol Amendment No.: Russia Amendment 1 / 25-JAN-
2019 
Protocol Name: SimpliciTB 
 
 
Protocol Amendment  
or Administrative Change 
 
TMP-C-SOP01-C V1.0 30-Nov-2018 
CONFIDENTIAL 
This document is proprietary and shall not be reproduced without prior written permission from TB Alliance. 
44
Protocol Section 
5.4 Treatment 
Discontinuation 
and/or Early 
Withdrawal 
A participant must be prematurely withdrawn from the trial 
(during the trial treatment or follow-up periods) because of 
the following: 
 
 
Withdrawal of informed consent 
 
Investigator considers that for safety reasons it is in 
the best interest of the participant that he/she be 
withdrawn, including a concern that the participant 
has 
symptomatic 
TB 
and/or 
bacteriological 
failure/relapse and requires a change in TB treatment.
 
Pregnancy 
 
At the specific request of the Sponsor or termination 
of the trial by the Sponsor. 
 
Lost to follow-up 
 
Drug-Sensitive TB treatment arms: participants, who 
have been randomised onto the trial as a rifampicin 
sensitive participant on the rapid sputum based test 
result, who on receipt of the rifampicin resistance 
testing using an indirect susceptibility test in liquid 
culture, shows a rifampicin resistant result. 
 
Participants, who have been randomised onto the trial 
as fluoroquinolone sensitive on the rapid sputum 
based 
test 
result, 
who 
on 
receipt 
of 
the 
fluoroquinolone resistance testing using an indirect 
susceptibility test in liquid culture; this shows a 
fluoroquinolone resistant result. 
 
A participant must be prematurely withdrawn from the trial 
(during the trial treatment or follow-up periods) because of 
the following: 
 
 
Withdrawal of informed consent 
 
Investigator considers that for safety reasons it is 
in the best interest of the participant that he/she be 
withdrawn, including a concern that the participant 
has 
symptomatic 
TB 
and/or 
bacteriological 
failure/relapse and requires a change in TB 
treatment 
 
Pregnancy 
 
At the specific request of the Sponsor or 
termination of the trial by the Sponsor 
 
Lost to follow-up 
 
Drug-Sensitive TB treatment arms: participants, 
who have been randomised onto the trial as a 
rifampicin sensitive participant on the rapid sputum 
based test result, who on receipt of the rifampicin 
resistance testing using an indirect susceptibility 
test in liquid culture, shows a rifampicin resistant 
result. 
 
Participants, who have been randomised onto the 
trial as fluoroquinolone sensitive on the rapid 
sputum based test result, who on receipt of the 
fluoroquinolone resistance testing using an indirect 
susceptibility test in liquid culture; this shows a 
fluoroquinolone resistant result. 
 
When Phenotypic DST and whole genome 
sequencing 
(WGS) 
results 
on 
baseline 
samples become available, any results that are 
discordant with the screening molecular test 
for the trial will be reviewed by the Sponsor 
Medical Monitor in consultation with the 
Investigator 
to 
determine 
whether 
that 
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# 
Section 
Previous Text 
Russia Version 1.0 dated 21-Feb-18 
 
Amended Text 
Version 2.0 dated 15-Jan-19 
Additional text - bold font. Deleted text  strike-through. 
Reason for 
Change 
Insert reason # 
from table above 
participant is unlikely to respond to treatment 
and should therefore be removed from the trial 
and given alternative treatment.  If a participant 
is removed from the trial for such a reason, 
they will be classified as a late exclusion. 
45
Protocol Section 
5.4 Treatment 
Discontinuation 
and/or Early 
Withdrawal 
- Participants, who have been randomised onto the trial 
as fluoroquinolone sensitive on the rapid sputum-based 
test result, who on receipt of the fluoroquinolone 
resistance testing using an indirect susceptibility test in 
liquid culture; this shows a fluoroquinolone resistant 
result. 
- Early withdrawal due to TB (see Section 5.4.4) 
 
- Participants, who have been randomised onto the trial 
as fluoroquinolone sensitive on the rapid sputum-based 
test result, who on receipt of the fluoroquinolone 
resistance testing using an indirect susceptibility test in 
liquid culture; this shows a fluoroquinolone resistant 
result. 
- Early withdrawal due to TB (see Section5.4.4) 
 
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46
Protocol Section 
5.4 Treatment 
Discontinuation 
and/or Early 
Withdrawal 
The following situation/s would require an unscheduled 
visit/s: 
 
- If both sputum samples (Early Morning and Spot) at 
Week 8 or later are contaminated, the participant should 
return for an unscheduled visit(s) to give additional 
sputum samples x 2 (one early morning and one spot at 
the research site under the coaching and observation of 
the trial staff) or to document that the participant is not 
able to produce sputum. 
- If there is a MTB confirmed positive culture at or after 
the end of treatment at Week 17 (4-month treatment) or 
Week 26 (6-month treatment), the participant should 
return for an Unscheduled visit(s) to give additional 
sputum samples x 2 (one early morning and one spot at 
the research site under the coaching and observation of 
the trial staff) or to document that the participant is not 
able to produce sputum. If no early morning sputum 
sample was provided by the participant, 2 samples may 
be collected at the site, at least 30 minutes apart. 
 
Table 6 is a new table and did not previously exist in 
Protocol Russia V1.0. 
 
If the Investigator is unsure of the outcome in any of the 
above scenarios the Investigator is to contact the Sponsor 
Medical Monitor and discuss and agree on how the 
participant is to be managed. 
 
The following situation/s would require an unscheduled 
visit/s: 
 
- For any medical reason, as determined by the 
Investigator or participant. 
- If both sputum samples (EMS and spot sputum sample) 
at Week 8 or later are contaminated, the participant 
should return for an unscheduled visit/s to give 2 (EMS 
and spot sputum sample, at each visit under the coaching 
and observation of the trial staff) additional sputum 
samples or to document that the participant is not able to 
produce sputum.  
- If there is a MTB confirmed positive culture If after 
having converted to culture negative, the participant 
has a MTB confirmed positive culture at or after the 
last visit of the treatment period (Week 17 or Week 26) 
Week 17 (4-month treatment) or Week 26 (6-month 
treatment), the participant should return for Unscheduled 
visit/s to provide 2 (EMS and spot sputum sample, at 
each visit) additional sputum samples under the 
coaching and observation of the trial staff), at a minimum 
of 7 days apart, or to document that the participant is not 
able to produce a sputum sample. 
 
Table 6: Summary of Scenarios Requiring 
Unscheduled Visits for Mycobacteriology Testing  
Time-point
Scenario
Unscheduled 
Visit/s 
Required? 
Comment
Week 8 or 
later 
Both sputum cultures 
are contaminated 
Yes
Provide additional 
samples until a positive 
or negative result is 
reported, or it is 
confirmed that the 
participant is unable to 
produce sputum 
At or after the 
last treatment 
visit (Week 17 
or Week 26) 
Previously converted 
to culture negative but 
now has an MTB-
positive culture 
Yes
Provide additional 
samples at least 7 days 
after the previous 
sample until the result 
is confirmed, or it is 
confirmed that the 
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# 
Section 
Previous Text 
Russia Version 1.0 dated 21-Feb-18 
 
Amended Text 
Version 2.0 dated 15-Jan-19 
Additional text - bold font. Deleted text  strike-through. 
Reason for 
Change 
Insert reason # 
from table above 
participant is unable to 
produce sputum.  
End of 
Follow-up 
Period (Week 
52 and 104)  
Early 
Withdrawal, if 
applicable 
outcome status cannot 
be confirmed by: 
Two sequential 
negative sputum 
culture results; or   
two sequential positive 
sputum culture results; 
or has been unable to 
produce sputum after 
documentation of two 
negative sputum 
cultures with no 
intervening positive 
and are clinically 
asymptomatic 
Yes
Provide additional 
samples at least 7 days 
after the previous 
sample until one of the 
criteria is met and the 
primary outcome status 
can be determined.  
 
If the Investigator is unsure of the outcome in any of the 
above scenarios, the Investigator should is to contact the 
Sponsor Medical Monitor to discuss and agree on how 
the participant is to be managed. 
 
47
Protocol Section 
5.4.4 Early 
Withdrawal due 
to TB 
The participants will be provided with a referral letter from 
the Investigator to take with them to the TB clinic.  A 
follow-up call will be made by the trial site staff to the 
clinic to ensure the participant attended the clinic. 
The participant will be provided with a referral letter from 
the Investigator to take with them to the TB clinic their 
National Treatment Program (NTP) clinic and the 
referral letter, at a minimum, should include all 
treatment received by the participant and information 
about any suspected/confirmed adverse 
concomitant medications.  A follow-up call will should 
be made by the trial site staff to the clinic to ensure the 
participant attended the NTP clinic.  
 
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# 
Section 
Previous Text 
Russia Version 1.0 dated 21-Feb-18 
 
Amended Text 
Version 2.0 dated 15-Jan-19 
Additional text - bold font. Deleted text  strike-through. 
Reason for 
Change 
Insert reason # 
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48
Protocol Section 
7.1 Demographic 
and Background 
Variables and 
Procedures 
Screening coached spot sputum samples: 
 
o 
Smear microscopy for acid-fast bacilli 
o 
Gene Xpert, Hain Assay MTBDRplus or 
equivalent to determine MTB complex and 
rifamycin resistance 
 
Screening coached spot sputum samples: 
o 
Smear microscopy for acid-fast bacilli  
o 
Gene Xpert Rapid molecular tests for 
isoniazid, rifampicin, fluoroquinolones 
resistance (Hain MTBDRplus and 
HainMTBRsl) 
o 
Liquid Culture (MGIT) for Mycobacterium 
tuberculosis (MTB), followed by a speciation 
test to detect presence or absence of MTB 
and obtain time to positivity (TTP) when 
positive. 
48 
49
Protocol Section 
7.1 Demographic 
and Background 
Variables and 
Procedures 
Method of birth control: male and female participants and 
their partners 
 
Method of birth control: male and female participants and 
their sexual partners 
 
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50
Protocol Section 
7.5 
Mycobacteriology 
Characterisation 
Variable and 
Procedures 
Mycobacteriology Characterization Variable and 
Procedures 
The following Mycobacterial Characterization variables 
will be collected: 
Positive Culture (for MTB) from: 
 
 
Day 1 or if Day 1 is not available, first positive 
result between screening through Week 4 
 
Pre-screening culture that was used for the tests 
that qualified the participant for inclusion into the 
trial to be sub-cultured and sent to the central 
microbiology laboratory from the applicable local 
microbiology laboratory, for relevant participants / 
no positive cultures from screening through week 
4  
 
When applicable, at last visit of the treatment 
period (Week 17 for the 4-month treatment arm 
and Week 26 for the 6-month treatment arm) or 
visits with positive cultures, during the post-
treatment follow-up period 
 
The MTB isolates will be processed at the central 
microbiology laboratory for: 
 
 
MIC against bedaquiline, pretomanid and 
moxifloxacin  
 
Drug Susceptibility Testing in liquid culture for 
streptomycin, rifampicin, isoniazid, ethambutol, 
moxifloxacin and pyrazinamide, and second line 
TB drugs including but not limited to 
fluoroquinolones, and injectables 
 
Extraction of organismal (MTB) DNA for whole 
genome sequencing, and the comparison of 
sequences from baseline and relapse isolates. 
 
Mycobacteriology Characterization Variable and 
Procedures 
The following Mycobacterial Characterization variables 
will be collected: 
Positive Culture (for MTB) from: 
 
 
Day 1 (Baseline) sputum sample (or any positive 
sample from Screening to Week 4, if the baseline 
cultures are contaminated or negative). 
 
Pre-screening culture that was used for the tests that 
qualified the participant for inclusion into the trial to be 
sub-cultured and sent to the central microbiology 
laboratory from the applicable local microbiology 
laboratory, for relevant participants / no positive 
cultures from screening through week 4  
 
MTB confirmed positive cultures (after the 
participant has previously converted to negative) 
at or after the last visit of the treatment period 
(Week 17 or Week 26) or visits with positive 
cultures, during the post-treatment follow-up 
period. 
 
Refer to the Mycobacteriology Laboratory Manual 
for full details. 
Mycobacterial Characterization - MTB isolates (from 
the first MTB positive culture) will be processed for: 
 
 
Rapid molecular tests for fluoroquinolones, 
injectables, isoniazid and rifampicin resistance 
(only on MTB positive cultures in the follow-up 
period); 
 
Minimum Inhibitory Concentration (MIC) against 
bedaquiline, pretomanid, and moxifloxacin;  
 
DST in liquid culture for streptomycin, rifampicin, 
isoniazid, ethambutol, moxifloxacin, and 
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# 
Section 
Previous Text 
Russia Version 1.0 dated 21-Feb-18 
 
Amended Text 
Version 2.0 dated 15-Jan-19 
Additional text - bold font. Deleted text  strike-through. 
Reason for 
Change 
Insert reason # 
from table above 
All Day 1 (Baseline) MTB isolates and isolates from 
positive cultures to be stored at the local and central 
microbiology laboratories, until trial closure.  Extracted 
MTB DNA to be stored at the central microbiology 
laboratory until trial closure. The extracted MTB DNA and 
isolates will then be stored for potential further work to 
advance new assay tools and understanding of MTB as a 
pathogen for a maximum of 5 years after trial closure.  
 
The MTB isolates will be processed at the trial 
microbiology laboratories for positive MTB complex 
at/after the last visit of the treatment period (Week 17 for 
the 4-month treatment arm and Week 26 for the 6-month 
treatment arm) via Hain MTBDRplus and HainMTBRsl. 
 
 
pyrazinamide, and second line TB drugs including but 
not limited to fluoroquinolones, and injectables in 
liquid culture;  
 
Extraction of organismal (MTB) DNA for whole 
genome sequencing (WGS), and comparison of 
sequences from baseline and relapse isolates. 
 
has a MTB positive culture at or after the last visit of 
the treatment period (Week 17 and Week 26), the MTB 
cultures isolates will be processed will be tested at the 
trial mycobacteriology laboratories for positive MTB 
complex using Hain MTBDRplus and HainMTBRsl to 
detect resistance to isoniazid, rifampicin, 
fluoroquinolones and injectables. 
 
All Day 1 (Baseline) MTB isolates and isolates from 
positive cultures to must be stored at the local 
mycobacteriology laboratories, until trial closure.  In 
addition, MTB DNA isolates as well as extracted MTB 
DNA from the applicable baseline and follow-up 
cultures will be stored at the central mycobacteriology 
laboratory for potential further work to advance new assay 
tools and understanding of MTB as a pathogen for a 
maximum of 5 years after trial closure.  
51
Protocol Section 
8.2.1 Follow-up 
of Adverse 
Events 
New or updated information will be recorded in the 
originally completed CRF and submitted to the Sponsor 
within 24 hours of receipt, per SAE reporting guidelines. 
 
New or updated SAE information will be recorded in the 
originally completed CRF and submitted to the Sponsor 
within 24 hours of receipt, per the SAE eCRF 
Completion Guideline. 
 
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# 
Section 
Previous Text 
Russia Version 1.0 dated 21-Feb-18 
 
Amended Text 
Version 2.0 dated 15-Jan-19 
Additional text - bold font. Deleted text  strike-through. 
Reason for 
Change 
Insert reason # 
from table above 
52
Protocol Section 
8.2.6 Pregnancy 
All women of childbearing potential will be instructed to 
contact the investigator immediately if they suspect they 
might be pregnant (for example, missed or late menses) 
for the following time-periods: 
 
Any time during the trial 
 
Within 6 months after the last dose of IMP
 
All women of childbearing potential will be instructed to 
contact the investigator immediately if they suspect they 
might be pregnant (for example, missed or late menses) 
at any time during the trial. for the following 
time-periods: 
 
Any time during the trial 
 
Within 6 months after the last dose of IMP
52 
53
Protocol Section 
8.3 Monitoring for 
Specific 
Toxicities 
Neurological 
Participants co-administration with a serotonergic agent, 
including anti-depressants, should be monitored closely 
for signs of serotonin syndrome.  The Investigator should 
determine whether the full regimen or the concomitant 
agent should be discontinued for those who experience 
signs or symptoms of serotonin syndrome such as 
cognitive dysfunction, hyperrexia, hyperreflexia and 
incoordination. 
Neurological 
Participants co-administration with a serotonergic agent, 
including anti-depressants, should be monitored closely 
for signs of serotonin syndrome.  The Investigator should 
determine whether the full regimen or the concomitant 
agent should be discontinued for those who experience 
signs or symptoms of serotonin syndrome such as 
cognitive dysfunction, hyperrexia, hyperreflexia and 
incoordination. 
53 
54
Protocol Section 
9.0 Statistical 
Analysis 
Statistical Analysis 
 
The statistical analysis plan (SAP), which will contain 
details of the analyses specified in this section, will be 
written and signed off prior to first patient randomized. 
 
Statistical Analysis 
 
The statistical analysis plan (SAP), which will contain 
details of the analyses specified in this section, will be 
written and signed off prior to the interim analysis. 
 
There will be 3 data analyses and trial reports 
generated for this trial:  
 
- When all participants have completed 8 weeks (2 
months) of treatment from baseline.  
- When all participants have completed 52 weeks (12 
months) follow-up from start of therapy.
- When all participants have completed 104 weeks (24 
months) follow-up from start of therapy.  
 
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# 
Section 
Previous Text 
Russia Version 1.0 dated 21-Feb-18 
 
Amended Text 
Version 2.0 dated 15-Jan-19 
Additional text - bold font. Deleted text  strike-through. 
Reason for 
Change 
Insert reason # 
from table above 
55
Protocol Section 
11.3 Protocol 
Deviations 
A protocol deviation is any noncompliance with the clinical 
trial protocol, GCP, or Monitoring Plan requirements.  
A protocol deviation is any noncompliance with the clinical 
trial protocol and GCP or Monitoring Plan requirements.  
55 
56
Appendix 6 
Appendix 7 
Appendix 8 
TB Symptom Profile  
 
Patient Reported Health Status Questionnaire 
TB Symptom Profile 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patient Reported Health Status Questionnaire 
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Liver Toxicity Management 
 
Standard anti-TB chemotherapy is known to cause 
derangement of liver function tests in a substantial 
number of patients. In many cases this will be 
asymptomatic and self-limiting. In some cases, severe 
hepatitis and even fulminant liver failure and death can 
occur. 
In pre-marketing clinical trials of new drugs and regimens 
it is especially important to identify and carefully manage 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Liver Toxicity Management 
 
Standard anti-TB chemotherapy is known to cause 
derangement of liver function tests in a substantial 
number of patients. In many cases this will be 
asymptomatic and self-limiting. In some cases, severe 
hepatitis and even fulminant liver failure and death can 
occur. 
In pre-marketing clinical trials of new drugs and regimens 
it is especially important to identify and carefully manage 
any trial participants who are at risk of progression to 
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any trial participants who are at risk of progression to 
serious liver injury. The observation of altered liver 
function to a degree that has a high risk of progressing to 
liver failure as been referred to informally as 
 
Law;(44, 45); this reflects that pure hepatocellular 
injury sufficient to cause hyperbilirubinemia is an 
ominous indicator of the potential for a drug to cause 
serious liver injury. Briefly, 
 Law cases have the 
following three components: 
1. The drug causes hepatocellular injury, generally 
shown by a higher incidence of 3-fold or greater 
elevations above the ULN of ALT or AST than the 
(non-hepatotoxic) control drug or placebo. 
2. Among 
trial 
participants 
showing 
such 
aminotransferase (AT) elevations, often with ATs 
much greater than 3x ULN, one or more also show 
elevation of serum total bilirubin (TBL) to >2x ULN, 
without initial findings of cholestasis (elevated 
serum alkaline phosphatase (ALP)). 
3. No other reason can be found to explain the 
combination of increased AT and total bilirubin level 
(TBL), such as viral hepatitis A, B, or C; pre-existing 
or acute liver disease; or another drug capable of 
causing the observed injury. 
 
During the trial, liver function will be monitored regularly 
with clinical assessment and blood tests in trial 
participants and this will assist in follow up laboratory 
measurements that can document either resolution of 
abnormalities or signal the potential for drug-induced 
liver injury (DILI). In a clinical trial of new drugs and 
combinations it is especially important for Investigators 
to follow closely any participants who have evidence 
of hepatic inflammation or potential toxicity. The 
serious liver injury. The observation of altered liver 
function to a degree that has a high risk of progressing to 
liver failure as been referred to informally as 
 
Law;(44, 45); this reflects that pure hepatocellular 
injury sufficient to cause hyperbilirubinemia is an 
ominous indicator of the potential for a drug to cause 
serious liver injury. Briefly, 
 Law cases have the 
following three components: 
4. The drug causes hepatocellular injury, generally 
shown by a higher incidence of 3-fold or greater 
elevations above the ULN of ALT or AST than the 
(non-hepatotoxic) control drug or placebo. 
5. Among 
trial 
participants 
showing 
such 
aminotransferase (AT) elevations, often with ATs 
much greater than 3x ULN, one or more also show 
elevation of serum total bilirubin (TBL) to >2x ULN, 
without initial findings of cholestasis (elevated 
serum alkaline phosphatase (ALP)). 
6. No other reason can be found to explain the 
combination of increased AT and total bilirubin level 
(TBL), such as viral hepatitis A, B, or C; pre-existing 
or acute liver disease; or another drug capable of 
causing the observed injury. 
 
During the trial, liver function will be monitored regularly 
with clinical assessment and blood tests in trial 
participants and this will assist in follow up laboratory 
measurements that can document either resolution of 
abnormalities or signal the potential for drug-induced 
liver injury (DILI). In a clinical trial of new drugs and 
combinations it is especially important for Investigators 
to follow closely any participants who have evidence 
of hepatic inflammation or potential toxicity. The 
following procedure describes the management of 
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following procedure describes the management of 
deranged liver function tests in trial participants. 
Procedure 
Blood tests for liver function will be taken routinely at 
screening (Day -9 to -1) and at the specific time points 
designated in the protocol, and at Early Withdrawal. If at 
any other visit the clinician suspects derangement of 
liver function, e.g. the participant describes nausea and 
vomiting, right upper abdominal pain or is jaundiced, 
blood should be taken for liver function tests and the 
participant comprehensively assessed for evidence of 
hepatitis or hepatic impairment and any potentially 
contributing causes. 
Suspected liver toxicity (or elevated liver enzymes 
detected in the absence of symptoms) must be taken 
seriously and detailed guidance will be provided in a 
separate document, Management of Hepatotoxicity 
Guideline. Investigators should refer to this document as 
a guide to management in cases of suspected or 
proven liver toxicity. Importantly, the Sponsor Medical 
Monitor is available to provide further assistance if there is 
any uncertainty or additional questions. 
The laboratory source (print-out of any results) should be 
stored alongside or transcribed into the clinical source 
document. Each abnormal value should be marked as 
clinically significant (CS) or non-clinically significant 
(NCS); the assessment of significance is at the 
discretion of the Investigator. All clinically significant 
abnormal results must be recorded as Adverse Events in 
the eCRF and graded clinically as per the DMID adult 
toxicity table grading, (Appendix 2). Assessments and 
decision making for elevations in aminotransferase values 
deranged liver function tests in trial participants. 
Procedure 
Blood tests for liver function will be taken routinely at 
screening (Day -9 to -1) and at the specific time points 
designated in the protocol, and at Early Withdrawal. If at 
any other visit the clinician suspects derangement of 
liver function, e.g. the participant describes nausea and 
vomiting, right upper abdominal pain or is jaundiced, 
blood should be taken for liver function tests and the 
participant comprehensively assessed for evidence of 
hepatitis or hepatic impairment and any potentially 
contributing causes. 
Suspected liver toxicity (or elevated liver enzymes 
detected in the absence of symptoms) must be taken 
seriously and detailed guidance will be provided in a 
separate document, Management of Hepatotoxicity 
Guideline. Investigators should refer to this document as 
a guide to management in cases of suspected or 
proven liver toxicity. Importantly, the Sponsor Medical 
Monitor is available to provide further assistance if there is 
any uncertainty or additional questions. 
The laboratory source (print-out of any results) should be 
stored alongside or transcribed into the clinical source 
document. Each abnormal value should be marked as 
clinically significant (CS) or non-clinically significant 
(NCS); the assessment of significance is at the 
discretion of the Investigator. All clinically significant 
abnormal results must be recorded as Adverse Events in 
the eCRF and graded clinically as per the DMID adult 
toxicity table grading, (Appendix 2). Assessments and 
decision making for elevations in aminotransferase values 
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or bilirubin of various levels of concern are detailed 
below: 
Elevated liver enzymes considered of clinical 
significance, but not accompanied by other signs and 
symptoms, should be reported as an adverse event 
and should usually be recorded as elevated liver 
enzymes. If the term "hepatitis" is used, the Safety Data 
Manager will question the site for additional evidence 
to support the diagnosis, such as clinical signs and 
serological or biopsy data. While a liver biopsy is not 
required to make a diagnosis of hepatitis, the term 
"hepatitis" should be reserved in most instances for 
cases where there is supportive evidence beyond a 
liver enzyme abnormality. However, if the Investigator 
will confirm the diagnosis of hepatitis just on the basis 
of clinical signs and laboratory values the diagnosis will 
be accepted. Should other symptoms or signs be 
present, these should also be recorded as adverse 
events. 
Temporarily Stopping and Restarting Trial Medication 
Liver function tests that are improving should be repeated 
regularly, such as every 3 days for the first week then 
once a week until they return to near baseline values for 
the participant. Manage the participant symptomatically 
as required using medications that are not potentially 
hepatotoxic and discontinue any concomitant drugs, if 
clinically warranted, that may be hepatotoxic. Infection 
control issues must be carefully managed whilst TB 
medications are being withheld, especially if the 
participant is still culture positive for acid fast bacilli. 
If t r i a l  medication has been temporarily stopped, 
once the liver function values have decreased 
or bilirubin of various levels of concern are detailed 
below: 
Elevated liver enzymes considered of clinical 
significance, but not accompanied by other signs and 
symptoms, should be reported as an adverse event 
and should usually be recorded as elevated liver 
enzymes. If the term "hepatitis" is used, the Safety Data 
Manager will question the site for additional evidence 
to support the diagnosis, such as clinical signs and 
serological or biopsy data. While a liver biopsy is not 
required to make a diagnosis of hepatitis, the term 
"hepatitis" should be reserved in most instances for 
cases where there is supportive evidence beyond a 
liver enzyme abnormality. However, if the Investigator 
will confirm the diagnosis of hepatitis just on the basis 
of clinical signs and laboratory values the diagnosis will 
be accepted. Should other symptoms or signs be 
present, these should also be recorded as adverse 
events. 
Temporarily Stopping and Restarting Trial Medication 
Liver function tests that are improving should be repeated 
regularly, such as every 3 days for the first week then 
once a week until they return to near baseline values for 
the participant. Manage the participant symptomatically 
as required using medications that are not potentially 
hepatotoxic and discontinue any concomitant drugs, if 
clinically warranted, that may be hepatotoxic. Infection 
control issues must be carefully managed whilst TB 
medications are being withheld, especially if the 
participant is still culture positive for acid fast bacilli. 
If t r i a l  medication has been temporarily stopped, 
once the liver function values have decreased 
42 of 48
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TB Alliance 
Protocol Number: NC-008 
Protocol Amendment No.: Russia Amendment 1 / 25-JAN-
2019 
Protocol Name: SimpliciTB 
 
 
Protocol Amendment  
or Administrative Change 
 
TMP-C-SOP01-C V1.0 30-Nov-2018 
CONFIDENTIAL 
This document is proprietary and shall not be reproduced without prior written permission from TB Alliance. 
# 
Section 
Previous Text 
Russia Version 1.0 dated 21-Feb-18 
 
Amended Text 
Version 2.0 dated 15-Jan-19 
Additional text - bold font. Deleted text  strike-through. 
Reason for 
Change 
Insert reason # 
from table above 
substantially a decision must be made about further TB 
management. This will be dependent on the clinical 
context and a decision must be made in discussion with 
the Sponsor Medical Monitor. Investigational treatment 
can only be restarted if the Sponsor Medical Monitor is 
in agreement with the plan. In all cases treatment 
should be recommenced under close supervision for any 
evidence of recurrent liver function abnormalities. 
If there is a further significant elevation of hepatic 
enzymes or bilirubin or symptoms of clinical concern 
after resumption of trial medication, the trial medication 
should be withdrawn permanently. Participants who 
permanently discontinue trial medication should be 
managed as clinically indicated according to local 
National TB Programme guidelines. The Sponsor 
Medical Monitor can be contacted for further advice when 
referring to the National Treatment Program. 
The Sponsor Medical Monitor is available to assist the 
Investigators in both the management of liver toxicity 
and decisions regarding the holding or re-introduction 
of trial medication. Investigators must involve the 
Sponsor Medical Monitor in any decisions regarding 
medication hold or re-start, and there should always be 
a low threshold for contacting the Sponsor Medical 
Monitor in cases of elevated liver enzymes.  
 
substantially a decision must be made about further TB 
management. This will be dependent on the clinical 
context and a decision must be made in discussion with 
the Sponsor Medical Monitor. Investigational treatment 
can only be restarted if the Sponsor Medical Monitor is 
in agreement with the plan. In all cases treatment 
should be recommenced under close supervision for any 
evidence of recurrent liver function abnormalities. 
If there is a further significant elevation of hepatic 
enzymes or bilirubin or symptoms of clinical concern 
after resumption of trial medication, the trial medication 
should be withdrawn permanently. Participants who 
permanently discontinue trial medication should be 
managed as clinically indicated according to local 
National TB Programme guidelines. The Sponsor 
Medical Monitor can be contacted for further advice when 
referring to the National Treatment Program. 
The Sponsor Medical Monitor is available to assist the 
Investigators in both the management of liver toxicity 
and decisions regarding the holding or re-introduction 
of trial medication. Investigators must involve the 
Sponsor Medical Monitor in any decisions regarding 
medication hold or re-start, and there should always be 
a low threshold for contacting the Sponsor Medical 
Monitor in cases of elevated liver enzymes.  
 
 
43 of 48
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TB Alliance 
Protocol Number: NC-008 
Protocol Amendment No.: Russia Amendment 1 / 25-JAN-
2019 
Protocol Name: SimpliciTB 
 
 
Protocol Amendment  
or Administrative Change 
 
TMP-C-SOP01-C V1.0 30-Nov-2018 
CONFIDENTIAL 
This document is proprietary and shall not be reproduced without prior written permission from TB Alliance. 
Sponsor 
I agree to the terms of this Protocol Russia Amendment #1. 
Signature of Study Physician 
 
Printed name 
 
Date 
Principal Investigator 
I hereby confirm I have read the above Protocol Amendment or Protocol Administrative Change and agree to conduct this clinical trial as outlined in the 
above. I will provide copies of the Protocol Amendment or Protocol Administrative Change and access to all of the information required to conduct the 
clinical trial according to the above Protocol Amendment or Protocol Administrative Change to the site personnel under my supervision. I will discuss 
this material with them and ensure they are fully informed on all trial requirements.  
Signature of Principal Investigator 
 
Printed name 
 
Date 
44 of 48
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Certificate Of Completion
Envelope Id: 168066114C0B499794E62215CC3B9C64
Status: Completed
Subject: Please DocuSign: SimpliciTB Russia Amendment #1.docx
Source Envelope: 
Document Pages: 44
Signatures: 1
Envelope Originator: 
Certificate Pages: 4
Initials: 0
Matt Betteridge
AutoNav: Enabled
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Time Zone: (UTC-05:00) Eastern Time (US & Canada)
40 Wall St FL 24
New York, NY  10005
Matt.Betteridge-consultant@tballiance.org
IP Address: 78.32.240.154
Record Tracking
Status: Original
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             Matt.Betteridge-consultant@tballiance.org
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Morounfolu Olugbosi
Morounfolu.Olugbosi@tballiance.org
Senior Director, Clinical Development
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CONFIDENTIAL 
Page 1 of 101 
 
 
 
Protocol Number: 
NC-008 (BPaMZ) 
Title: 
An Open-Label, Partially Randomized Trial to Evaluate the 
Efficacy, Safety and Tolerability of a 4-month Treatment of 
Bedaquiline 
plus 
Pretomanid 
plus 
Moxifloxacin 
plus 
Pyrazinamide (BPaMZ) Compared to a 6-month Treatment of 
HRZE/HR (Control) in Adult Participants with Drug-Sensitive 
Smear-Positive Pulmonary Tuberculosis (DS-TB) and a 6-month 
Treatment of BPaMZ in Adult Participants with Drug Resistant, 
Smear-Positive Pulmonary Tuberculosis (DR-TB). 
Drug(s)/Combination(s): 
Bedaquiline tablets (B), pretomanid tablets (Pa), moxifloxacin 
tablets (M), pyrazinamide tablets (Z), HRZE tablets [isoniazid 
(H), rifampicin (R), pyrazinamide (Z) and ethambutol (E)] and HR 
tablets [isoniazid (H) plus rifampicin (R) combination tablets] 
Protocol Version/Date: 
 
Russia V3.0 / 1 October 2019, Incorporating Protocol V4.0 / 30 
September 2019 
Protocol Name: 
SimpliciTB 
 
 
 
 
 
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TB Alliance
Protocol Number: NC-008 (B-Pa-M-Z)
Protocol Version:
Russia V3.0 / 1 OCT 2019, Incorporating Protocol V4.0 / 30 SEP 2019
Protocol Name:
SimpliciTB
Confidential
Page 2 of 101
PROTOCOL SIGNATURE PAGE
Protocol Title:  An Open-Label, Partially Randomized Trial to Evaluate the Efficacy, 
Safety and Tolerability of a 4-month Treatment of Bedaquiline plus Pretomanid plus 
Moxifloxacin plus Pyrazinamide (BPaMZ) Compared to a 6-month Treatment of 
HRZE/HR (Control) in Adult Participants
with Drug-Sensitive Smear-Positive 
Pulmonary Tuberculosis (DS-TB) and a 6-month Treatment of BPaMZ in Adult 
Participants with Drug Resistant, Smear-Positive Pulmonary Tuberculosis (DR-TB).
Protocol Number: 
NC-008 (BPaMZ)
Protocol Date:
Russia V3.0 / 1 October 2019, Incorporating Protocol V4.0 / 30
September 2019
Protocol Name:
SimpliciTB
SPONSOR:
TB Alliance
I agree to the terms of this trial protocol.
Morounfolu Olugbosi
Signature of Study Physician
Printed Name
40 Wall Street, 24th Floor
New York, NY 10005
Phone +27 87 700 3900 / +27 79 045 4917
E-mail: morounfolu.olugbosi@tballiance.org
Date
741 of 852


TB Alliance 
Protocol Number: NC-008 (B-Pa-M-Z) 
Protocol Version: Russia V3.0 / 1 OCT 2019, Incorporating Protocol V4.0 / 30 SEP 2019 
Protocol Name: 
SimpliciTB 
Confidential 
Page 3 of 101 
 
PRINCIPAL INVESTIGATOR PROTOCOL SIGNATURE PAGE 
 
An Open-Label, Partially Randomized Trial to Evaluate the Efficacy, Safety and 
Tolerability of a 4-month Treatment of Bedaquiline plus Pretomanid plus Moxifloxacin 
plus Pyrazinamide (BPaMZ) Compared to a 6-month Treatment of HRZE/HR (Control) in 
Adult Participants with Drug-Sensitive Smear-Positive Pulmonary Tuberculosis 
(DS-TB) and a 6-month Treatment of BPaMZ in Adult Participants with Drug Resistant, 
Smear-Positive Pulmonary Tuberculosis (DR-TB). 
Protocol Number:  
NC-008 (BPaMZ) 
Protocol Date:  
Russia V3.0 / 1 October 2019, Incorporating Protocol V4.0 / 30 
 
September 2019 
Protocol Name:  
SimpliciTB 
 
I hereby confirm that I have read the above protocol and agree to conduct this clinical trial as 
outlined in the above protocol. I will provide copies of the protocol and access to all the 
information required to conduct the clinical trial according to the above protocol to the site 
personnel under my supervision. I will discuss this material with them and ensure they are fully 
informed on all trial requirements. 
 
 
 
 
 
Signature 
 
Printed Name 
 
 
 
Date 
 
 
 
 
742 of 852


TB Alliance 
Protocol Number: NC-008 (B-Pa-M-Z) 
Protocol Version: Russia V3.0 / 1 OCT 2019, Incorporating Protocol V4.0 / 30 SEP 2019 
Protocol Name: 
SimpliciTB 
Confidential 
Page 4 of 101 
List of Tables ...................................................................................................................... 7 
List of Figures ..................................................................................................................... 7 
List of Appendices .............................................................................................................. 7 
Abbreviations and Definition of Terms ................................................................................ 8 
1.0 
Synopsis .................................................................................................................... 10 
1.1 
Synopsis Summary ................................................................................................ 10 
1.2 
Synopsis Flow Chart and Procedures .................................................................... 17 
2.0 
Introduction and Rationale ......................................................................................... 22 
2.1 
Tuberculosis Disease ............................................................................................. 22 
2.2 
Tuberculosis Clinical Research .............................................................................. 22 
2.3 
Trial Rationale ........................................................................................................ 24 
2.3.1 
Trial Design Rationale ...................................................................................................................... 24 
2.3.2 
Trial Drug Regimen Rationale .......................................................................................................... 25 
2.4 
Agents used within SimpliciTB ............................................................................... 26 
2.5 
Background of Agents to be Studied in SimpliciTB................................................. 28 
2.5.1 
Bedaquiline (B) ................................................................................................................................. 28 
2.5.2 
Pretomanid (P) ................................................................................................................................. 35 
2.5.3 
Moxifloxacin (M) .............................................................................................................................. 41 
2.5.4 
Pyrazinamide (Z) .............................................................................................................................. 43 
2.6 
Overall Benefit/Risk Assessment ........................................................................... 44 
2.6.1 
Bedaquiline (B) ................................................................................................................................. 44 
2.6.2 
Pretomanid (P) ................................................................................................................................. 45 
2.6.3 
Moxifloxacin (M) .............................................................................................................................. 46 
2.6.4 
Pyrazinamide (Z) .............................................................................................................................. 46 
2.6.5 
HRZE/HR Control .............................................................................................................................. 46 
3.0 
Trial Objectives .......................................................................................................... 46 
3.1 
Primary Endpoint ................................................................................................... 46 
3.2 
Secondary Endpoints ............................................................................................. 47 
3.3 
Exploratory Objectives ........................................................................................... 47 
4.0 
Trial Design ............................................................................................................... 48 
4.1 
Summary of Trial Design........................................................................................ 48 
4.2 
Treatment Plan: Schedule of Assessments ............................................................ 48 
5.0 
Trial Population ......................................................................................................... 49 
5.1 
Inclusion Criteria .................................................................................................... 49 
5.2 
Exclusion Criteria ................................................................................................... 51 
5.3 
Restrictions ............................................................................................................ 54 
5.4 
Treatment Discontinuation and/or Early Withdrawal ............................................... 56 
5.4.1 
Early Withdrawal ............................................................................................................................. 56 
5.4.2 
Unscheduled Visits ........................................................................................................................... 57 
5.4.3 
Lost-to-Follow-up ............................................................................................................................. 59 
5.4.4 
Early Withdrawal due to TB ............................................................................................................. 59 
5.5 
Participant Progress Definitions ............................................................................. 60 
5.6 
Trial Stopping Rules ............................................................................................... 61 
6.0 
Treatment .................................................................................................................. 61 
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TB Alliance 
Protocol Number: NC-008 (B-Pa-M-Z) 
Protocol Version: Russia V3.0 / 1 OCT 2019, Incorporating Protocol V4.0 / 30 SEP 2019 
Protocol Name: 
SimpliciTB 
Confidential 
Page 5 of 101 
6.1 
IMP Administration ................................................................................................. 61 
6.1.1 
Instructions for Dosing of Test Regimen (BPaMZ): .......................................................................... 61 
6.1.2 
Instructions for Dosing Control Treatment Regimen (HRZE/HR): .................................................... 61 
6.2 
Participant Compliance .......................................................................................... 61 
6.3 
Treatment Modification(s) ...................................................................................... 62 
6.4 
IMP Packaging and Labelling ................................................................................. 62 
6.5 
Blinding and Procedures for Breaking the Blind ..................................................... 63 
6.6 
Handling, Storage and Accountability..................................................................... 63 
7.0 
Trial Variables and Procedures ................................................................................. 64 
7.1 
Demographic and Background Variables and Procedures ..................................... 64 
7.2 
Efficacy Variables and Procedures ........................................................................ 65 
7.3 
Safety and Tolerability Assessments ..................................................................... 66 
7.4 
PK Variables and Procedures ................................................................................ 67 
7.5 
Mycobacteriology Characterization Variable and Procedures ................................ 67 
8.0 
Adverse Events ......................................................................................................... 69 
8.1 
Definitions .............................................................................................................. 69 
8.1.1 
Adverse Event (AE) ........................................................................................................................... 69 
8.1.2 
Serious Adverse Event (SAE) ............................................................................................................. 69 
8.1.3 
Attribution/Causality ....................................................................................................................... 69 
8.1.4 
Severity ............................................................................................................................................ 71 
8.2 
Reporting ............................................................................................................... 71 
8.2.1 
Follow up of Adverse Events ............................................................................................................ 72 
8.2.2 
Clinical Laboratory Adverse Events .................................................................................................. 72 
8.2.3 
Disease Symptoms During Trial ....................................................................................................... 72 
8.2.4 
Overdose .......................................................................................................................................... 73 
8.2.5 
Drug Interaction ............................................................................................................................... 73 
8.2.6 
Pregnancy ........................................................................................................................................ 73 
8.3 
Monitoring for Specific Toxicities ............................................................................ 73 
8.3.1 
ALT, AST and Bilirubin Elevations ..................................................................................................... 74 
8.3.2 
Lipase ............................................................................................................................................... 74 
8.3.3 
Musculoskeletal System and Cardiac Muscle Myalgia .................................................................... 74 
8.3.4 
Cardiac Rhythm Disturbances .......................................................................................................... 74 
8.4 
Safety Monitoring by Data Monitoring Committee .................................................. 75 
9.0 
Statistical Analysis ..................................................................................................... 75 
9.1 
Analysis Populations .............................................................................................. 75 
9.2 
Sample Size........................................................................................................... 76 
9.3 
Interim Analyses .................................................................................................... 76 
9.4 
Primary and Secondary Efficacy Endpoint Analysis ............................................... 77 
9.4.1 
Primary Efficacy Endpoint, Time to Culture Conversion at 8 Weeks ................................................ 77 
9.4.2 
Key Secondary Efficacy Endpoint, Clinical Outcome at 52 Weeks from Randomization .................. 77 
9.4.3 
Other Secondary Efficacy Endpoints ................................................................................................ 77 
9.5 
Safety and Tolerability Assessments ..................................................................... 77 
9.6 
Pharmacokinetics................................................................................................... 78 
9.7 
Pharmacokinetics/Pharmacodynamics ................................................................... 78 
10.0 
Records Management ............................................................................................... 78 
10.1 
Data Collection ...................................................................................................... 78 
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TB Alliance 
Protocol Number: NC-008 (B-Pa-M-Z) 
Protocol Version: Russia V3.0 / 1 OCT 2019, Incorporating Protocol V4.0 / 30 SEP 2019 
Protocol Name: 
SimpliciTB 
Confidential 
Page 6 of 101 
10.2 
Source Documents ................................................................................................ 78 
10.3 
File Management at the Trial Centre ...................................................................... 79 
10.4 
Records Retention at the Trial Centre .................................................................... 79 
11.0 
Quality Control and Assurance .................................................................................. 80 
11.1 
Site Procedures ..................................................................................................... 80 
11.2 
Monitoring .............................................................................................................. 80 
11.3 
Protocol Deviations ................................................................................................ 81 
11.4 
Auditing .................................................................................................................. 81 
12.0 
Ethics and Regulatory ............................................................................................... 82 
12.1 
Basic Principles ..................................................................................................... 82 
12.2 
Independent Ethics Committee/Institutional Review Board (EC/IRB) Review ......... 82 
12.3 
Regulatory Authorities ............................................................................................ 82 
12.4 
Informed Consent .................................................................................................. 82 
12.5 
Confidentiality ........................................................................................................ 83 
13.0 
Publication Policy ...................................................................................................... 84 
14.0 
Protocol Amendment Policy ....................................................................................... 84 
15.0 
Sponsor, Financial Aspects, Insurance and Indemnity ............................................... 84 
16.0 
References ................................................................................................................ 86 
Appendices .......................................................................................................................... 90 
 
 
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TB Alliance 
Protocol Number: NC-008 (B-Pa-M-Z) 
Protocol Version: Russia V3.0 / 1 OCT 2019, Incorporating Protocol V4.0 / 30 SEP 2019 
Protocol Name: 
SimpliciTB 
Confidential 
Page 7 of 101 
List of Tables 
Table 1.  Bedaquiline Adverse Drug Reactions .................................................................... 33 
Table 2.  Key findings of Pretomanid in Safety and Toxicity Trials........................................ 36 
Table 3.  Summary of Phase 2b trials in which moxifloxacin were administered as part of a 
four-drug regimen during the intensive phase of treatment (total treatment duration: 2 months)
 ............................................................................................................................................ 42 
Table 4: Treatment Groups .................................................................................................. 49 
Table 5: Follow-up Visits Required for Early Withdrawal Participants ................................... 57 
Table 6: Summary of Scenarios Requiring Unscheduled Visits for Mycobacteriology Testing
 ............................................................................................................................................ 58 
Table 7: Participant Progress Definitions.............................................................................. 60 
Table 8: Adverse Events Attribution/Causality Ratings ......................................................... 70 
Table 9: Definitions for Adverse Event Severity Gradings .................................................... 71 
 
List of Figures 
Figure 1.  Unified Drug Sensitive/Drug Resistant Regimen Development Path .................... 23 
Figure 2.  Log10 CFU Counts in Lungs ................................................................................ 36 
Figure 3.  Mean log Colony Forming Unit Values over Time Trial CL-010 ............................ 39 
 
List of Appendices 
Appendix 1: The IUATLD Scale ........................................................................................... 90 
Appendix 2: Division of Microbiology and Infectious Disease (DMID) Toxicity Table ............ 91 
Appendix 3: Who Clinical Staging of HIV/AIDS for Adults and Adolescents ......................... 98 
Appendix 4: Cardiovascular Safety .................................................................................... 100 
Appendix 5: Karnofsky Performance Status Scale Definitions Rating (%) Criteria .............. 101 
 
 
 
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TB Alliance 
Protocol Number: NC-008 (B-Pa-M-Z) 
Protocol Version: Russia V3.0 / 1 OCT 2019, Incorporating Protocol V4.0 / 30 SEP 2019 
Protocol Name: 
SimpliciTB 
Confidential 
Page 8 of 101 
Abbreviations and Definition of Terms 
3TC 
Lamivudine 
ABC 
Abacavir 
AE  
Adverse Event  
AFB 
Acid-fast bacilli 
AIDS 
Acquired Immune Deficiency Syndrome 
ALP 
Alkaline Phosphatase 
ALT 
Alanine aminotransferase 
AREDS2 
Age Related Eye Disease Scale 2 
ART 
Anti-Retroviral Therapy 
AST 
Aspartate aminotransferase 
AUCτ 
Area Under Curve over a dosing interval 
B 
Bedaquiline 
BA 
Bacterial activity 
BMI 
Body Mass Index 
BPaMZ 
Combination of bedaquiline plus pretomanid plus moxifloxacin plus 
pyrazinamide 
C 
Clofazimine 
CFU 
Colony Forming Units 
C(max), (min) 
plasma Concentration (maximum), (minimum) 
CO2 
Carbon dioxide 
CPK 
Creatine Phosphokinase 
CYP3A4 
Cytochrome P450 3A4 
DMID 
Division of Microbiology and Infection Disease 
DNA 
Deoxyribonucleic Acid 
DR-TB 
Drug-resistant tuberculosis 
For this particular protocol defined as TB participants with  
1. mono-resistance to rifampicin or isoniazid, OR 
2. resistance to both rifampicin and isoniazid (MDR-TB) 
(participants with fluoroquinolone resistance are excluded) 
DS-TB 
Drug-sensitive tuberculosis 
DSMC  
DST 
Data Safety and Monitoring Committee 
Drug Susceptibility Testing 
E 
Ethambutol 
EBA 
Early Bactericidal Activity 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
EFV 
Efavirenz 
(e)CRF 
(electronic) Case Report Form 
EMS 
Early Morning Sputum 
EWD 
Early Withdrawal 
FTC 
Emtricitabine 
FSH 
Follicle-stimulating hormone 
GCP  
Good Clinical Practice 
GMR 
Geometric Mean Ratio 
H 
Isoniazid 
HR 
Hazard Ratio 
hERG 
Human Ether-à-go-go Related Gene 
HIV  
Human Immunodeficiency Virus 
HRZE 
Isoniazid, Rifampicin, Pyrazinamide, Ethambutol 
HR 
Isoniazid plus rifampicin combination tablet 
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TB Alliance 
Protocol Number: NC-008 (B-Pa-M-Z) 
Protocol Version: Russia V3.0 / 1 OCT 2019, Incorporating Protocol V4.0 / 30 SEP 2019 
Protocol Name: 
SimpliciTB 
Confidential 
Page 9 of 101 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IMP 
Investigational Medicinal Product 
IRB 
Institutional Review Board 
ITT 
Intent to Treat 
IUATLD 
International Union Against Tuberculosis and Lung Disease 
IWRS 
Interactive Web Randomization System 
kg 
Kilogram 
L 
Linezolid 
LH 
Luteinizing hormone 
LLN 
Lower Limit of Normal 
LPV 
Lopinavir 
LTFU 
Lost to follow-up  
M 
Moxifloxacin 
MBD 
Minimum Bactericidal Dose 
MIC 
Minimum Inhibitory Concentration 
MTB 
Mycobacterium tuberculosis 
MDR-TB 
Multi Drug Resistant Tuberculosis 
MGIT 
Mycobacterial Growth Inhibiting Tube 
mITT 
Modified Intent to Treat 
ms 
millisecond 
NVP 
Nevirapine 
NO 
Nitric Oxide 
NOAEL 
No Observed Adverse Effect Level 
NRTI 
(Triple) Nucleosidase Reverse Transcriptase Inhibitor 
Pa 
Pretomanid 
PD 
Pharmacodynamic 
PP 
Per Protocol 
PK 
Pharmacokinetic 
PR 
PR interval 
R 
Rifampicin 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SSCC 
Serial sputum colony counting 
TB 
Tuberculosis 
TDF 
Tenofovir 
TEAE 
Treatment Emergent Adverse Events 
TTP 
Time to Positivity  
ULN 
Upper Limit of Normal 
WGS 
Whole Genome Sequencing 
WHO 
World Health Organization 
XDR-TB 
Extensively Drug Resistant Tuberculosis 
μg(/ml) 
micrograms (per millilitre) 
Z 
Pyrazinamide (tablets) 
 
 
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TB Alliance 
Protocol Number: NC-008 (B-Pa-M-Z) 
Protocol Version: Russia V3.0 / 1 OCT 2019, Incorporating Protocol V4.0 / 30 SEP 2019 
Protocol Name: 
SimpliciTB 
Confidential 
Page 10 of 101 
1.0 
Synopsis 
1.1 
Synopsis Summary 
Synopsis 
Description  
Name of 
Sponsor/Company 
TB Alliance 
Name of Finished 
Products 
Bedaquiline tablets (B), pretomanid tablets (Pa), moxifloxacin 
tablets (M), pyrazinamide tablets (Z), HRZE tablets [isoniazid 
(H), rifampicin (R), pyrazinamide (Z) and ethambutol (E)] and 
HR tablets [isoniazid (H) plus rifampicin (R) combination tablets] 
Protocol Number/Title 
NC-008 (BPaMZ) An Open-Label, Partially Randomized Trial to 
Evaluate the Efficacy, Safety and Tolerability of a 4-month 
Treatment of Bedaquiline plus Pretomanid plus Moxifloxacin 
plus Pyrazinamide (BPaMZ) Compared to a 6-month Treatment 
of HRZE/HR (Control) in Adult Participants with Drug-Sensitive 
Smear-Positive Pulmonary Tuberculosis (DS-TB) and a 6-
month Treatment of BPaMZ in Adult Participants with Drug 
Resistant, Smear-Positive Pulmonary Tuberculosis (DR-TB) 
Treatment Indication 
Pulmonary Tuberculosis (TB) 
Trial Objective(s) 
To evaluate the efficacy, safety and tolerability at 8 weeks (2-
months), 52 weeks (12-months), and 104 Weeks (24-months) 
post the start of the treatment regimens in participants with Drug 
Sensitive TB (DS-TB) and Drug Resistant TB (DR-TB). 
 
DR-TB is defined as participants with:  
 
1. mono-resistance to rifampicin or isoniazid, OR 
2. resistance to both rifampicin and isoniazid (MDR-TB) 
 
Trial Design 
Phase 2c multi-centre, open-label, partially randomized clinical 
trial in Drug Sensitive-TB (DS-TB) and Drug Resistant-TB (DR-
TB) participants.  
 
All participants will enter post-treatment follow-up which 
continues until Week 104 from start of treatment / 
randomisation. 
 
Participants with DS-TB: 
 
Participants with DS-TB will be randomized to one of two 
treatment arms. These participants will receive either BPaMZ 
daily for 17 weeks (4 months), or HRZE/HR tablets daily for 26 
weeks (6 months). Participants will be stratified for co-infection 
with human immunodeficiency virus (HIV) and cavitation. 
 
Participants with DR-TB: 
 
Participants with DR-TB will be assigned to receive BPaMZ daily 
for 26 weeks (6 months). 
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Synopsis 
Description  
Participant Population 
Up to 450 male and female participants, diagnosed with DS-TB 
or DR-TB, aged 18 years and over with a target of up to 50% 
being HIV positive. 
 
300 DS-TB participants (150 per treatment arm) will be 
randomized and stratified for co-infection with HIV and 
cavitation. 
 
Up to 150 DR-TB participants will be enrolled. 
Test Product, Dose and 
Mode of Administration 
The Test Product (BPaMZ) consists of a combination of the 
following products and will be supplied as: 
 
Product 
Tablet Strength 
Abbreviation  
Bedaquiline 
100 mg  
(B) 
Pretomanid 
200 mg  
(Pa) 
Moxifloxacin 
400 mg 
(M) 
Pyrazinamide 
500 mg 
(Z) 
 
Instructions for Dosing BPaMZ:  
 
Investigational Medicinal Product (IMP) will be administered 
orally once daily, to be taken during breakfast, with a full glass 
of water (approximately 240 ml), for 17 weeks (4 months) or 26 
weeks (6 months) in the following dosing schemes: 
 
Participants with DS TB: 
Bedaquiline 200 mg daily for 8 weeks then 100 mg daily 
for 9 weeks, together with pretomanid 200 mg + 
moxifloxacin 400 mg + pyrazinamide 1500 mg daily for 
17 weeks (total treatment duration 4 months)  
 
OR 
 
Participants with DR-TB: 
Bedaquiline 200 mg daily for 8 weeks then 100 mg daily 
for 18 weeks, together with pretomanid 200 mg + 
moxifloxacin 400 mg + pyrazinamide 1500 mg daily for 
26 weeks (Total treatment duration 6 months). 
 
Positive Control 
Product, Dose and 
Mode of Administration 
The Control Treatment Regimen (HRZE/HR) will be supplied as:  
 
HRZE Tablets: isoniazid 75 mg plus rifampicin 150 mg plus 
pyrazinamide 400 mg plus ethambutol 275 mg combination 
tablets. This combination will be given for the first 8 weeks. 
 
AND 
 
HR Tablets: isoniazid 75 mg plus rifampicin 150 mg 
combination tablets. This combination will be given from Weeks 
9 to 26. 
 
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Protocol Name: 
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Synopsis 
Description  
Instructions for Dosing Control Treatment Regimen 
 
To be taken with a glass of water (approximately 240 ml).  HRZE 
or HR should not be taken with a meal (generally, no closer to 
meals than 1 hour before or 2 hours after a meal) in the following 
dosing schemes: 
 
Treatment will be administered orally once daily to the HRZE/HR 
randomized DS-TB participants as follows: 
 
 
Weeks 1-26: HRZE/HR tablets daily dose per the 
 
participant’s weight as follows:  
 
 
Weight Band 
Weight Range 
Number of 
tablets  
1 
30-39 kg 
2 
2 
40-54 kg 
3 
3 
55-70 kg 
4 
4 
≥ 71 kg 
5 
 
The participant’s weight at the Screening (HRZE) and Week 8 
(HR) visits will be used to determine which weight band and 
HRZE and HR dose to administer. 
 
Vitamin B6 daily supplement to be taken with the HRZE/HR 
treatment, as per each country’s TB Treatment Guidelines.  
 
Treatment 
Interruptions/Pauses 
For All Trial Regimens  
The trial treatment regimens may require interruptions/pauses 
due to toxicities. All dose interruptions/pauses should be 
discussed with the Sponsor’s Medical Monitor prior to 
implementation, unless an interruption/pause is required 
urgently for a safety concern.   
Action required for participants missing the following number of 
doses within the trial treatment regimens:  
• 
Up to 7 consecutive doses: restart treatment, no 
extension of treatment required. 
• 
If more than 7 and to ≤ 35 consecutive doses missed, 
before the end of the treatment period (Week 17/26): 
restart treatment, extend the treatment by the number of 
consecutive doses missed. In this case, the last visit of 
the treatment period should also be pushed out to the 
date of the last dose 
• 
If more than 35 consecutive doses: discontinue 
treatment and withdraw participant from the trial  
• 
If the participant misses a total of 56 cumulative missed 
doses, discontinue the IMP and withdraw the 
participant from the trial. 
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Protocol Version: Russia V3.0 / 1 OCT 2019, Incorporating Protocol V4.0 / 30 SEP 2019 
Protocol Name: 
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Synopsis 
Description  
• 
If more than 7 to ≤ 35 consecutive doses are missed, 
these must be made up with the same treatment 
combination or dose, that was missed.  
 
Any participant for whom the trial IMP is discontinued (including 
for non-adherence) should be discussed with the Sponsor 
Medical Monitor and, if applicable, the participant will be 
restarted on trial IMP as soon as possible. 
Statistical Methods: 
A general description of the statistical methods planned to be used to analyse efficacy data 
is outlined below. Specific details will be provided in the statistical analysis plan (SAP,) 
which will be written and signed off prior to the interim analysis. 
 
Criteria for Evaluation 
 
Primary Endpoint 
 
The primary efficacy endpoint will be time to culture negativity over 8 weeks. The primary 
hypothesis to be evaluated is:  
 
• 
In the participants with DS-TB in the experimental BPaMZ treatment regimen, the time 
to culture negativity by 8 weeks will be superior, compared to the participants who are 
treated with the standard HRZE/HR regimen. 
 
 
Secondary Endpoints 
 
• 
A key secondary efficacy endpoint will be the proportion of participants experiencing 
bacteriologic failure or relapse or clinical failure (unfavourable outcome) at 52 weeks.  
 
The hypothesis to be evaluated for this endpoint is: 
 
• 
In the participants with DS-TB in the experimental BPaMZ treatment regimen, the 
proportion experiencing an unfavourable outcome will be non-inferior compared to the 
participants who are treated with the standard HRZE/HR regimen. 
 
Abbreviated Definitions, full definitions will be described in the Statistical Analysis Plan 
(SAP): 
 
• 
Bacteriologic failure: During the treatment period, failure to attain or maintain culture 
conversion to negative.  
• 
Bacteriologic relapse: During the follow-up period, failure to maintain culture conversion 
to negative status, with culture conversion to positive status with a strain of 
Mycobacterium tuberculosis (MTB) genetically identical to the infecting strain at 
baseline.  
• 
Clinical failure: A change from protocol-specified TB treatment to a new regimen before 
end of protocol specified treatment due to treatment failure, retreatment for TB during 
follow up, or TB-related death.  
 
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Synopsis 
Description  
Note:  
 
o Culture conversion requires at least 2 consecutive culture negative/positive 
samples at least 7 days apart.  
o Participants who are documented at a visit as unable to produce sputum and who 
are clinically considered to be responding well to treatment will be considered to be 
culture negative at that visit.  
 
Other Secondary Endpoints 
 
Efficacy: 
 
• 
Incidence of bacteriologic failure or relapse or clinical failure at 104 weeks from the 
start of treatment.  
• 
Proportion of participants with sputum culture conversion to negative status in liquid 
culture (MGIT) at 4, 6, 12 and 17 weeks to be explored as a potential biomarker of 
outcome at 52 weeks from start of treatment. 
• 
Change from baseline in weight. 
• 
Change from baseline in TB symptoms. 
• 
Change from baseline in Participant Reported Health Status. 
 
Safety and Tolerability: 
 
• 
Incidence of Treatment Emergent Adverse Events (TEAEs) presented by incidence, 
severity, drug relatedness, seriousness, leading to early withdrawal, and leading to 
death.  
• 
Quantitative and qualitative clinical safety laboratory measurements, including 
observed and change from baseline. 
• 
Quantitative and qualitative electrocardiogram (ECG) results (heart rate, RR interval, 
PR interval, QRS interval, QT interval and QTc interval), including observed. QT/QTc 
intervals, change from baseline, will be categorized as these will be centrally read. 
• 
Changes in male reproductive hormones. 
• 
Changes in lens opacities. 
 
These data will be presented as descriptive analyses, and no inferential tests will be 
carried out. 
 
Pharmacokinetics (PK) and Pharmacokinetics/Pharmacodynamics (PK/PD): 
 
Plasma concentrations from sparse sampling will be used to update existing population PK 
models and derive exposure metrics (e.g., minimum plasma concentration [Cmin], 
maximum plasma concentration [Cmax], area under curve over a dosing interval [AUC]) for 
bedaquiline and its M2 metabolite, pretomanid, moxifloxacin, and pyrazinamide.  
 
Effects of baseline covariates on exposure will be assessed; so too, will the effects of 
concomitant medications, including antiretroviral therapy (ART), where feasible. Data from 
other trials may be included to enhance the model-based analysis. Relationships will be 
explored between drug exposure and efficacy and safety endpoints. These exploratory 
PK/PD analyses may include HIV status as a covariate. 
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Protocol Version: Russia V3.0 / 1 OCT 2019, Incorporating Protocol V4.0 / 30 SEP 2019 
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Synopsis 
Description  
 
Exploratory Objectives: 
 
Evaluate whether any of the secondary endpoints predict relapse free cure. Subgroup 
analysis of populations by HIV status will be performed. 
 
No formal statistical comparisons will be made for the participants enrolled with DR-TB. 
The responses of participants with DR-TB receiving BPaMZ will be compared for 
consistency with those responses of the DS-TB participants on the same regimen.   
 
 
Sample Size 
 
Primary endpoint: 150 participants per arm (DS-TB patients) will provide at least 90% 
power (5% 2-sided significance) to detect a hazard ratio (HR) of at least 2 assuming 50% 
of control participants are culture negative by 8 weeks.  
 
Additional efficacy parameters will be evaluated including the incidence of bacteriologic 
failure or relapse or clinical failure (unfavourable outcome) at 52 weeks and 104 weeks 
from the start of treatment. Time to unfavourable outcome from assignment of trial 
treatment through follow-up as a function of time will be analysed using Kaplan-Meier 
analysis. 
 
Interim Analysis 
 
There is one planned interim efficacy analysis which will occur after approximately 60 
assessable participants have been randomised to the control arm and have reached the 8-
week primary endpoint. Time to culture negative status in liquid media up to 8 weeks will 
be analysed using a Cox regression model, censoring for death and lost to follow 
up/withdrawal to estimate the hazard ratio (HR). Following a review of these interim 
findings, the following considerations will be given to modify the trial objectives and sample 
size: 
If the observed HR (time to culture negativity, experimental arm vs. HRZE control arm) is 
>2, the sample size may be increased to adequately power the trial on the key 
secondary efficacy endpoint (clinical and microbiological outcome at 52 weeks from 
randomization), which will then become the primary efficacy endpoint. The trial efficacy 
objectives will be updated as follows: 
• 
Primary Objective 
 
To determine the incidence of bacteriologic failure or  
relapse or clinical failure 
at 52 weeks from the start of  treatment / randomisation.  
• 
Secondary Objective 
 
To evaluate the time to culture negativity over 8 weeks,  
from the start of 
treatment / randomisation. 
All other trial objectives will remain unchanged. 
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Synopsis 
Description  
To achieve 90% power and overall 5% 2-sided significance after adjusting for the 
interim analysis, this will mean increasing the sample size to 225 participants per 
randomised arm, i.e., to a total of 450 DS-TB participants (and up to 225 DR-TB 
participants). This adaptation is based on the Multi-arm Multi-stage (MAMS) framework 
[46,47,48] and full details are provided in the Statistical Analysis Plan. 
 
Trial Duration: 
Approximately 4 years (18-month enrolment period for DS-TB participants, up to 26 week-
treatment, and follow-up until 104 weeks from start of treatment). Depending on the DR-TB 
recruitment rate, enrolment into this arm may continue after enrolment into the DS-TB 
arms are complete.  
 
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1.2 
Synopsis Flow Chart and Procedures 
Period 
Screen-
inga 
Treatment 
Follow-Upc 
Visitb 
Day -9 to -1 
Day 1 
(Baseline)d 
Week 1 
Week 2 
Week 3 
Week 4 
Week 5 
Week 6 
Week 7 
Week 8  
Week 12 
Week 17 
4-mth treatmente 
Week 17  
6-mth treatmente 
Week 22  
Week 26  
4-mth treatmente 
Week 26  
6-mth treatmente 
Week 39 
Week 52 
Week 65 
Week 78 
Week 104 
Early 
Withdrawalc
Visit Windowv 
N/A 
+/- 3 Days 
+/- 5 Days 
+/- 14 Days 
Written Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/Treatment/ 
Smoking 
History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sputum Samplingf,g 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HIV Statush and CD4 Counti 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Karnofsky Scorex 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Drug Screenj 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Pregnancy Testk 
X 
X 
 
 
 
 
 
 
 
X 
 
X 
X 
 
X 
X 
 
 
 
 
 
X 
Laboratory Safety Testl 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
 
 
 
 
X 
Male Reproductive Hormone Testsm 
X 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
X 
 
 
 
 
X 
12-lead ECGn 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
 
 
 
X 
Chest X-Rayo 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TB Symptoms Profile 
X 
X 
 
X 
 
X 
 
 
 
X 
 
X 
X 
 
X 
X 
 
X 
 
 
X 
X 
Patient Reported Health Status  
X 
X 
 
X 
 
X 
 
 
 
X 
 
X 
X 
 
X 
X 
 
X 
 
 
X 
X 
Vital Signs and weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Ophthalmic Examinationp 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
X 
X 
 
 
 
 
X 
Physical Examination – fullq 
X 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
Physical Examination – limitedr 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
Pharmacokinetic Samplings 
 
X 
 
X 
 
 
 
 
 
X 
X 
X 
X 
 
 
 
X 
 
X 
X 
X 
 
IMP Randomization/ Assignmentt 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IMP Compliance Checku 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 Xe 
 
X 
 
 
 
 
 
Xt 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Investigator Assessmentv 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
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GENERAL: Vital signs and blood draws are to be performed before dosing, unless 
otherwise specified. Vital signs and/or ECGs should be done before blood draws 
(safety and PK) on days with those assessments. 
 
a. Screening: Screening assessments can occur on different days within nine days 
before to Day 1 (Baseline).  
b. Visit Schedule (due to unforeseen circumstances): If the duration of treatment is 
extended due to dose interruptions / pauses (7 to ≤ 35 consecutive doses), the last 
visit of the corresponding treatment period should also be pushed out to the date of 
the last dose. It is not necessary to have an unscheduled visit at the time that the last 
visit of the treatment period would have been scheduled on.   
c. Follow-up Visits for Early Withdrawal Participants: Once a participant has been 
permanently withdrawn from the trial, they will be required to attend an Early 
Withdrawal visit (Week 52, if not already performed) and Week 104 follow-up visits. 
The Week 52 and Week 104 visits will be performed to collect Serious Adverse Event 
(SAE) information (including verification of survival) and the participant reported TB 
outcome information only, and may be performed telephonically, at home or a site visit. 
Visits will occur at Week 52 and/or Week 104 after the participant’s start of treatment 
date.  Refer to Table 5 for additional guidance. 
d. Day 1 (Baseline): All procedures are to be completed before dosing.  
e. Last Visit of the Treatment Period: Investigational Medicinal Product (IMP) 
Compliance Check is not performed at the Week 22 visit for participants who have 
completed treatment at Week 17. 
f. Sputum Sampling: The sputum sampling methodology/requirements and tests will be 
described in a separate document, the Mycobacteriology Laboratory Manual. 
 
• 
Screening (Days -9 to -1). Two spot sputum samples taken 30 minutes apart will 
be collected at the research site under the coaching and observation of the trial 
staff. The following analyses will be performed on the first of these samples: 
o Smear microscopy for acid-fast bacilli (AFB); 
o Rapid molecular tests for fluoroquinolones, isoniazid and rifampicin 
resistance (Hain MTBDplus and Hain MTBRsl);  
o Liquid Culture (MGIT) for Mycobacterium tuberculosis (MTB), followed by 
a speciation test to detect the presence or absence of MTB and obtain the 
time to positivity (TTP) when positive. 
o The second sample is collected as a back-up sample to the first sample in 
case it is technically not possible to obtain a result/s from the first sample. 
If the Screening spot sputum smear shows an indeterminate result or is 
AFB negative, the test may be repeated on the back-up sample or on a 
freshly collected spot sputum, and then that result will be used.  
• 
Day 1 (Baseline) to Week 104 and Unscheduled visits for additional sputum 
samples:  
o Two sputum samples are collected, ideally one Early Morning Sputum 
(EMS) brought from home and one spot sputum sample at the research 
site, under the coaching and observation of the trial staff. If the participant 
forgets to bring in the EMS, then two spot sputum samples are to be 
collected at the site, at least 30 min apart, and this altered sample collection 
is captured within case report form (CRF).   
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o If both sputum cultures at Weeks 8 or later are contaminated, the participant 
should return for an unscheduled visit(s) to give additional sputum samples 
or to document that the participant is not able to produce a sputum sample.  
 
• 
If after having converted to culture negative, and the participant has a MTB 
confirmed positive culture at or after the last visit of the treatment period (Week 17 
or Week 26), the participant should return for an unscheduled visit/s to provide 
additional sputum samples, at a minimum of 7 days apart, or to document that the 
participant is not able to produce a sputum sample.  
• 
Additional samples may be required to define a participants’ primary outcome 
status as described in Sections 5.4.2 and 7.2.  
• 
Liquid Culture (MGIT) for MTB, followed by a speciation test to detect the presence 
or absence of MTB and obtain TTP when positive, will be performed on all samples. 
g. Mycobacteriology Characterisation Tests performed: 
• 
Day 1 (Baseline) sputum sample (or any positive sample from Screening to Week 
4, if the baseline cultures are contaminated or negative); 
• 
MTB confirmed positive cultures (after the participant has previously converted to 
culture negative) at or after the last visit of the treatment period (Week 17 or Week 
26) or visits with positive cultures, during the post-treatment follow-up period. 
• 
Refer to Mycobacteriology Laboratory Manual for full details.   
Mycobacterial Characterization - MTB isolates (from the first MTB positive culture) will 
be processed for: 
• 
Rapid molecular tests for fluoroquinolones, injectables, isoniazid and rifampicin 
resistance (only on MTB positive cultures in the follow-up period); 
• 
Minimum Inhibitory Concentration (MIC) against bedaquiline, pretomanid, and 
moxifloxacin;  
• 
Drug Susceptibility Testing (DST) for streptomycin, rifampicin, isoniazid, 
ethambutol, moxifloxacin, and pyrazinamide in liquid culture; 
• 
Extraction of organismal (MTB) DNA for whole genome sequencing (WGS), and 
comparison of sequences from baseline and relapse isolates. 
 
h. HIV Testing: If HIV status is a confirmed known positive, a repeated HIV test is not 
needed provided that a documented HIV test result (ELISA, Western Blot or Electro-
Chemiluminescence) is available. If the HIV status is unknown or suspected negative, 
a HIV test will be requested. If an ELISA and/or Western Blot and/or Electro-
Chemiluminescence based HIV test was performed within 4 weeks prior to screening, 
it should not be repeated if documentation of testing method and negative HIV results 
can be provided. Repeated HIV testing, during the Screening period is permitted for 
indeterminate HIV results. 
i. 
CD4 Count: Required for all HIV-positive participants.  
j. 
Urine 
Drug 
Screen: 
Cannabinoids, 
cocaine, 
amphetamines, 
opiates, 
benzodiazepines, barbiturates, at Screening only. Investigator to utilize this result to 
determine whether participant meets Exclusion Criteria 2. Positive results will not 
automatically exclude a participant from the trial. 
k. Urine Pregnancy Test: Women of childbearing potential only, whether they are 
sexually active or not.  
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l. 
Safety Laboratory Assessments: The safety laboratory sampling methodology and 
requirements will be described in a separate document, the Safety Laboratory Manual, 
which will be provided prior to the trial start. The following analyses will be performed: 
• 
Full Blood Count (haemoglobin, haematocrit, red blood cell count, white blood cell 
count with differential, platelet count).  
• 
Clinical Chemistry (albumin, serum urea, creatinine, direct, indirect and total 
bilirubin, uric acid, total protein, alkaline phosphatase [ALP], aspartate 
aminotransferase [AST], alanine aminotransferase [ALT], lipase, phosphate, 
sodium, potassium, calcium (corrected for albumin), chloride, magnesium, 
glucose, bicarbonate/carbon dioxide [CO2], creatine phosphokinase [CPK]). GGT 
is only routinely included at the Screening visit (Day -9 to -1).  
• 
Urinalysis (pH, specific gravity, protein, glucose, micro-albumin, ketones, bilirubin, 
creatinine, nitrite, sodium, urobilinogen, blood, leukocytes). Microscopy will be 
completed as follow-up to abnormal urinalysis per discretion of Investigator.  
• 
When managing participants with elevated liver enzymes at an Unscheduled visit, 
the investigator should request additional tests, in addition to the repeat LFT [e.g. 
Gamma Glutamyl Transferase (GGT), screening for Hepatitis A, B, C; to assist in 
ruling out other causes of a dysfunctional liver test (e.g. alcohol induced hepatic 
cell injury, hepatobiliary disease, hepatic viral infection)]. 
• 
Hepatitis A, B and C serology test to be performed at Day 1 (baseline) or where 
available, the backup PK sample at Day 1 (pre-dose) will be used to obtain a 
hepatitis A, B and C serology result for all participants already enrolled prior to 
Russia Protocol V3.0. 
m. Male Reproductive Hormone Tests: Testosterone, follicle-stimulating hormone 
(FSH), luteinizing hormone (LH) and Inhibin B to be done on male participants in ALL 
treatment groups. 
n. Single 12-Lead ECG: ECGs to be performed prior to pre- and post-dose PK 
sampling as described below: 
• 
Day 1: pre-dose (within 2 hours prior to dosing) 
• 
Week 2: pre-dose (within 2 hours prior to dosing), 1.5–3 hours post-dose and 4-6 
hours post-dose 
• 
Week 8: pre-dose (within 2 hours prior to dosing), 1.5–3 hours post-dose and 4-6 
hours post-dose 
• 
Week 12: pre-dose (within 2 hours prior to dosing)  
• 
Week 17 or at early withdrawal if prior to week 17: pre-dose (within 2 hours prior 
to dosing) and 1.5–3 hours post-dose 
Central ECG analysis will be performed. Results from central reading of Screening 
ECG must be used to determine eligibility.  
o. Chest X-Ray: A chest x-ray (digital image only) within 6 months prior to or at the 
Screening visit, will be obtained and read locally by the Investigator or designee. Digital 
images will be provided to the Sponsor and this process will be described in a separate 
document, the Radiology Manual. 
p. Slit Lamp Ophthalmic Examination: Slit lamp examination will be done at the 
Screening visit, the last visit of the treatment period (Week 17 or 26) and at Week 39 
for both treatment groups.  An additional slit lamp at Week 26 will be done for the 4-
month treatment group. Slit lamp ophthalmology examination will be performed by an 
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Ophthalmologist with AREDS2 training. Ophthalmology examinations may occur at 
any time within the window period for the applicable visit i.e. they do not have to be 
performed on the same day as the trial procedures. 
q. Physical Examination, Full: Height (m) will only be collected at Screening.  
r. Physical Exam, Limited: Limited physical exams will include weight and gross 
neurological, pulmonary, cardiovascular and abdominal exam(s). 
s. Pharmacokinetic (PK) Sampling: This process will be described in a separate 
document, the PK Sampling Manual. No PK samples will be collected for the HRZE/HR 
treatment arm.  Blood draws for PK samples collected pre-and post-dose must be done 
after the ECG is performed.  The dates and times of IMP taken prior to all pre-dose PK 
samples will be collected.  Specific PK blood draws will be obtained as follows: 
 
• 
*Day 1: pre-dose (within 2 hours prior to dosing) 
• 
Week 2: pre-dose (within 2 hours prior to dosing), 1.5–3 hours post-dose and 4-6 
hours post-dose 
• 
Week 8: pre-dose (within 2 hours prior to dosing), 1.5–3 hours post-dose and 4-6 
hours post-dose 
• 
Week 12: pre-dose (within 2 hours prior to dosing)  
• 
Week 17 or at early withdrawal if prior to week 17: pre-dose (within 2 hours prior 
to dosing) and 1.5–3 hours post-dose 
• 
Weeks 39, 65, 78 and 104 (for bedaquiline, bedaquiline metabolite M2): PK 
samples are to be obtained at any time on the day of the scheduled visit. 
Only bedaquiline and M2 will be measured. 
If IMP is not administered during Week 2, 8 and or 17, then only a single PK sample is 
required to be obtained at any time during the visit assessment.  
* Where available, the backup PK sample at Day 1 (pre-dose) will be used to obtain a 
hepatitis A, B and C serology result for all participants already enrolled prior to Russia 
Protocol V3.0. 
t. Investigational 
Medicinal 
Product 
(IMP) 
Randomization/Assignment: 
Randomization/Assignment may occur once all the Screening results are available and 
the Investigator has determined that the participant is eligible for the trial. 
u. IMP/Compliance Check: IMP administration will be supervised per local site practice 
to assure compliance to the regimen. Performed at all visits and Early Withdrawal 
(EWD), if during the treatment period.  
v. Investigator Assessment: Investigator to review the participant status and assess 
whether IMP or TB treatment at Week 52 and 104 is considered a “success” or “failure”.  
If considered a failure, the Investigator should specify if the assessment is based on 
bacteriology and/or clinical deterioration and/or radiological deterioration. Investigator 
Assessment to be completed, at Week 52 and 104, and at any time the Investigator 
determines that the participant fulfils the criteria for outcome of treatment failure. 
w. Visit Windows: The windows noted on the flowchart for timing of visit also apply to 
the timing within a visit.  Procedures should be performed within +/- 3 days of 
scheduled visit from Day 1 to Week 8 or +/- 5 Days of scheduled visit from Week 12 to 
Week 26 or +/- 14 days of scheduled visit at or after Week 39.  Sites should make 
every effort to ensure all procedures are done on the same day, when possible. 
x. Karnofsky Score: Only to be performed on HIV+ participants. 
 
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2.0 
Introduction and Rationale 
2.1 
Tuberculosis Disease 
Although some progress has been made in recent years in controlling tuberculosis (TB) 
globally, TB has remained a persistent problem in the developing countries of Africa, Asia and 
South America.  TB is currently one of the top three killer infectious diseases, and there is 
more TB in the world today than at any other time in history.  The current first-line anti-
tuberculosis agents have been in use for over 40 years and are relatively ineffective in 
controlling TB as a public health problem.  Although the current regimens and drugs have 
been very successful in controlled clinical trials resulting in the permanent cure of more than 
95% of trial participants, treatment takes 6 months or more to complete. This, long duration 
treatment plus side effects, result in poor adherence which particularly occurs after the 
second month of treatment.  
The current TB treatment regimens and treatments for drug-sensitive TB are decades old. The 
available treatments have a lengthy duration of treatment, involve multi-drug therapy, and 
require large commitments of resources and infrastructure. High rates of noncompliance are 
common, which often results in increased mortality and chronic, infectious, drug-resistant 
cases. The present TB epidemic and the challenge of current treatment options demonstrate 
the clear need for effective novel TB drugs and drug regimens that are safe for drug sensitive 
and drug resistant TB disease and that are well-tolerated and will shorten the current treatment 
duration for patients. 
The full application of the Directly Observed Treatment, Short-Course strategy is becoming 
more and more difficult in the developing countries of the world that are also battling to control 
the HIV-epidemic.  Because of poor treatment adherence, drug resistance is becoming more 
common and fears of an epidemic with virtually untreatable strains of TB are growing.  Since 
the discovery of the rifamycins,[1] and their introduction into standard antituberculosis 
regimens, very few new classes of drugs have been evaluated with a view to their registration 
as antituberculosis agents.  On December 28, 2012 the U.S. Food and Drug Administration 
approved bedaquiline (B) as part of combination therapy to treat adults with multi-drug 
resistant (MDR) pulmonary tuberculosis (TB) when other alternatives are not available. 
Following the declaration of TB as a global emergency by the World Health Organization 
(WHO) in 1993, there has been a resurgence of efforts to develop improved TB therapies and 
several promising new agents are presently in or approaching clinical evaluation.   
New combination regimens are desperately needed for two reasons: to shorten treatment to 
a duration more easily manageable by patients and public health services, and to provide 
more efficacious, safer and better tolerated, affordable treatments for the growing number of 
patients suffering from multidrug-resistant and extensively drug-resistant tuberculosis. 
2.2 
Tuberculosis Clinical Research 
TB currently must be treated with multiple drugs to achieve maximal efficacy and prevent 
resistance. To transform treatment, novel TB regimens are needed. To telescope the time, it 
takes to develop novel, tolerable multi-drug treatments, it is necessary to use the regimen 
development paradigm. This approach tests promising combinations of drugs together to find 
the most impactful treatment once the individual drug candidates have been tested in a robust 
pre-clinical program and the establishment of the individual drug candidates’ safety and 
efficacy have been evaluated.  It evaluates novel combinations of TB drugs — instead of single 
drugs — as part of a single development program, enabling the development of novel TB drug 
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regimens that have potential to transform treatment for drug-sensitive and drug-resistant 
tuberculosis. This approach offers the potential to reduce the time previously needed to 
develop a novel treatment regimen by up to 75%, shortening the clinical development from 
decades to years. The steps followed in this development model are shown in Figure 1 
Between each step on the unified development pathway a decision is made as to whether to 
proceed. 
Figure 1.  Unified Drug Sensitive/Drug Resistant Regimen Development Path 
 
Early Bactericidal Activity (EBA) Trials 
EBA trials are the backbone clinical trials to quantify the bactericidal action of anti-tuberculosis 
agents alone or in combination by either trialling the fall in the number of colony forming units 
(CFU) or measuring the TTP in liquid culture of M. tuberculosis (MTB) present in the sputum 
of participants with microscopy smear-positive pulmonary TB. EBA trials have been conducted 
over 2, 5, 7 and 14 days.[2]. A review of EBA trials conducted on the key anti-TB drugs has 
shown the value these trials offer to demonstrate the early anti-TB effect that a new therapeutic 
agent may have and to explore the relationships between dose, pharmacokinetics and 
bactericidal activity in participants.[3] 
8-week Bactericidal Activity (BA) Trials 
EBA methodology of quantitative colony counting on solid medium has been adapted to Phase 
2, 8-week TB treatment trials based on serial sputum colony counting (SSCC) or measurement 
of TTP liquid culture to provide a more sensitive efficacy endpoint than the previously used 
binary endpoint of rate of sputum conversion measured after 8 weeks of treatment.[4-6] Such 
trials are conducted to provide data on which to base the selection of treatment-shortening 
regimens.  
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2.3 
Trial Rationale 
The  SimpliciTB NC-008 (BPaMZ) trial will evaluate and support that, in additional to previous 
studies evaluated with BPaMZ, this drug regimen (BPaMZ) will be safe and effective, is well-
tolerated and could potentially shorten the current treatment duration compared to the 
standard HRZE/HR treatment for patients with drug sensitive TB disease. This trial will also 
evaluate if the BPaMZ drug regimen given for 6 months will be safe and effective in drug 
resistant TB disease. 
Therefore, the trial design addresses the need to find and evaluate a potentially effective and 
shorter regimen compared to regimens (standard HRZE/HR) that are currently being used. 
2.3.1 
Trial Design Rationale 
The SimpliciTB NC-008 (BPaMZ) trial is a Phase 2c multi-centre, open-label, partially 
randomized clinical trial in DS-TB and DR-TB participants. This trial is to evaluate the 
combination regimen of Bedaquiline (B) plus Pretomanid (Pa) plus Moxifloxacin (M) plus 
Pyrazinamide (Z), (BPaMZ), in participants with pulmonary TB. 
All participants will enter post-treatment follow-up which continues until Week 104 after start 
of treatment / randomisation. 
 
Participants with DS-TB: 
Participants with DS-TB will be randomized to one of two treatment arms. These 
participants will receive either: 
• 
BPaMZ daily for 17 weeks (4 months),  
 
OR 
• 
 HRZE/HR combination tablets daily for 26 weeks (6 months).  
 
Participants will be stratified for co-infection with HIV and cavitation. 
Participants with DR-TB are defined as: 
1. mono-resistance to rifampicin or isoniazid, OR 
2. resistance to both rifampicin and isoniazid (multi-drug resistant tuberculosis [MDR-
TB]) 
Up to 150 participants with DR-TB will be assigned to receive BPaMZ daily for 26 weeks (6 
months).  Approximately 300 DS-TB participants (150 per treatment arm) will be randomized 
and stratified for co-infection with HIV and cavitation to either BPaMZ for 4 months or 
HRZE/HR for 6 months.  
 
The trial is sufficiently statistically powered to not only show superiority of 8 Weeks culture 
conversion but should also demonstrate non-inferiority for cure at 52 Weeks (this is in the 
participants with DS-TB in the experimental BPaMZ treatment regimen, the proportion 
experiencing an unfavourable outcome will be non-inferior compared to the participants who 
are treated with the standard HRZE regimen). 
 
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There is one planned interim efficacy analysis which will occur after approximately 60 
assessable participants have been randomised to the control arm and have reached the 8-
week primary endpoint. Time to culture negative status in liquid media up to 8 weeks will be 
analysed using a Cox regression model, censoring for death and lost to follow up/withdrawal 
to estimate the hazard ratio (HR). Following a review of these interim findings, the following 
considerations will be given to modify the trial objectives and sample size: 
If the observed HR (time to culture negativity, experimental arm vs. HRZE control arm) is >2, 
the sample size may be increased to adequately power the trial on the key secondary efficacy 
endpoint (clinical and microbiological outcome at 52 weeks from randomization), which will 
then become the primary efficacy endpoint. The trial efficacy objectives will be updated as 
follows: 
- 
Primary Objective 
To determine the incidence of bacteriologic failure or relapse or clinical failure at 
52 weeks from the start of treatment / randomisation.  
- 
Secondary Objectives 
To evaluate the time to culture negativity over 8 weeks, from the start of treatment 
/ randomisation. 
All other trial objectives will remain unchanged. 
To achieve 90% power and overall 5% 2-sided significance after adjusting for the 
interim analysis, this will mean increasing the sample size to 225 participants per randomised 
arm, i.e., to a total of 450 DS-TB participants (and up to 225 DR-TB participants). This 
adaptation is based on the Multi-arm Multi-stage (MAMS) framework [46, 47, 48] and full details 
are provided in the Statistical Analysis Plan.  
 
As previously described in the background information, in order to telescope the time it takes 
to develop novel, tolerable multi-drug treatments, it is necessary to use the regimen 
development paradigm and utilize data generated in non-clinical and clinical studies regarding 
combining of anti-tuberculosis agents which could contribute significantly to the sterilization of 
lesions and thus treatment shortening. Therefore, the trial design and proposed trial regimen 
(BPaMZ) which is supported with previous non-clinical and clinical studies outlined below 
should address the need and manner of evaluating an effective shorter regimen compared to 
regimes that are currently being used. 
2.3.2 
Trial Drug Regimen Rationale 
The BPaMZ regimen has been studied singularly and in different combinations as outlined 
above. Moxifloxacin has been added to the B-Pa-Z regimen because of the high rate of 
pyrazinamide resistance seen in MDR-TB participants in the NC-002 trial. It essentially 
provides protection against the development of new resistance to the B-Pa-Z drugs. Based on 
the exciting and promising results seen in NC-005, this regimen can be initiated in drug 
sensitive and drug resistant TB participants whom are sensitive to the individual drugs in the 
regimen (excluding extensively drug-resistant tuberculosis [XDR-TB]) and has the potential to 
shorten TB treatment to less than 4 months in drug sensitive TB. These are also oral regimens, 
removing the need for injectables as part of MDR-TB treatment and also project to be markedly 
less expensive than current MDR-TB therapy. Additionally, these regimens can be 
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administered in a fixed dose for all patients, and will therefore be simpler for health systems 
to deliver and patients to use. 
2.4 
Agents used within SimpliciTB 
Bedaquiline (TMC207; SirturoTM package insert)[7]  is a novel agent approved for TB 
treatment. As detailed in the Investigator’s Brochure,[8] bedaquiline is a diarylquinoline that 
offers a novel mechanism of anti-tuberculosis action by specifically inhibiting mycobacterial 
adenosine triphosphate synthase.[9, 10]) In vitro, bedaquiline potently inhibits both drug-
sensitive and drug-resistant M. Tb isolates,[10, 11], and is also bactericidal against non-
replicating M. Tb.[12] In the murine model of TB, bedaquiline was as active as the triple 
combination of isoniazid (H), rifampin (R), and pyrazinamide (Z). Addition of bedaquiline to 
HRZ results in accelerated clearance of M. Tb.[3, 4] There appears to be a synergistic 
interaction with pyrazinamide: 100% of mice were culture negative after 8 weeks of treatment 
with bedaquiline and pyrazinamide compared to 0% of mice treated with the standard regimen 
of rifampicin, isoniazid and pyrazinamide.[13] Collectively, these findings in the mouse model 
have led to the suggestion that regimens containing bedaquiline and pyrazinamide could be 
effective in the treatment of both DS- and MDR-TB and shorten treatment duration in patients. 
While the combination of bedaquiline and pretomanid in the murine model of TB appeared 
somewhat antagonistic relative to bedaquiline alone, it was as active as the triple combination 
of HRZ[13] and in a subsequent trial it was more active in the mouse model than HRZ.[14] Thus, 
a novel regimen with a bedaquiline plus pretomanid core could be effective in the treatment of 
MDR-TB by providing two novel drugs for which there is no known pre-existing resistance.  
Pretomanid, (Pa)[15]  is a new chemical entity being developed by TB Alliance for the treatment 
of TB.  It is a member of a class of compounds known as nitroimidazo-oxazines, which possess 
significant anti-tuberculosis activity and a unique mechanism of action.[16] PRETOMANID has 
been under development for several years, and entered clinical trials in 2005. Several trials of 
pretomanid have also been conducted previously in healthy volunteers.  Collectively, these 
trials in participants with active TB and healthy participants have defined the efficacy, safety 
and pharmacokinetic features of the drug.  Overall, pretomanid has mycobactericidal activity 
in participants and is well tolerated and bioavailable after oral dosing.  Pretomanid 
demonstrated in vitro activity against both drug-sensitive (DS) and MDR-TB,[17] and in vivo 
activity in a mouse model of TB[17, 18] with a significant promise for shortening treatment of 
active TB. 
Moxifloxacin (M)[19]  is a microbial compound, approved in most countries around the world 
for the treatment of acute bacterial sinusitis, acute bacterial exacerbation of chronic bronchitis, 
community-acquired pneumonia, skin and soft tissue infections.  Clinical studies have been 
carried out for many additional indications (urinary tract infections, pelvic infections, 
pharyngitis/tonsillitis, and tuberculosis). Moxifloxacin is an 8-methoxyquinolone whose oral 
formulation (which will be used in this trial) has enhanced activity against Gram-positive 
pathogens, and anaerobes while retaining useful activity against Gram-negative organisms. 
Moxifloxacin is not metabolized by or induces the cytochrome P450 system, thus the risk of 
clinically relevant drug interactions is reduced. It has a positive safety profile within the 
fluoroquinolone class at the approved daily dose of 400 mg. Moxifloxacin while not approved 
for TB by most regulatory authorities, it is regularly used in second line MDR-TB treatment. 
The WHO TB Treatment Guidelines place moxifloxacin in the category of Group 3 drugs and 
notes that “all patients [with MDR-TB] should receive a Group 3 medication if the MTB strain 
is susceptible or if the agent is thought to have efficacy. One of the higher generation 
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fluoroquinolones, such as levofloxacin or moxifloxacin, is the fluoroquinolone of choice.[5]” It is 
currently in late stage clinical development for first-line TB treatment in combination with other 
TB drugs, including pyrazinamide in two different four-month long regimens.  
Pyrazinamide (Z)[20] is a pyrazine analogue of nicotinamide and an approved anti-tuberculosis 
agent which is indicated for the initial treatment of active tuberculosis in adults and children 
when combined with other anti-tuberculosis agents and contributes significantly to the 
sterilization of lesions and thus treatment shortening.[21]   
Control Group: HRZE/HR 
The HRZE/HR combination [HRZE tablets [isoniazid (H), rifampicin (R), pyrazinamide (Z) and 
ethambutol (E)] and HR tablets [isoniazid (H) plus rifampicin (R) combination tablets] is 
approved indicated and commonly used as a 6-month treatment for drug-sensitive TB patients.  
Participants with DS-TB that are randomized to the HRZE/HR control arm in this trial will be 
given standard weight-adjusted doses of HRZE.  Please see the HRZE package insert for 
more information.[22]   
Additional background data supporting the combined use of new novel agents in this 
BPaMZ regimen for the treatment of TB: 
Data from preclinical studies suggest that a regimen consisting of moxifloxacin plus 
pretomanid plus pyrazinamide may not only be appropriate for treating both DS and MDR-TB 
but may also shorten duration of therapy.  Results from an 8-week Phase 2b SSCC trial, 
NC-002-(M-Pa-Z), showed that this combination regimen was effective as measured by time 
dependent decline of viable bacteria in participants with DS pulmonary TB.  The combination 
was also shown to be safe and well tolerated supporting the evaluation of this combination in 
a Phase 3 trial. In this NC-002 trial 71.4% of participants with DS-TB treated with PaMZ at the 
100-mg daily dose of pretomanid converted sputum to negative for MTB growth in liquid 
culture in comparison with only 37.8 % of participants treated with the HRZE control (p<0.05).  
Studies in mice infected with MTB demonstrated reductions in cultured colony counts from 
lungs over an 8-week period when treated with the PaMZ regimen that were substantially, and 
statistically significantly greater, than the reductions in mice treated with an HRZ control.  
Experiments in mice found that mice did not relapse with MTB infection when treated with 
PaMZ for 4 months and followed for 3 months off treatment, in comparison to mice that 
required 6 months of treatment with HRZ to prevent relapse.[14]   
Drug Resistant TB Background: 
Although some progress has been made in recent years in controlling tuberculosis (TB) 
globally, TB has remained a persistent problem in many countries. TB is the world’s leading 
cause for mortality from infectious disease and is responsible for more deaths than HIV.[23] It 
is the leading cause of death among HIV-infected individuals, and there is more TB in the 
world today than at any other time in history. Because of poor treatment adherence, in addition 
to primary transmission, drug resistance is becoming more common and fears of an epidemic 
with strains of extensively drug-resistant TB (XDR-TB) that is very difficult to treat are growing.  
Novel drugs and regimens for TB are needed for the growing number of patients with drug 
resistant-TB.  
The regulatory approvals of bedaquiline and delamanid have given hope that outcomes for 
patients with drug resistant TB might be improved when added to background regimens. 
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Experience recently published from the C209 uncontrolled trial of bedaquiline given on a 
background of multiple drugs notes that the subset of 38 participants with XDR-TB had rates 
of sputum culture conversion to negative of 62.2%.[24] However, in this trial only one participant 
with XDR-TB was co-infected with HIV. All participants were required to have Mycobacterium 
tuberculosis (MTB) isolates susceptible to at least 3 drugs at enrolment and participants had 
a median of only 5.4 months of treatment-free follow-up. This trial added bedaquiline for 6 
months to a background regimen of many drugs given for 18 months or longer. While 
treatment success for MDR-TB is better than for XDR-TB, overall success in treating MDR-
TB is still approximately 50% according to the World Health Organization 2015 Global TB 
Report.[23]  This report presented that overall, the proportion of MDR-TB patients in the 2012 
cohort who successfully completed treatment (i.e. cured or treatment completed) was 50%; 
16% died, 16% were lost to follow-up, 10% failed treatment, and for 8% there was no outcome 
information.   
With such poor historical outcomes for patients with drug resistant-TB and with the complexity, 
expense and toxicity of treatments for all forms of drug resistant TB, novel drug 
combinations are desperately needed to improve treatment outcomes. Linezolid was 
identified in a small trial as a potentially efficacious drug in patients with XDR-TB when added 
to a failing regimen[25] and this drug has increasingly been added to complex regimens to treat 
patients with MDR-TB. 
With the current availability of the following three drugs for which there is little, if any, pre-
existing resistance among strains of MTB (pretomanid [Pa], bedaquiline [B], and linezolid [L]). 
Mice infected with MTB had relapse-free cures with 3 months of treatment with a B-Pa-L 
regimen. While it is not known whether that treatment duration will translate to humans, the 
ongoing Nix-TB clinical trial hypothesizes patients with pulmonary XDR-TB or MDR-TB not 
responsive to or intolerant to therapy may have relapse-free cure after as little as 6 months’ 
treatment with the B-Pa-L regimen.[26]  Moxifloxacin has been added to the B-Pa-Z regimen 
because of the high rate of pyrazinamide resistance seen in MDR-TB participants in the NC-
002 trial. The proposed trial [SimpliciTB] allows the opportunity to assess the efficacy, safety 
and tolerability of BPaMZ, a new 6 months regimen that may be administered orally once daily 
to treat patients with drug resistant -TB (excluding participants with XDR-TB). 
Therefore, the overall purpose of the present proposed trial [SimpliciTB] is to assess the 
efficacy, safety and tolerability of the BPaMZ regime after 4 months of treatment in adult 
participants with drug sensitive TB and after 6 months of treatment in participants with multi 
drug-resistant TB. The trial will also generate data of the potential for a shorted treatment 
duration with the BPaMZ regime after 4 months compared to a 6-month HRZE/HR (control) 
treatment regime in adult participants with drug sensitive TB. 
This trial will be conducted in accordance with the Protocol, ICH Guidelines for Good Clinical 
Practice (GCP), the ethical principles that have their origin in the Declaration of Helsinki and 
the applicable regulatory requirement(s). 
2.5 
Background of Agents to be Studied in SimpliciTB 
2.5.1 
Bedaquiline (B) 
Bedaquiline (formerly known as TMC-207; SirturoTM package insert[7]) is approved agent for 
TB treatment. As detailed in the Investigator’s Brochure,[8] bedaquiline is a diarylquinoline that 
offers a novel mechanism of anti-tuberculosis action by specifically inhibiting mycobacterial 
adenosine triphosphate  synthase.[11] In vitro, bedaquiline potently inhibits both drug-sensitive 
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and drug-resistant MTB isolates,[11, 12] and is also bactericidal against non-replicating MTB[12] 
In the murine model of TB, bedaquiline was as active as the triple combination of isoniazid 
(H), rifampicin (R), and pyrazinamide (Z). Addition of bedaquiline to HRZ results in accelerated 
clearance of MTB.[1, 2]. There appears to be a synergistic interaction with pyrazinamide: 100% 
of mice were culture negative after 8 weeks of treatment with bedaquiline and pyrazinamide 
compared to 0% of mice treated with the standard regimen of rifampicin, isoniazid and 
pyrazinamide.[27].Collectively, these findings in the mouse model have led to the suggestion 
that regimens containing bedaquiline and pyrazinamide could be effective in the treatment of 
both drug sensitive and drug resistant TB and shorten treatment duration in patients. While 
the combination of bedaquiline and pretomanid in the murine model of TB appeared somewhat 
antagonistic relative to bedaquiline alone, it was as active as the triple combination of HRZ[27] 
and in a subsequent trial it was more active in the mouse model than HRZ.[28]. Thus, a novel 
regimen with a bedaquiline plus pretomanid core could be effective in the treatment of MDR-
TB/XDR-TB by providing two novel drugs for which there is no known pre-existing resistance. 
Bedaquiline is currently registered in many countries to be administered to patients with 
pulmonary tuberculosis by the following scheme: 400mg once daily for Days 1-14 followed by 
200mg three times per week for the remainder of treatment. In this trial bedaquiline will be 
administered as 200 mg daily for 8 weeks then 100 mg daily for 9 weeks in participants with 
DS-TB and 200 mg daily for 8 weeks then 100 mg daily for 18 weeks in participants with DR-
TB.  This daily dosing scheme will allow more convenient dosing that should ultimately 
enhance patient adherence and may allow the formulation of fixed dose combinations with 
other drugs.  This daily dosing regimen is supported by safety and efficacy demonstrated in 
the NC-005 trial that administered bedaquiline 200 mg daily over 8 weeks, and by 
pharmacokinetic modelling and simulation of the daily dosing scheme.  This supportive 
information is detailed below. 
2.5.1.1 
Bedaquiline Non-Clinical Studies 
Full details of the preclinical studies are provided in the current bedaquiline Investigator’s 
Brochure,[8] and Sirturo 
TM label.[7] In vitro studies have demonstrated that the range of 
minimum inhibitory concentrations (MICs) for MTB H37Rv, the international reference strain, 
and 6 fully drug-susceptible clinical isolates, was 0.030 to 0.120 μg/ml. The activity of 
bedaquiline appears to be specific for mycobacteria, as the MICs for non- mycobacteria were 
at least 500-fold higher. The activity of the main metabolite of bedaquiline, M2, was determined 
against MTB.  H37Rv in both solid and liquid media and its MIC was found to be 0.1 μg/ml. 
This MIC shows that M2 is active against MTB but 3-6 times less active than the parent 
compound bedaquiline. Bedaquiline demonstrated similar in vitro efficacy against MTB clinical 
isolates resistant to the known anti-TB drugs (isoniazid, rifampicin, pyrazinamide, 
streptomycin, ethambutol, or fluoroquinolones). As expected, from the lack of cross-resistance 
with currently used anti-tuberculosis agents, bedaquiline retained activity against MDR-TB 
isolates. 
The non-clinical safety evaluation of bedaquiline includes pharmacology, pharmacokinetics, 
toxicology and metabolism studies that were conducted in accordance with current 
International Council for Harmonisation (ICH) guidelines. Repeated dose toxicity studies were 
performed with dosing durations up to 3 months in mice and up to 6 months in rats and in 
dogs. Recovery was studied in rats and dogs. In repeated dose toxicity studies, up to 3 months 
in mice, up to 6 months in the rat and up to 9 months in dogs, bedaquiline was associated with 
target organ changes in the mononuclear phagocytic system (indicative of phospholipidosis), 
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stomach, liver, pancreas, and muscle. Toxicity was often associated with an increased 
presence of neutrophils in some tissues such as the female genital tract and this was preceded 
by a peripheral neutrophilia. For more detailed information please refer to the bedaquiline IB.[8] 
Respiratory parameters in rats were unaffected by treatment. There were no effects 
suggestive of neurological impairment or delayed neurotoxicity in rats. In single dose toxicity 
studies, there were no mortalities following oral doses of up to 200 mg/kg in mice and rats. No 
mutagenicity or clastogenic effects were seen in a series of in vitro and in vivo genotoxicity 
tests. Bedaquiline was evaluated for possible developmental toxicity effects in the rat and the 
rabbit. No teratogenic effects were found. In vitro, bedaquiline slightly to moderately inhibited 
the delayed rectifier potassium current (IKr) in the human ether-à-go-go-related gene (hERG) 
model. Bedaquiline and M2 had no notable effects on IKr at 0.01 μM (0.006 and 0.005 μg/mL, 
respectively). However, at higher concentrations (0.03 to 3 μM), both compounds had a slight 
to strong concentration-dependent effect with a 50% inhibitory concentration (IC50) of 0.37 μM 
(0.2 μg/mL) for bedaquiline and up to 0.45 μM (0.24 μg/mL) for M2. However, this effect did 
not manifest as a prolongation of repolarization in subsequent in vivo studies. 
There were no relevant effects on the isolated right atrium of guinea pigs in vitro, or in the 
isolated Langendorff-perfused rabbit heart. In vivo, positive chronotropic effects were seen in 
the anesthetized guinea pig after IV administration, but not in the conscious dog. In conscious, 
telemetered dogs, oral bedaquiline had no relevant effects on cardio-hemodynamic and ECG 
parameters. 
Prior to the use of pretomanid in combination with bedaquiline in clinical trial NC-001, a 
preclinical cardiovascular safety pharmacology trial was conducted in unrestrained beagle 
dogs with both drugs to explore the potential for additive effects on QT prolongation induced 
by the combination. Results indicate that administration of 100 mg/kg bedaquiline daily, for 7 
days, causes a small increase in QTc interval by Day 6 in some animals that is not influenced 
by the addition of 100 mg/kg pretomanid on Day 7.[28] 
 The effect of pretomanid dosing alone 
on QT interval appeared to be due to discomfort related to the SC route of administration and 
not related to the plasma exposure (please see the pretomanid) Investigators Brochure for 
more detail. 
2.5.1.2 
Bedaquiline Clinical Studies 
In the clinical studies conducted to date, a total of approximately 645 participants (including 
265 healthy volunteers) have been exposed to bedaquiline in the Phase 1 and 2 clinical trials 
conducted as a part of the development program for the treatment of MDR-TB. An additional 
45 participants received bedaquiline, either as monotherapy (B) or in combination with other 
agents (B-Pa or B-Z) in trial NC-001, and 45 more in trial NC-003 (B-Pa-Z, B-Pa-C, B-Pa-Z-
C). Four short-term Phase 2a trials enrolled treatment-naïve participants (C202, TMC207-
CL001, NC-001 and NC-003). One long-term, open-label, Phase 2 trial, in MDR-TB 
participants (bedaquiline- TiDP13-C209) and one long-term, Phase 2b trial, consisting of 2 
different stages in participants infected with newly diagnosed sputum smear-positive 
pulmonary MDR-TB (bedaquiline-TiDP13-C208), have been completed. The principal findings 
of these trials are summarized below. Full details of the completed clinical studies are provided 
in the current bedaquiline IB,[8] and Sirturo
TM label.[7]. 
The Phase 1 trials have provided a basic understanding of bedaquiline’s pharmacokinetic 
characteristics, drug- drug interaction potential, and short-term safety/tolerability profile in 
healthy participants. Bedaquiline was well absorbed with time to reach the maximum plasma 
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concentration at approximately 5 hours post-dose. The maximum plasma concentration and 
AUC increased proportionally up to the highest doses studied (up to 700 mg in a single dose-
ranging trial, 800 mg single dose in trial bedaquiline-TBC1003 and 400 mg q.d. multiple 
doses). Accumulation from Days 1 to 14 was approximately 2-fold expressed as increase in 
AUC, while trough concentrations increased up to 3.5-fold. The pharmacokinetics of 
bedaquiline were comparable between healthy participants and participants with pulmonary 
TB. The apparently close to steady-state concentrations in plasma after 14 days of daily 
treatment is ascribed to the important amount of the drug that is eliminated from the circulation 
during the ἀ and β phases of the plasma concentration-time curve. The average terminal 
elimination half-life of bedaquiline and metabolite M2 noted on extended follow-up after repeat 
dosing of participants with TB infection is about 5.5 months. 
Administration of bedaquiline as the tablet formulation with food, increased the relative 
bioavailability (by 95%) compared to administration without food, and drug-drug interaction 
trials confirmed the role of cytochrome P450 3A4 (CYP3A4) in the metabolism of bedaquiline 
to M2. A recently completed trial (DMID 10-0043) demonstrated that when given in 
combination, rifampicin, and to a lesser degree rifabutin, decreased exposure to bedaquiline 
presumptively due to induction of P450 enzymes. The clinical significance of these findings is 
unknown, however the current trial (NC-005) will not permit the concomitant use of bedaquiline 
with any rifamycin. 
The efficacy of bedaquiline was initially demonstrated in two monotherapy EBA studies C202 
and TMC207- CL001. Trial C202 was a 7-day trial of three daily doses of bedaquiline (25, 100 
and 400mg) in treatment-naïve participants with MDR-TB. In this trial, the 400mg dose group 
demonstrated positive EBA and was numerically superior to the 25 and 100mg doses. In trial 
TMC207-CL001, doses of 100, 200, 300 and 400mg daily (following a 2-day loading dose) 
were studied in participants with newly-diagnosed pulmonary TB for 14 days. There were no 
statistically significant differences between the treatment groups, although there was a 
numerical trend suggesting a positive dose-response relationship. Taken together, these 
studies establish that bedaquiline monotherapy has EBA in participants with TB and that 
higher doses appear to have greater efficacy. 
A 14-day EBA regimen trial (TB Alliance Trial NC-001-(B-M-Pa-Z)) evaluated bedaquiline 
administered as monotherapy at 400 mg/d or in combination at that dose with either 
pretomanid administered at 200 mg/d or weight-adjusted pyrazinamide, to participants with 
pulmonary TB at 2 clinical sites in South Africa. The results indicate that over 14 days, the 
mean logCFU decreased by 1.3 from baseline in the 15 participants given bedaquiline 400 
mg/d after a 2-day loading dose. In the cohort of 15 participants given bedaquiline 400 mg/d 
after a loading dose plus weight-adjusted daily doses of pyrazinamide (Z), the mean logCFU 
decreased by 2.0 logs from baseline, indicating that Z potentiates the early bactericidal effect 
of bedaquiline. In the cohort with 15 participants given bedaquiline 400 mg/d after a loading 
dose plus 200 mg/d pretomanid, the mean logCFU decreased by 1.9. While it appeared that 
the addition of pretomanid potentiated the anti-tuberculosis activity of bedaquiline, the mean 
logCFU decrease of the combination was similar to that of two previous EBA studies using 
pretomanid monotherapy at 200 mg/day. 
The second 14-day EBA combination trial (NC-003) included a number of bedaquiline-
containing arms: bedaquiline, pyrazinamide and clofazimine (B-Z-C), bedaquiline, pretomanid 
and clofazimine (B-Pa-C), bedaquiline, pretomanid, and pyrazinamide (B-Pa-Z) and 
bedaquiline, pretomanid, pyrazinamide and clofazimine (B-Pa-Z-C). Among these, B-Pa-Z had 
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the best activity which was at least as good as the HRZE control (Daily Log CFU – 0.167 vs 
0.151, respectively). 
The long-term efficacy of bedaquiline in participants with MDR-TB has been studied in a 
placebo-controlled, randomized Phase 2b trial (C208) and an open-label, uncontrolled, Phase 
2b trial (C209). In the Phase 2b placebo-controlled trial, C208, the addition of bedaquiline to a 
5-drug MDR-TB regimen resulted in significantly faster time to culture conversion compared to 
placebo. During the 8-week treatment in Stage 1, 47.6% of participants in the bedaquiline group 
became MGIT culture negative compared to 8.7% of participants in the placebo group. At Week 
24 in Stage 1, after 8 weeks of investigational treatment and 24 weeks of background 
treatment, 81.0% of participants in the bedaquiline group and 65.2% of participants in the 
placebo group showed treatment success, (i.e., completed week 24 and were liquid culture 
negative, at this time point). 
For C208 Stage 2, in the interim analysis as well as in the primary efficacy analysis, a 
statistically significant difference in time to culture conversion between the treatment groups (p 
< 0.0001) in favour of bedaquiline was shown. In both analyses, an identical number of 
participants with culture conversion at week 24 (i.e., 24-week responders [missing = failure]) 
was observed: 78.8% in the bedaquiline group and 57.6% in the placebo group, which was 
statistically significantly different (p =   0.008) based on a logistic regression model with only 
treatment as covariate. Microbiological response at Week 24 was durable in C208 Stage 2: the 
percentage of responders (missing = failure) at week 72 was 71.2% in the bedaquiline group 
and 56.1% in the placebo group. 
In the Phase 2b uncontrolled trial, C209, treatment with bedaquiline in combination with an 
individualized MDR- TB treatment regimen was effective against pulmonary MDR-TB both in 
newly diagnosed and in non-newly diagnosed participants. Culture conversion rates after 
2 weeks of treatment with bedaquiline as part of an individualized anti-tuberculosis regimen 
were higher in participants with lower extent of resistance of the M. Tb strain and in participants 
with no lung cavitation compared to participants with cavitations (in one or both lungs). 
2.5.1.3 
Bedaquiline Clinical Safety 
In the clinical trials conducted to date, a total of approximately 645 participants (including 
265 healthy volunteers) have been exposed to bedaquiline in the Phase 1 and 2 clinical trials 
conducted as a part of the development program for the treatment of MDR-TB. An additional 
60 participants received bedaquiline in a monotherapy EBA trial of 14 days (trial TMC207-
CL001) 45 participants received bedaquiline, either as monotherapy (B) or in combination with 
other agents (B-Pa or B-Z) in trial NC-001 and 45 more in trial NC- 003 (B-Pa-Z, B-Pa-C, B-
Pa-Z-C). In these trials, bedaquiline has been shown to be an effective treatment for 
participants with both DS and MDR-TB. Specifically, the regimen B-Pa-Z was demonstrated 
to have efficacy at least as good as the HRZE control in trial NC-003. Furthermore, bedaquiline 
is a novel agent with no pre-existing resistance and, based on mouse model data, may result 
in shortened treatment durations when included in novel regimens to treat both DS- and MDR-
TB. Based on the combined experience in these clinical trials, the following known and 
potential risks have been identified. 
Adverse Drug Reactions for bedaquiline 
During the Investigational Treatment phase in the controlled trials, the most frequently reported 
Adverse Drug Reactions in the any bedaquiline group (> 10.0% of participants) were nausea, 
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arthralgia, headache, vomiting, and dizziness. Details of Adverse Events, none of which were 
Serious, that were considered Adverse Drug Reactions are in the table below: 
Table 1.  Bedaquiline Adverse Drug Reactions 
 
 
Mortality 
Overall, there was an imbalance in the number of deaths in the pooled Stage 1 and Stage 2 
C208 trial. In the pooled analysis (Stage 1 and Stage 2), 12 participants in the Any bedaquiline 
group and 5 participants in the Any Placebo group experienced a SAE leading to death; 
causes of death were varied with only death due to TB reported more than once, and none of 
these participants had a treatment-emergent QTcF ≥ 500 ms. The imbalance in deaths is 
primarily driven by the C208 Stage 2 results in which the imbalance was 10 bedaquiline 
participants (12.7%) compared to 3 placebo participants (3.7%). Based on the pooled results 
(Stage 1 and 2) while being followed in the placebo- controlled trial, 7 participants in the Any 
bedaquiline group and 1 Participant in the Any Placebo group died. Of these deaths, 1 
occurred during the Investigational Treatment phase with bedaquiline/placebo, the remaining 
deaths occurred afterwards. In the Any bedaquiline group, causes of death were myocardial 
infarction, TB (2 cases), alcohol poisoning, hepatitis and hepatic cirrhosis (1 case), septic 
shock and peritonitis (1 case), and cerebrovascular accident. In the Any Placebo group, cause 
of death was haemoptysis. The Investigator considered the SAEs leading to death not related 
to bedaquiline intake in the Any bedaquiline group and doubtfully related to investigational 
medication in the Any Placebo group. The analysis of long-term follow-up for survival 
outcomes in participants who prematurely discontinued in trial C208 (Stage 1 and 2), based 
on data collection every 24 weeks (6 months) after withdrawal (up to LSLV in the rollover arm 
[16 Oct 2012] in Stage 2), included 9 deaths. One Participant in the bedaquiline group 
(pulmonary TB) and 2 participants in the Placebo group (TB-related illness and pulmonary TB) 
in Stage 1 died, and 4 participants in the bedaquiline group (3 participants with TB-related 
illness, 1 Participant motor vehicle accident) and 2 participants in the Placebo group (both TB-
related illness) died after they discontinued Stage 2 of the trial. None of these participants had 
a treatment-emergent QTcF ≥ 500 ms. The imbalance in deaths is unexplained.  In addition, 
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no discernible pattern between death and sputum culture conversion, relapse, sensitivity to 
other drugs used to treat TB, human immunodeficiency virus (HIV) status, or severity of disease 
was observed. 
In the uncontrolled Phase 2b trial, C209, the most frequently reported AEs during the 
investigational phase were hyperuricemia, arthralgia, nausea, vomiting, headache, diarrhoea, 
blood uric acid increased, hypokalaemia, pruritus, injection site pain, insomnia, and tinnitus. 
From start of the trial up to the final analysis, 12 participants died during the C209 trial due to 
SAEs that included TB (5 cases), congestive cardiac failure, renal impairment, lung infection, 
cardiac 
arrest 
(underlying 
cause 
pneumonia), 
haemoptysis, 
hypertension, 
and 
pyopneumothorax/respiratory failure. These SAEs leading to death were considered not 
related to bedaquiline by the Investigator, except for renal impairment that was judged 
doubtfully related to bedaquiline. 
The analysis of long-term follow-up for survival outcomes for participants who prematurely 
discontinued in trial C209, based on data collection every 24 weeks (6 months) after 
withdrawal, included 4 deaths (all described as TB-related). In total, since the start of the C209 
trial, 16 participants (6.9%) have died (12 participants during the trial and 4 participants during 
the survival follow-up phase after premature discontinuation). None of the fatal SAEs were 
considered related to bedaquiline by the Investigator and none of these participants has a 
treatment- emergent adverse event. 
Cardiovascular safety 
During clinical trials with bedaquiline a prolongation of QTc interval was observed. The US 
Product Label for bedaquiline[7] notes that treatment initiation is not recommended in patients 
with: 
• 
Heart failure; 
• 
QTcF interval > 500 ms (confirmed by repeat electrocardiogram); 
• 
A personal or family history of congenital QT prolongation; 
• 
Concomitant administration of fluoroquinolone antibiotics that have a greater 
potential for significant QT prolongation (i.e., gatifloxacin, moxifloxacin and 
sparfloxacin). 
• 
Hypokalaemia 
The US Product Label recommends that bedaquiline treatment must be discontinued if the 
patient develops clinically significant ventricular arrhythmia. An additive or synergistic effect 
on QT prolongation of bedaquiline when co-administered with other medicinal products that 
prolong the QT interval cannot be excluded. Caution is recommended when using bedaquiline 
concomitantly with medicinal products with a known risk of QT prolongation. If co-
administration of such medicinal products with bedaquiline is necessary, clinical monitoring 
including frequent ECG assessment is recommended. 
Hepatic safety 
The US product label notes increases in transaminases were seen in clinical trials during 
administration of bedaquiline with the background regimen. participants should be monitored 
during treatment. Other hepatotoxic medicinal products and alcohol should be avoided while 
taking bedaquiline, especially in those participants with diminished hepatic reserve.[7]  
Additional safety information from a recently completed trial 
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In a recently completed phase I trial not yet included in the bedaquiline Investigators Brochure 
that evaluated drug-drug interactions between bedaquiline and either rifampin or rifabutin, 7 
participants experienced SAEs. Of those participants, 5 experienced SAEs of 
lymphocytopenia (all received rifabutin), which did not appear to be related to the AUC or 
Cmax of TMC207 or rifabutin. One participant experienced an SAE of elevated Creatine 
Kinase (rifampicin arm) and one experienced a grade 4 Total Bilirubin SAE (rifampicin arm). 
Lymphopenia was previously noted to be an infrequent toxicity associated with rifabutin, but 
not previously seen with bedaquiline. 
The bedaquiline/rifabutin regimen demonstrated significant reversible lymphopenia, which did 
not appear to be related to the AUC or Cmax of TMC-207 or rifabutin. 
2.5.2 
Pretomanid (P) 
As detailed in the Investigator’s Brochure,[15] pretomanid is a new chemical entity and a 
member of a class of compounds known as nitroimidazo-oxazines, which possess significant 
anti-tuberculosis activity and a unique mechanism of action.[16] Pretomanid demonstrated in 
vitro activity against both DS- and MDR-TB,[17] and in vivo activity in a mouse model of 
tuberculosis.[16, 17]  
2.5.2.1 
Pharmacology 
Key in Vitro Evaluation of Pretomanid Bactericidal Activity 
Non-clinical in vitro trials demonstrated that pretomanid was active against actively growing 
drug- sensitive and drug-resistant MTB strains as well as against non-replicating MTB. The 
minimum inhibitory concentration (MIC) of pretomanid against a variety of drug-sensitive MTB 
isolates in vitro was shown to be like the MIC of isoniazid (MIC of pretomanid, ≤0.015 to 0.25 
µg/mL; MIC of isoniazid, 0.03 to 0.06 µg/mL). Pretomanid was efficacious in vitro against drug-
resistant clinical isolates of MTB with MIC values ranging from 0.03 to 0.53 µg/mL. The 
Investigator’s Brochure contains further information on in vitro bactericidal activity.[16] 
Although not thoroughly elucidated at this time, pretomanid has a novel mechanism of action 
that appears to involve inhibition of the synthesis of cell wall lipids under aerobic conditions 
and generation of reactive nitrogen species under anaerobic conditions. Reduction of 
pretomanid by a deazaflavin (F420)-dependent nitroreductase has been shown to be 
associated with generation of reactive nitrogen species, including nitric oxide (NO),[29] although 
the exact target(s) of the reactive nitrogen species are not known. Transcriptional profiling 
trials also suggest that pretomanid affects both cell wall biosynthesis and the respiratory 
complex of MTB.[30, 31] 
2.5.2.2 
Key Non-Clinical Trials of Pretomanid 
The activity of pretomanid as a single agent or as part of a multi-drug combination regimen 
has been examined in a number of mouse trials.[13, 14, 18, 32, 33] In a mouse model of established 
TB, the activity of various doses of pretomanid (given once daily, 5 days/week, for 1 month), 
initiated 22 days after inhalation infection with H37Rv MTB is shown in Figure 2. In this model, 
the minimum effective dose (MED) for pretomanid, defined as the lowest dose able to prevent 
the development of gross lung lesions and splenomegaly, was 12.5 mg/kg/day, while the 
minimum bactericidal dose (MBD), defined as the lowest dose able to reduce lung colony 
forming units (CFU) by 99%, was 100 mg/kg/day. Moreover, in these experiments, the activity 
of pretomanid at 100 mg/kg was comparable to the activity of isoniazid at 25 mg/kg. 
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Figure 2.  Log10 CFU Counts in Lungs  
After One Month of Daily Treatment with the Indicated Dose (in mg/kg) of Pretomanid 
 
Arrows denote the minimum effective dose (MED) and minimum bactericidal dose (MBD). 
2.5.2.3 
Non-Clinical Toxicology and Safety 
Pretomanid has been evaluated in an ICH recommended battery of safety pharmacology trials, 
in repeat-dose toxicity trials in rats (2 to 26 weeks) and cynomolgus monkeys (7 days to 
9 months), in 8 genotoxicity trials, and in fertility and teratology trials in rats and rabbits.  
In the repeat-dose toxicity trials, the lowest no-observed adverse effect level (NOAELs) was 
10 mg/kg/day in a 26-week trial in rats, 50 mg/kg/day in a 13-week trial in monkeys and 
<25 mg/kg/day (based on findings of thickening of the gastrointestinal tract at all doses) in a 
9-month trial in monkeys. The major findings in safety and toxicity trials are listed below in 
Table 2 and are detailed in the Investigator’s Brochure.[15] 
Table 2.  Key findings of Pretomanid in Safety and Toxicity Trials 
Nervous system-related effects.  
Rats given single oral pretomanid doses had decreased body tone, touch responses and 
decreased grooming behaviour at ≥150 mg/kg, which resolved within 24 hours. Rats given 
repeated daily doses of pretomanid had convulsions, ataxia, hypoactivity, recumbency, 
hyperactivity and sensitivity to touch, and squinting at ≥100 mg/kg/day, and early deaths 
occurred at doses ≥500 mg/kg/day. Monkeys given repeated daily doses of pretomanid had 
hypoactivity, ataxia, tremors, and convulsions at ≥450/300 mg/kg/day. These effects were 
reversible when dosing stopped and were absent at ≤30 mg/kg/day in rats and 
≤150 mg/kg/day in monkeys. 
Testicular toxicity 
Although rat and rabbit embryonic development trials indicate no effects of pretomanid on 
foetal development, testicular atrophy in rats was observed in 3-month and 6-month repeat-
dose toxicology trials and a Segment I fertility trial. In this fertility trial, testicular atrophy was 
associated with infertility; an approximate 30% reduction in fertility was also observed at a 
lower dose not associated with testicular atrophy. A detailed trial in sexually mature male 
monkeys demonstrated no effects on testicular histology or function in adult cynomolgus 
monkeys after 3 months’ dosing.  
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Cataracts 
Cataracts developed in rats with prolonged daily administration of pretomanid at doses 
≥100 mg/kg/day. In one 13-week trial in monkeys, cataracts did develop at 
450/300 mg/kg/day, but only by the end of a 13-week recovery period. In a second 13-week 
trial in monkeys that included extensive ophthalmic examinations, cataracts did not develop 
at the high-dose level of 300 mg/kg/day. 
hERG inhibition and QT prolongation 
Altered ventricular repolarisation due to inhibition of hERG-mediated potassium current and 
manifested on the ECG as a prolonged QT interval corrected for heart rate (QTc). 
Pretomanid inhibited hERG current with IC50 values of approximately 6.2 µg/mL. Following 
a single pretomanid dose of 450 mg/kg in monkeys, QTc interval prolongation ranged from 
21 to 36 msec using Fridericia’s formula (QTcF) to correct for heart rate. Co-administration 
of pretomanid with moxifloxacin in the monkey or with bedaquiline in the dog did not result 
in any greater effect on the QT interval than with either agent alone. After repeated daily 
doses, the QTc interval in the monkey was prolonged at pretomanid doses of 
≥150 mg/kg/day. 
 
2.5.2.4 
Clinical Background Information 
Pretomanid has been evaluated in 8 single- and multi-dose Phase 1 trials with healthy adult 
male and female participants, with 163 participants receiving single oral doses ranging from 
50 to 1500 mg and multiple oral doses ranging from 50 to 1000 mg/day given for up to 7 days. 
These Phase 1 trials have evaluated the safety, tolerability, and pharmacokinetics (PK) of 
pretomanid. Two additional Phase 1 trials Sponsored by the NIH included a Thorough QT trial 
and a trial of drug interactions among pretomanid, efavirenz and ritonavir/lopinavir.  Further 
details of the trials are in the Investigator’s Brochure.[15] 
2.5.2.5 
Pharmacokinetics 
Several Phase 1 trials have evaluated the safety, tolerability, and pharmacokinetics (PK) of 
pretomanid and have demonstrated that pretomanid has a half-life of approximately 18 hours, 
which supports daily dosing, and an effect of food with the 200-mg dose that increases total 
exposure by 88%. Interaction trials with midazolam, efavirenz and ritonavir/lopinavir 
demonstrate effects that are not likely to be clinically significant. 
Drug interaction with midazolam: Trial CL-006 was an open-label, fixed-sequence drug-drug 
interaction trial to evaluate the effects of multiple-dose administration of pretomanid on the PK 
of midazolam, a sensitive probe substrate and representative compound for drugs 
metabolised by CYP3A enzymes. Dosing with pretomanid at 400 mg/day for 14 days (to 
steady state) had minimal effect on the PK of midazolam and its 1-hydroxy metabolite as 
assessed by measurement of the Day 17: Day 1 ratios of maximum concentration (Cmax, AUC0-
t, and AUC0-inf. The Cmax and AUC values for midazolam after co-administration with 
pretomanid were approximately 85% of those observed after treatment with midazolam alone. 
Furthermore, midazolam and 1-hydroxy midazolam time to maximum concentration (Tmax) and 
half-life (t1/2) values were not different in the presence or absence of pretomanid. Therefore, 
14 days’ dosing with 400 mg/day pretomanid does not appear to significantly inhibit CYP3A4 
in humans. 
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Drug interaction with efavirenz, ritonavir/lopinavir, and rifampicin: The US NIH Sponsored this 
drug interaction trial with rifampicin, a known hepatic enzyme inducer, and with the 
antiretroviral drugs efavirenz and ritonavir/lopinavir (LPV/r) in healthy participants. Participants 
in Arm 1 were randomised to Sequence 1 (pretomanid 200 mg once daily for 7 days, two-
week washout period, efavirenz (EFV) 600 mg once daily for 14 days, then both drugs for 7 
days) or Sequence 2 (Treatment 1B: EFV, then EFV + pretomanid, washout, and pretomanid). 
Results indicate that comparing pretomanid given with EFV versus pretomanid alone in 16 
participants, the geometric mean ratio (GMR) for Cmax was 0.71, the GMR for AUC0-24h was 
0.65, and the GMR for Cmin was 0.54. Concentrations of EFV when given with pretomanid 
versus given alone were similar. Participants in Arm 2 were randomised to Sequence 1 
(pretomanid 200 mg once daily for 7 days, then a 2-week washout period, then LPV/r 400/100 
mg twice daily for 14 days, then LPV/r + pretomanid together for 7 days) or Sequence 2 (LPV/r, 
then LPV/r + pretomanid, washout, then pretomanid alone). Comparing pretomanid + LPV/r 
versus pretomanid- alone from 16 PK-evaluable participants, the GMR for Cmax was 0.87, for 
AUC0-24h was 0.83, and for Cmin was 0.78. In Arm 3, participants received pretomanid for 7 
days, then rifampicin 600 mg for 7 days, then pretomanid + rifampicin together for 7 days. 
Comparing pretomanid + rifampicin versus pretomanid alone from 16 PK-evaluable 
participants, the GMR for Cmax, AUC0-24h, and Cmin were 0.47, 0.34, and 0.15, respectively.  
In conclusion, compared to pretomanid alone, plasma pretomanid values (based on geometric 
mean ratios) for Cmax, AUC0-24h, and Cmin were reduced 28%, 35%, and 46% with efavirenz; 
13%, 17%, and 21% with LPV/r; and 53%, 66%, and 85% with rifampicin, respectively. 
2.5.2.6 
Pretomanid Clinical Efficacy 
The first two Phase 2 trials to evaluate the early bactericidal effect (EBA) of pretomanid oral 
monotherapy (50 to 1200 mg/day for 14 days) examined the dose-response for pretomanid in 
participants with newly diagnosed pulmonary TB infection. The first trial (CL-007) 
demonstrated good EBA, but all doses in this trial (200 to 1200 mg/day) had the same activity. 
The second trial (CL-010) evaluated a lower dose range (50 to 200 mg/day) and the maximum 
effect on EBA was seen at a dose of 100 mg/day over 14 days (Figure 3).[34] 
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Figure 3.  Mean log Colony Forming Unit Values over Time Trial CL-010 
 
CFU = colony-forming unit; PRETOMANID = pretomanid 
* Day 0 = (Day -2 + Day -1)/2 = baseline measurement 
Pretomanid has been evaluated in patients with TB as monotherapy for a maximum duration 
of 14 days, the longest considered acceptable for a TB patient to be treated in a clinical trial 
with a single drug.  Trials of pretomanid for both 14 days and for up to 6 months, in combination 
with either bedaquiline and/or linezolid, are described below.  
2.5.2.7 
Pretomanid Clinical Safety 
The pretomanid Investigator’s Brochure[15] provides detailed safety information. 
Across the 16 clinical trials with pretomanid completed to date, a total of 649 participants have 
been exposed to pretomanid, including 289 healthy participants across the 10 Phase 1 trials 
and 360 participants with newly diagnosed smear positive pulmonary TB across 5 Phase 2 
trials.  Among the 289 healthy participants, 174 received exposure to a single dose of 
pretomanid ranging from 50 to 1500 mg and 115 received exposures to repeated daily doses 
of pretomanid (50 to 1000 mg) for up to 14 days. The 360 participants with newly diagnosed 
smear positive pulmonary TB were exposed to pretomanid either as a single agent at daily 
doses of 50 to 1200 mg for 14 days or in combination with other anti-TB agents (bedaquiline, 
moxifloxacin, pyrazinamide, linezolid and/or clofazimine) at a dose of 100 mg or 200 mg for 
up to 26 weeks.  The overall safety profile determined from the clinical trials completed to date 
indicates pretomanid is well tolerated in healthy adults and in TB patients when administered 
alone and in combination with moxifloxacin, pyrazinamide, bedaquiline and clofazimine.   
4
4.5
5
5.5
6
logCFU
0
2
4
6
8
10
12
14
Day
 PA-824 50mg
 PA-824 100mg
 PA-824 150mg
 PA-824 200mg
 Rifafour e275 
Bi-linear regression of logCFU vs day over treatment
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Pretomanid is an investigational drug and there is limited experience in humans; the safety 
database is being developed and Investigators should be vigilant to any adverse events noted 
in clinical trials.  Across these trials, the most common side effects or AEs associated with 
pretomanid exposure include: 
• 
Headache 
• 
Stomach discomfort (nausea, vomiting, flatulence, and/or diarrhoea) 
• 
Skin and subcutaneous tissue disorders 
The only adverse drug reaction identified in clinical trials completed to date as likely caused 
by pretomanid is blood creatinine increased.  A trial of the effects of repeat doses of 
pretomanid in healthy volunteers determined that the drug does not adversely affect 
glomerular filtration rate, effective renal plasma flow or filtration fraction and the elevations in 
serum creatinine reverse.  
The following parameters will be followed with particular care in the Phase 3 development 
program: 
• 
Hepatic Safety – Specific guidelines are included in the protocol to assure close 
surveillance and careful management of participants who have elevations in 
aminotransferases and/or bilirubin. Serious liver injury, including death in 3 participants 
taking a combination of pretomanid, pyrazinamide and moxifloxacin, has occurred during 
clinical trials and the risk of liver injury may be higher for participants taking a combination 
of pretomanid and pyrazinamide than it is for the standard HRZE treatment. Therefore, 
close monitoring of liver function is required for participants who are administered 
pretomanid, especially when combined with pyrazinamide.  Administration of the regimen 
of PaMZ has been associated with death in 3 participants associated with hepatic injury. 
Furthermore, the HRZE control regimen, and both pyrazinamide and moxifloxacin, has 
been associated with drug induced liver injury and in rare cases hepatic necrosis.  
Consequently, hepatic safety will be under close surveillance in all clinical trials. 
• 
Ophthalmologic Evaluations – while the detailed examinations in Phase 2 have not raised 
concern for humans, ophthalmologic examinations, with slit lamp exam and grading of lens 
opacities, will continue in all human trials that involve exposure to pretomanid longer than 
14 days.  These examinations will be conducted at baseline, near the end of the dosing 
period and 3 months after the end of trial drug exposure.  These examinations are to follow 
up on the finding of cataracts in rats exposed to pretomanid in clinical trials. 
• 
Cardiovascular Safety – All participants will have ECGs taken at baseline and at multiple 
time points during the trial.  Although the Thorough QT Trial in healthy participants found 
that pretomanid did not increase corrected QT intervals in a clinically meaningful way and 
did not add to the known effect of moxifloxacin, the ECGs will be carefully monitored during 
Phase 3.  All ECGs will be interpreted and conduction intervals will be confirmed by a 
central cardiology service. 
• 
Central Nervous System Safety –While pretomanid alone or combined in various regimens 
has been well tolerated overall, one participant in Trial NC-002 of the Pa-M-Z regimen had 
a seizure without any prior seizure history, and some animals in toxicology trials have had 
seizures at high drug exposures.  Consequently, close surveillance will be made of 
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participants in the Phase 3 trial for seizures or any central nervous system adverse events 
of potential concern. 
Of note, preclinical toxicology trials found that rats, but not primates, had testicular toxicity 
when treated with pretomanid. Clinical evaluations of potential testicular toxicity in Phase 2 
trials have evaluated over 300 participants exposed to pretomanid over 2-6 months with 
evaluations of testosterone, LH, or Inhibin B (2 trials) or FSH values (3 trials) at baseline and 
after daily dosing of regimens containing pretomanid in various combinations with 
moxifloxacin, pyrazinamide and bedaquiline.  A review of data from the 3 trials by an 
independent reproductive endocrine expert concluded that, based on the hormone evaluations 
to date, there is no evidence that pretomanid is a testicular toxicant in men at the doses and 
exposure times evaluated. 
2.5.3 
Moxifloxacin (M) 
Moxifloxacin (M)[19]  is an 8-methoxyquinolone whose oral formulation (which will be used 
in this trial) has enhanced activity against Gram-positive pathogens, and anaerobes while 
retaining useful activity against Gram-negative organisms. Moxifloxacin is not metabolized by 
nor induces the cytochrome P450 system, thus the risk of clinically relevant drug interactions 
is reduced. It has a positive safety profile within the fluoroquinolone class at the approved daily 
dose of 400 mg. Moxifloxacin while not approved for TB by most regulatory authorities, it is 
regularly used in second line MDR-TB treatment. The WHO TB Treatment Guidelines place 
moxifloxacin in the category of Group 3 drugs and notes that “all patients [with MDR-TB] 
should receive a Group 3 medication if the strain of MTB is susceptible or if the agent is thought 
to have efficacy. One of the higher generation fluoroquinolones, such as levofloxacin or 
moxifloxacin, is the fluoroquinolone of choice.[5]” It is currently in late stage clinical 
development for first-line TB treatment in combination with other TB drugs, including 
pyrazinamide in two different four-month long regimens.  
2.2.3.1. 
Moxifloxacin Clinical Trials 
Moxifloxacin is commonly used as second line therapy for TB (e.g. MDR- TB), and has also 
been evaluated in several clinical studies of participants with TB, including four 8-week 
treatment period Phase 2b studies (see Table 3 below).  
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Table 3.  Summary of Phase 2b trials in which moxifloxacin were administered 
as part of a four-drug regimen during the intensive phase of treatment (total 
treatment duration: 2 months) 
Trial 
Design 
Objective 
Participants 
(N) 
Status 
Trial 27 
Randomized, 
double-blind, 
controlled 
To compare the sputum culture-
conversion rate at the end of the 4-
drug (intensive) phase of therapy 
using the standard 4-drug regimen 
HRZE with a standard regimen with M 
replacing E.  
336 
Completed 
OFLOTUB 
Trial 
Randomized, 
Open label, 
Controlled 
To compare the bactericidal activities 
of regimens where gatifloxacin, M, 
and ofloxacin were substituted for E in 
the 2-month initial phase of standard 
TB treatment with HRZE.  
 
217 
Completed 
Johns 
Hopkins 
(FDA 
orphan 
drug) Trial 
Randomized, 
double-blind, 
Controlled 
To compare the sputum culture 
conversion rate at the end of the 4-
drug (intensive) phase of therapy 
using a standard 4-drug regimen 
(HRZE) with a regimen with M 
replacing E (HRZM). 
170 
Completed 
Trial 28 
Randomized, 
double-blind, 
Controlled 
To compare the culture-conversion 
rate at the end of the 4-drug 
(intensive) phase of therapy using a 
standard 4-drug regimen (HRZE 5 
days per week) with a regimen with M 
replacing H (MRZE 5 days per week). 
 
433 
Completed 
 
2.5.3.1 
Moxifloxacin Clinical Safety 
In Trial 27,[35] the moxifloxacin-containing TB regimens (HRZM) were shown to be safe and 
well tolerated. There was no difference in SAEs between the HRZM and HRZE treatment 
arms, and most SAEs were hospitalizations thought to be unrelated to the trial treatment.  
Participants treated with the moxifloxacin-containing regimen were more likely to report 
nausea (22% vs. 9%, p = 0.002), but this was generally mild and did not lead to treatment 
discontinuation as similar proportions of participants in both groups completed trial drug 
treatment (88% HRZM-treated vs. 89% HRZE-treated).  The one death during the first 2 
months of treatment was thought to be caused by a pulmonary embolism unrelated to 
tuberculosis therapy.   
In the OFLOTUB trial,[36] AEs and SAEs occurred with equal frequency in the four treatment 
arms.  The most frequent AEs were raised amylase (in 41% of participants due to HIV 
infection), raised transaminase (10%), arthralgia (9%), anaemia (7%), hypokalaemia (6%) and 
vomiting (5%).  No Participant was withdrawn from the trial due to an adverse event.  There 
were 4 deaths in the trial: 2 in the control group, 1 each in the moxifloxacin and ofloxacin arms.  
Importantly, participants in this trial who received moxifloxacin and pyrazinamide in addition 
to isoniazid and rifampin had more rapid sputum clearance than participants on the four 
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standard first line drugs (isoniazid, rifampin, pyrazinamide and ethambutol). This difference 
was evident 14 days after initiation of treatment. 
In the JHU trial,[37] AEs did not differ by treatment group. There were 16 SAEs (8 in each 
group) in 12 participants. Only 1 event was judged related to trial drug (grade 3 cutaneous 
reaction in the ethambutol group). Eight participants died during the trial, including 1 in each 
group still receiving trial phase treatment. No death was attributed to trial treatment. Only 5 
participants discontinued treatment because of toxic effects; 2 participants in the moxifloxacin 
group stopped because of grade 2 nausea and vomiting and 1 because of grade 2 
paraesthesia’s and ataxia. Two participants in the E group stopped because of grade 2 rash 
and pruritus and 1 because of grade 3 peripheral neuropathy.  There was no change in the 
QTc interval on serial electrocardiograms taken during the trial. 
In Trial 28,[38] the proportions of participants with SAEs during the intensive phase treatment 
were similar between arms (isoniazid 3.9% vs. moxifloxacin 4.2%; P = 0.88). Three SAEs 
attributed to trial treatment during the first 2 months occurred among the moxifloxacin group 
and two in the isoniazid group.  Seven participants died during the trial including 3 participants 
receiving the moxifloxacin treatment regimen and 4 participants receiving the isoniazid 
treatment regimen. The 3 moxifloxacin participants died during the intensive phase of TB 
treatment. Two participants died from advanced pulmonary TB judged not related to trial 
treatment and 1 Participant (who developed diabetic ketoacidosis considered possibly related 
to trial treatment) died from possible acute pulmonary embolus unrelated to trial treatment. 
The 4 isoniazid deaths occurred during the continuation phase, and all 4 were considered 
unrelated to trial treatment.  Nausea was more common among participants in the moxifloxacin 
arm than in the isoniazid arm (19.6% vs. 11.7%, respectively; P = 0.03) although similar 
proportions reported vomiting.  However, the proportions of participants with hepatitis, defined 
as serum AST 3 times or greater than the upper limit of normal, were similar between treatment 
arms during intensive phase (isoniazid 3.4% vs. moxifloxacin 3.3%; P = 0.93).  Moxifloxacin 
has also been evaluated in combination with pretomanid for two weeks in participants with TB 
(Trial NC-001) and for 8 weeks in NC002 as reviewed above in Section 2.5.3 (Trial NC-001). 
For additional information on moxifloxacin, refer to the IB[39] and the manufacturer’s package 
insert.[19] 
2.5.4 
Pyrazinamide (Z) 
Pyrazinamide (Z) is a standard drug used as part of the four drug HRZE regimen used for the 
first two months of intensive therapy for drug-sensitive TB as recommended by the WHO and 
many National TB programs.  Please see the Package Insert[20] for more detail.  Z is active 
against TB in vitro and it potentiates the bactericidal and sterilizing activity of both bedaquiline 
and  pretomanid in mouse models of TB infection.[8, 15]  Pyrazinamide enhanced the 
bactericidal activity of both bedaquiline and  pretomanid in Trial NC-001-(J-M-Pa-Z) as noted 
by decreases over 14 days in the CFU counts in sputum among participants. 
The pyrazinamide product label notes that pyrazinamide is contraindicated in persons with 
severe hepatic damage, who have shown hypersensitivity to it, and with acute gout.  The most 
serious side effect is hepatotoxicity. Its frequency appears to be dose-related and thus liver 
function should be assessed before and regularly during treatment with pyrazinamide.  
Hyperuricemia commonly occurs and is occasionally accompanied by arthralgia and may lead 
to attacks of gout. Photosensitivity and skin rash have been reported less frequently. Other 
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side effects that have been reported are anorexia, nausea and vomiting, malaise, fever, 
sideroblastic anaemia and dysuria.  
Pyrazinamide may decrease the efficacy of gout therapy (e.g. allopurinol, colchicine, 
probenecid or sulphinpyrazone) and dosage adjustments of these medications may be 
necessary.  For additional information on pyrazinamide, refer to the manufacturer’s package 
insert. [20] 
2.6 
Overall Benefit/Risk Assessment 
Some participants with pulmonary TB in this trial will be given a regimen of BPaMZ. These 
drugs individually and in combination are known to have anti-tuberculosis activity and is not 
expected to have an adverse impact on the ultimate cure of TB in these participants. Based 
on NC-005 and other regimens using each of the regimen drugs in different combinations 
there is good evidence that this may be a highly effective therapy for both DS-TB and DR-TB.  
For DS-TB the potential for a shorter regimen than 6 months is expected to be successful 
based on preclinical and clinical information as listed before.  Participants in this trial will have 
their TB infection carefully characterized, with drug sensitivity profiles established, and they 
will receive treatment with trial drugs that have demonstrated activity against MTB.   
Participants will receive individualized medical attention; this will allow a continuous monitoring 
of the health conditions of each participant, any of whom can be withdrawn at any stage of the 
trial and removed from trial treatment should his/her condition suggest to the Investigator that 
this would be in his/her best interest.  Multiple blood samples will be taken for safety laboratory 
studies, and ECGs will be taken at multiple time points.  
One concern, the combination of two agents with known QT-prolonging effects (bedaquiline 
and moxifloxacin), has been addressed specifically by carefully identifying and excluding 
participants with risk factors that might predispose them to cardiac arrhythmias, screening all 
participants for evidence of existing cardiac disease and monitoring all participants with ECGs 
throughout the trial.  
The trial drugs in the proposed regimens to be tested in this trial have all demonstrated safety 
and efficacy in the treatment of pulmonary tuberculosis in non-clinical and clinical studies. 
Specifically, the regimen B-Pa-Z was generally well-tolerated and demonstrated bactericidal 
activity in a 14-day EBA trial. The potential risks associated with the trial drugs and regimens 
has been identified as outlined below and will be monitored carefully throughout the conduct 
of the trial. 
The BPaMZ regimen is a novel regimen treatment expected to be effective, safe and well-
tolerated and might even shorten the current treatment duration for patients with TB. Based 
on data from previous trial evaluations of key monitoring and safety information as outlined 
before suggests a favourable benefit-to-risk ratio trials.  
Key Monitoring and Safety Information Regarding Regimen Agents 
2.6.1 
Bedaquiline (B) 
2.6.1.1 
Adverse Drug Reactions for bedaquiline  
Participants in the Any bedaquiline group compared to the Any Placebo group (difference > 
5.0%) had headache (23.5% versus 11.4%, respectively), nausea (35.3% versus 25.7%, 
respectively), arthralgia (29.4% versus 20.0%, respectively), and transaminases increased 
(6.9% versus 1.0%, respectively).and diarrhoea (11.4% versus 5.9%, respectively). 
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2.6.1.2 
Cardiovascular safety 
During clinical studies with bedaquiline a prolongation of QTc interval was observed. An ECG 
should be obtained prior to and after initiation of therapy with bedaquiline to monitor the QTc 
interval. 
Bedaquiline treatment initiation is not recommended in patients with: 
• 
Heart failure 
• 
QTcF interval > 450 ms (confirmed by repeat electrocardiogram) 
• 
A personal or family history of congenital QT prolongation 
• 
Concomitant administration of fluoroquinolone antibiotics that have a greater potential 
for significant QT prolongation (i.e., gatifloxacin, moxifloxacin and sparfloxacin) 
• 
Hypokalemia 
 
Bedaquiline treatment must be discontinued if the patient develops clinically significant 
ventricular arrhythmia. An additive or synergistic effect on QT prolongation of bedaquiline 
when co-administered with other medicinal products that prolong the QT interval cannot be 
excluded. Caution is recommended when using bedaquiline concomitantly with medicinal 
products with a known risk of QT prolongation. If co-administration of such medicinal products 
with bedaquiline is necessary, clinical monitoring including frequent ECG assessment is 
recommended. 
In the DR-TB treatment arm of the present trial, moxifloxacin will be co-administered with 
bedaquiline. This is to prevent the development of resistance to the other drugs in the regimen 
in case the participant’s strain of MTB is resistant to pyrazinamide. ECG assessments will be 
performed on all participants at screening, baseline, and at treatment visits specified in the 
flow chart.   
2.6.1.3 
Hepatic safety 
Increases in transaminases were seen in clinical studies during administration of bedaquiline 
with the background regimen. Participants should be monitored during treatment. 
Other hepatotoxic medicinal products and alcohol should be avoided while taking bedaquiline, 
especially in participants with diminished hepatic reserve. 
2.6.2 
Pretomanid (P) 
The most common side effects or AEs associated with pretomanid exposure include: 
• 
Headache 
• 
Benign, isolated and reversible elevations of serum creatinine 
• 
Stomach discomfort (nausea, vomiting, flatulence, and/or diarrhoea) 
• 
Skin and subcutaneous tissue disorders 
2.6.2.1 
Hepatic Safety 
Hepatic enzyme increases have been seen in participants treated with pretomanid in 
combinations with various other medications during the clinical development program. It is 
difficult to assign specific causality to any one drug within a regimen; nonetheless, the NC-008 
trial will include specific monitoring of hepatic enzymes. 
For additional information refer to  pretomanid IB.[15] 
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2.6.3 
Moxifloxacin (M) 
In the usual daily doses of 400 mg/day, moxifloxacin is well tolerated.  As stated in the Package 
Insert[19]  the most frequent individual drug related AEs observed in clinical trials with 400 mg 
oral moxifloxacin therapy were nausea (7.5%) and diarrhoea (5.8%).  Fluoroquinolones, 
including moxifloxacin, are associated with an increased risk of tendinitis and tendon rupture 
in all ages.   
A known but rare side effect of fluoroquinolones, including moxifloxacin is exacerbation of 
myasthenia gravis. In addition, moxifloxacin has been shown to prolong the QT interval of the 
electrocardiogram in some participants.  It should be used with caution in participants being 
treated concomitantly with other drugs where an additive effect on the QT interval cannot be 
excluded.  
Serious and sometimes fatal hypersensitivity reactions, including anaphylactic reactions, as 
well as peripheral neuropathy may occur after the first or subsequent doses of moxifloxacin. 
For additional information, refer to the moxifloxacin package insert.[19] 
2.6.4 
Pyrazinamide (Z) 
The dose of pyrazinamide that will be used in this trial is an approved dosage for the treatment 
of TB. The most serious side-effect of pyrazinamide is hepatotoxicity and its frequency 
appears to be dose-related. Hyperuricemia commonly occurs, occasionally accompanied by 
arthralgia and may lead to attacks of gout.  Photosensitivity and skin rash have been reported 
less frequently.  Other side-effects that have been reported are anorexia, nausea and 
vomiting, malaise, fever, sideroblastic anaemia and dysuria.  Pyrazinamide may decrease the 
efficacy of gout therapy (e.g. allopurinol, colchicine, probenecid or sulphinpyrazone) and 
dosage adjustments of these medications may be necessary.  For additional information on 
pyrazinamide, refer to the manufacturer’s package insert.[20] 
2.6.5 
HRZE/HR Control 
The HRZE (isoniazid 75 mg plus rifampicin 150 mg plus pyrazinamide 400 mg plus ethambutol 
275 mg combination tablets) combination will be given the first 8 weeks and the HR (isoniazid 
75 mg plus rifampicin 150 mg combination tablets) combination will be given from Weeks 9 to 
26. 
Participants with DS-TB that are randomized to the HRZE/HR control arm in this trial will be 
given standard weight-adjusted doses of HRZE.   
Please see the HRZE and HR Package Inserts[22, 40] for known and potential risks and benefits. 
3.0 
Trial Objectives 
3.1 
Primary Endpoint 
To evaluate the time to culture negativity over 8 weeks from the start of the treatment regimens 
in participants with: 
• 
Drug Sensitive TB (DS-TB) 
• 
Drug Resistant TB (DR-TB)  
 
DR-TB are defined as participants with: 
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1. mono-resistance to rifampicin or isoniazid, OR 
2. resistance to both rifampicin and isoniazid (DR-TB) 
3.2 
Secondary Endpoints 
Efficacy: 
 
• 
Incidence of bacteriologic failure or relapse or clinical failure at 52 weeks (12 months) and 
104 weeks (or 24 months) weeks from the start of therapy.  
• 
Proportion of participants with sputum culture conversion to negative status in liquid culture 
(MGIT) at 4, 6, 12 and 17 weeks to be explored as a potential biomarker of outcome at 52 
weeks from start of therapy. 
• 
Change from baseline in weight. 
• 
Change from baseline in TB symptoms. 
• 
Change from baseline in Participant Reported Health Status. 
 
Safety and Tolerability: 
 
• 
Incidence of Treatment Emergent Adverse Events (TEAEs) presented by incidence, 
severity, drug relatedness, seriousness, leading to early withdrawal, and leading to death.  
 
Quantitative and qualitative clinical safety laboratory measurements, including 
observed and change from baseline. 
 
Quantitative and qualitative ECG results (heart rate, RR interval, PR interval, QRS 
interval, QT interval and QTc interval), including observed. QT/QTc intervals, change 
from baseline, will be categorized as these will be centrally read. 
• 
Changes in male reproductive hormones. 
• 
Changes in lens opacities. 
 
These data will be presented as descriptive analyses, and no inferential tests will be carried 
out. 
Pharmacokinetics (PK) and Pharmacokinetics/Pharmacodynamics (PK/PD): 
 
Plasma concentrations from sparse sampling will be used to update existing population PK 
models and derive exposure metrics (e.g., minimum plasma concentration [Cmin], maximum 
plasma concentration [Cmax], area under curve over a dosing interval [AUC]) for bedaquiline 
and its M2 metabolite, pretomanid, moxifloxacin, and pyrazinamide. Effects of baseline 
covariates on exposure will be assessed; so too, will the effects of concomitant medications, 
including antiretroviral therapy (ART), where feasible.  
Data from other trials may be included to enhance the model-based analysis. Relationships 
will be explored between drug exposure and efficacy and safety endpoints. These exploratory 
PK/PD analyses may include HIV status as a covariate. 
3.3 
Exploratory Objectives 
• 
Evaluate whether any of the secondary endpoints predicts relapse free cure. 
• 
Subgroup analysis of populations by HIV status.  
 
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4.0 
Trial Design 
4.1 
Summary of Trial Design 
This is a Phase 2c, multi-centre, open-label, partially randomized clinical trial conducted in 3 
treatment groups.  Participants, trial Investigators and staff, including laboratory staff, will not 
be blinded to treatment randomization and allocation during the treatment phase of the trial. 
The trial will be performed globally at multiple centres located throughout the world.    
A total of 300 DS-TB participants (150 per treatment arm) will be randomized and stratified for 
co-infection with HIV and cavitation, with a target of 50% of the participants being HIV positive.  
Up to 150 DR-TB participants will be enrolled and assigned to the treatment arm described in 
Table 4 below. 
Refer to Section 3.0 Trial Objectives above and Section 9.3 Interim Analysis for details of the 
planned interim analysis and potential updates to the trial objectives and sample size.   
Participants with Drug Sensitive TB (DS-TB): 
 
Participants with DS-TB will be randomized to one of two treatment arms. These participants 
will receive either BPaMZ daily for 17 Weeks, or HRZE/HR combination tablets daily for 26 
Weeks.  Participants will be stratified for co-infection with human immunodeficiency virus (HIV) 
and cavitation. 
 
Participants with Drug Resistant TB (DR-TB): 
 
Participants with DR-TB will be assigned to receive BPaMZ daily for 26 weeks (6 months). 
Eligible participants who meet all the inclusion criteria and none of the exclusion criteria, aged 
18 and over, male or female will be assigned to one of the 3 treatment groups with a target of 
50% of the participants being HIV positive.  
DR participants will be treated with 6 months of BPaMZ. DS participants will be randomized 
using an interactive web response system (IWRS) stratifying for cavitation and HIV status to 
allocate participants evenly across the arms after they have given written, informed consent 
during the Screening Visit (Days -9 to -1).  
 
4.2 
Treatment Plan: Schedule of Assessments 
• 
Screening Period (Day -9 to Day -1) 
• 
Treatment Period (Day 1 to Week 17 / Week 26)  
• 
Follow-Up Period (Week 39 to Week 104) 
 
Refer to: 
• 
Synopsis Flow Chart and Procedures (Section 1.2) for the timing of all procedures and 
laboratory samples to done at each visit.   
• 
Trial Procedures (Section 7.0, Trial Variables and Procedures) for details regarding 
specific procedures or laboratory tests. 
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Each participant will receive up to 26 weeks of treatment.  The trial IMP regimens may require 
interruptions/pauses due to toxicities. All dose interruptions/pauses should be discussed with 
the Sponsor’s Medical Monitor prior to implementation unless an interruption/pause is required 
urgently for a safety concern.  
 
All participants will enter post-treatment follow-up which continues until Week 104 after start 
of treatment / randomisation. 
 
Participants will receive daily dosing, orally. They will be randomized to one of the following 
arms: 
Table 4: Treatment Groups 
 
Treatment Group 
Treatment 
Duration 
No of 
Participants 
1 Bedaquiline 200 mg daily for 8 weeks  
then 100 mg daily for 9 weeks, together with 
pretomanid 200 mg + moxifloxacin 400 mg + 
pyrazinamide 1500 mg daily 
17 weeks 
(4 months) 
150 DS-TB 
2 HRZE Tablets (Weeks 1-8): (isoniazid 75 mg plus 
rifampicin 150 mg plus pyrazinamide 400 mg plus 
ethambutol 275 mg combination tablets).  
 
Followed by 
 
HR Tablets (Weeks 9-26): (isoniazid 75 mg plus 
rifampicin 150 mg combination tablets).   
First 8 weeks  
(2 months) 
 
 
then 
 
17 weeks  
(4 months) 
 
Total 6 months 
150 DS-TB 
3 Bedaquiline 200 mg daily for 8 weeks  
then 100 mg daily for 18 weeks, together with 
pretomanid 200 mg + moxifloxacin 400 mg + 
pyrazinamide 1500 mg daily. 
26 weeks 
(6 months) 
Up to 150 
DR-TB 
5.0 
Trial Population 
The participant must meet all inclusion and no exclusion criteria within the screening period.  
Retesting for any laboratory or ECG parameters is allowed within the screening period.  
Sponsor may consider replacement of late exclusions. It is the intent of the protocol that the 
participants are hospitalized according to local practices and at the judgment of the treating 
physician / investigator. 
5.1 
Inclusion Criteria 
Participants are required to meet all the following inclusion criteria during the screening period 
to be randomized. 
1. Signed written consent prior to undertaking any trial-related procedures. 
2. Male or female, aged 18 years or over. 
3. Body weight (in light clothing and no shoes) ≥ 30 kg. 
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4. Sputum positive for tubercule bacilli (at least 1+ on the International Union Against 
Tuberculosis and Lung Disease [IUATLD]/WHO scale (Appendix 1) on smear microscopy) 
at the trial laboratory. 
5. Disease Characteristics - Participants with one of the following pulmonary TB conditions: 
DS-TB treatment arm participants should be: 
a. sensitive to rifampicin, isoniazid and fluoroquinolones by rapid sputum-based 
test AND 
b. either newly diagnosed for TB or have a history of being untreated for at least 
3 years after cure from a previous episode of TB. 
DR-TB treatment arm participants should be: 
a. Resistant to rifampicin and/or isoniazid; but sensitive to fluoroquinolones by 
rapid sputum-based test AND  
b. Should not have had previous treatment for DR-TB/MDR-TB, although may 
have been on a DR-TB/MDR-TB treatment regimen for no longer than 3 days 
at start of screening. 
c. Participants with resistance to injectables by rapid sputum-based test are 
allowed in the trial. 
When Phenotypic DST and / or whole genome sequencing (WGS) results on baseline 
samples become available, any results that are discordant with the screening 
molecular test results used to qualify a participant’s eligibility for the trial will be 
reviewed by the Sponsor Medical Monitor in consultation with the Investigator to 
determine whether that participant is unlikely to respond to treatment and should 
therefore be removed from the trial and given alternative treatment. If a participant is 
removed from the trial for such a reason, they will be classified as a late exclusion.  
6. A chest x-ray, within 6 months prior to or during the Screening visit, which in the opinion 
of the Investigator is compatible with pulmonary TB.  
7. Contraception: 
 
Be of non-childbearing potential or using effective methods of birth control, as defined 
 
below: 
Non-childbearing potential: 
a. Female participant or male participants female sexual partner - bilateral 
oophorectomy, bilateral tubal ligation and/or hysterectomy or has been 
postmenopausal with a history of no menses for at least 12 consecutive months; 
or  
b. Male participant 
Effective birth control methods: 
a. Double barrier method which can include a male condom, diaphragm, cervical cap, 
or female condom; or  
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b. Female participant: Barrier method combined with hormone-based contraceptives 
or an intra-uterine device. 
c. Male participants’ female sexual partner: Barrier method combined with hormone-
based contraceptives or an intra-uterine device.  
Both male and female participants must be willing to continue practicing birth control 
methods and are not planning to conceive throughout treatment and for 6 months after 
the last dose of trial IMP or discontinuation from trial IMP in case of premature 
discontinuation.  
Note: Hormone-based contraception alone may not be reliable when taking IMP; therefore, 
hormone-based contraceptives alone cannot be used by female participants to prevent 
pregnancy. 
 
5.2 
Exclusion Criteria 
Participants will be excluded from participation if they meet any of the following criteria: 
Medical History and Concurrent Conditions: 
1. Any non-TB related condition where participation in the trial, as judged by the 
Investigator, could compromise the well-being of the participant or prevent, limit or 
confound protocol specified assessments. 
2. Abuse of alcohol or illegal drugs that in the opinion of the Investigator would 
compromise the participants’ safety or ability to follow through with all protocol-
specified restrictions, visits and evaluations. 
3. Historical and or current use of local traditional medications/herbs which in the opinion 
of the Investigator would compromise the participants’ safety or ability to follow through 
with all protocol-specified restrictions, visits and evaluations.  
4. Being, or about to be, treated for malaria. 
5. Is critically ill and, in the judgment of the Investigator, has a diagnosis likely to result in 
death during the trial or the follow-up period. 
6. TB meningitis or other forms of extrapulmonary tuberculosis with high risk of a poor 
outcome, or likely to require a longer course of therapy (such as TB of the bone or 
joint), as judged by the Investigator. 
7. History of allergy or hypersensitivity to any of the trial IMP or related substances, 
including known allergy to any fluoroquinolone antibiotic, history of tendinopathy 
associated with quinolones or suspected hypersensitivity to any rifampicin antibiotics. 
8. For HIV infected participants any of the following: 
 
a. CD4+ count <100 cells/µL  
b. Karnofsky score <60% (Appendix 5) 
c. Received intravenous antifungal medication within the last 90 days 
d. WHO Clinical Stage 4 HIV disease (Appendix 3) 
 
9. Participants who recently started or expected to need to start ART within 1 month after 
randomization. Participants who have been on ARTs for more than 30 days prior to 
start of the Screening visit or expected to start ART greater than 30 days after 
randomization may be included.  
 
10. Having participated in other clinical trials with investigational agents within 8 weeks 
prior to start of trial medication or currently enrolled in an investigational trial. 
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11. Participants with any of the following at the Screening visit (per measurements and 
reading done by ECG): 
 
a. QTcF interval on ECG >500 msec.  Participants with QTcF > 450 must be 
discussed with the Sponsor Medical Monitor before enrolment. 
b. Heart failure 
c. A personal or family history of congenital QT prolongation 
d. A history of or known, untreated, ongoing hypothyroidism 
e. A history of or ongoing bradyarrhythmia 
f. 
A history of Torsade de Pointe 
 
12. Unstable Diabetes Mellitus which required hospitalization for hyper- or hypo-glycaemia 
within the past year prior to start of screening. 
13. Females who have a positive pregnancy test at the Screening visit or already known 
to be pregnant, breast-feeding, or planning to conceive a child during the trial or within 
6 months of stopping treatment.  Males planning to conceive a child during the trial or 
within 6 months of stopping treatment.  
14. Participants with lactose intolerance, lactase deficiency and/or glucose-galactose 
malabsorption. 
 
Previous and Concomitant Therapy 
15. Previous treatment for TB which includes: 
 
• 
For DS-TB participants: Previous treatment for tuberculosis within 3 years prior to 
the Screening visit. Participants who have previously received isoniazid 
prophylactically may be included in the trial if that treatment is/was discontinued at 
least 7 days at the start of the Screening visit. 
• 
For the DR-TB participants: Previous treatment for DR-TB/MDR-TB, although may 
have been on a DR-TB/MDR-TB treatment regimen for no longer than 3 days at 
the start of the Screening visit. 
16. Any diseases or conditions in which the use of the standard TB drugs or any of their 
components is contra-indicated, including but not limited to drug allergy. 
17. Use of any drug within 30 days prior to randomisation known to prolong QTc interval 
(including, but not limited to, amiodarone, amitriptyline, bepridil, chloroquine, 
chlorpromazine, cisapride, clarithromycin, disopyramide dofetilide, domperidone, 
droperidol, 
erythromycin, 
halofantrine, 
haloperidol, 
ibutilide, 
levomethadyl, 
mesoridazine, methadone, pentamidine, pimozide, procainamide, quinacrine, 
quinidine, sotalol, sparfloxacin, thioridazine). 
18. Use of systemic glucocorticoids within one year of the start of the Screening visit 
(topical, inhaled or intranasal glucocorticoids are allowed), as they can lead to visual 
opacities or cataracts. 
19. For HIV infected participants: 
 
a. The following antiretroviral therapy (ART) should not be used with either 
(BPaMZ and HRZE/HR) trial regimen: 
 
1. Stavudine  
2. Didanosine  
3. Triple NRTI regimen is not considered optimal for HIV treatment (poor 
efficacy) 
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b. In the case where participants are randomised to HRZE arm, rilpivirine and 
etravirine cannot be given with rifampicin due to drug-drug interactions. A 
standard NRTI backbone may be used in combination with one of the 
following: 
 
1. Efavirenz requires no dose adjustment  
2. Dolutegravir dose adjustment is required – double dose when co-
prescribed with rifampicin. 
3. Raltegravir requires no dose adjustment 
4. Lopinavir/r dose adjustment is required – double dose when co-
prescribed with rifampicin 
5. Nevirapine requires no dose adjustment, however please note that 
nevirapine based regimens are associated with higher ART failure in 
participants having or known to have a previous viral load more than 
or equal to 100,000/ mL 
 
c. In the case where participants are randomized to the BPaMZ trial regimen, a 
standard NRTI backbone may be combined with the following:  
 
1. Rilpivirine 
2. Dolutegravir  
3. Raltegravir 
4. Nevirapine  
5. Lopinavir/r  
6. Participants who are on efavirenz, atazanavir/r or darunavir/r at the 
time of screening and have an undetectable viral load, should have 
their ART switched to one of the agents listed above (1-5). It would be 
preferable to switch to another permissible ARV within the same class 
accompanied by the same nucleoside backbone. 
 
d. ART regimen choice should be discussed with the Sponsor Medical Monitors 
if there are any concerns. 
 
Confirmed plans to use Isoniazid prophylaxis for HIV positive participants during the 
treatment and follow up period is not permitted. 
Diagnostic and Laboratory Abnormalities 
20. Participants with the following toxicities at screening as defined by the enhanced 
Division of Microbiology and Infectious Disease (DMID) adult toxicity table (Draft 
November 2007) (Appendix 2) where applicable: 
 
a. platelets <75,000/mm3 
b. creatinine 1.5 times upper limit of normal [ULN])  
c. eGFR ≤ 60 mL/min/ 
d. haemoglobin <8.0 g/dL 
e. serum potassium less than the lower limit of normal for the laboratory. This may 
be repeated once 
f. GGT: greater than 3 x ULN 
g. AST: 
• 
≥3.0 x ULN to be excluded; 
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• 
results between 1.5 x ULN and 3 x ULN must be discussed with and 
approved by the Sponsor Medical Monitor 
h. ALT: 
• 
≥3.0 x ULN to be excluded 
• 
greater than ULN must be discussed with and approved by the Sponsor 
Medical Monitor 
i. 
 ALP: 
• 
≥3.0 x ULN to be excluded 
• 
2.0 – <3.0 x ULN must be discussed with and approved by the Sponsor 
Medical Monitor 
j. 
Total bilirubin: 
• 
>1.5 x ULN to be excluded; 
• 
Greater than 1 – 1.5 x ULN must be discussed with and approved by 
the Sponsor Medical Monitor 
k. Direct bilirubin: 
• 
greater than 1x ULN to be excluded 
All the inclusion and none of the exclusion criteria must be met. If no single variable/value is 
outside of the ranges of acceptability, but when multiple values are close to the limits and/or 
whenever the Investigator has reason to suspect that there might be a health problem (other 
than TB), enrolment should only be considered after discussing the case with the Sponsor 
Medical monitor. 
 No protocol waivers will be granted by the TB Alliance. 
 
5.3 
Restrictions 
Concomitant medications should be kept to a minimum during the trial. However, if 
concomitant medications are necessary for the participant’s welfare, they may be given at the 
discretion of the Investigator. For any concomitant medications given as a treatment for a new 
condition or a worsening of an existing condition occurring after signing of the informed 
consent form, the condition must be documented on the Adverse Event pages of the electronic 
Case Report Form (eCRF). 
The prescribing information for all concomitant medication should be reviewed carefully. The 
determinations listed in the respective contraindicated, warning, and precaution sections must 
be respected to prevent any potentially serious and/or life-threatening drug interactions. 
The following recommendations should be followed with regards to concomitant medication to 
avoid possible drug interaction with the IMP: 
Participants on a moxifloxacin containing treatment arm: The IMP should be taken either 
4 hours before or 8 hours after taking the following products: 
• 
An antacid, multivitamin, or other product that has magnesium, aluminium, iron 
or zinc 
• 
Sucralfate 
• 
Didanosine 
Participants on the HRZE/HR treatment arm: 
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• 
Any aluminium-containing antacids should be taken at least one hour after the IMP 
dose. 
The following medicinal products are prohibited from the Screening visit and during the 
treatment period: 
• 
Quinolone antimalarial (e.g., chloroquine and quinacrine). Participants who have 
malaria at screening are to be excluded. However, if a participant develops malaria 
during the trial, the Investigator is advised to consult the Malaria Treatment 
Guidance document regarding the interaction between moxifloxacin and 
bedaquiline with anti-malarial drugs. Investigators may also contact the Sponsor 
Medical Monitor for further guidance. 
• 
Chronic systemic glucocorticoids (topical, inhaled or intranasal glucocorticoids are 
allowed) due to their potential to cause visual opacities. Short term systemic 
glucocorticoids are allowed for emergency situations (e.g. for treatment of 
pulmonary exacerbation when inhaled glucocorticoids is inadequate). 
• 
Medicinal products used to treat pulmonary TB: including but not limited to 
gatifloxacin, amikacin, cycloserine, rifabutin, kanamycin, para-aminosalicylic acid, 
rifapentine, thioacetazone, capreomycin, other quinolones, thioamides, and 
metronidazole. 
The following medicinal products should be avoided from Day 1 (Baseline visit) and during the 
treatment period as much as possible (unless this is required for emergency management of 
the participant). Investigators may also contact the Sponsor Medical Monitor for further 
guidance. 
• 
Any drug known to prolong QTc interval (including but not limited to amiodarone, 
bepridil, chloroquine, chlorpromazine, cisapride, clarithromycin, disopyramide 
dofetilide, domperidone, droperidol, erythromycin, halofantrine, haloperidol, 
ibutilide, levomethadyl, mesoridazine, methadone, pentamidine, pimozide, 
procainamide, quinidine, sotalol, sparfloxacin, thioridazine). The exception is 
moxifloxacin and bedaquiline administered as part of the trial IMP, with ECG 
monitoring, to help ensure participant safety. 
• 
Any 
drug 
known 
to 
be 
hepatotoxic 
(including 
but 
not 
limited 
to 
acetaminophen/paracetamol, 
acetazolamide, 
allopurinol, 
amiodarone, 
amitriptyline, amoxicillin, amprenavir, atorvastatin, augmentin/co-amoxiclav, 
azathioprine, baclofen, bumetanide, captopril, carbamazepine, celecoxib, 
chlorpromazine, 
chlorpromazine, 
clindamycin, 
clopidogrel, 
co-trimoxazole, 
darunavir, delavirdine, diclofenac, doxycycline, enalapril, fluconazole, fluoxetine, 
fosamprenavir, furosemide, gliclazide, glimeperide, glipizide, ibuprofen, irbesartan, 
ketoconazole, 
lisinopril, 
loperamide, 
losartan, methotrexate, 
metolazone, 
mirtazepine, nitrofurantoin, omeprazole, other non-steroidal anti-inflammatory 
drugs, paroxetine, phenobarbital, phenothiazines, phenytoin, pravastatin, 
probenecid, prochlorperazine, risperidone, rosuvastatin, sertraline, simeprevir, 
simvastatin, sodium valproate, sotalol, sulfasalazine, sumatriptan, tamsulosin, 
terbinafine, tetracycline, theophyllin/uniphyllin, tipranavir, tolazamide, tolbutamide, 
topiramate, trazodone, tricyclic antidepressants, trimethoprim, verapamil).  
 
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5.4 
Treatment Discontinuation and/or Early Withdrawal  
Any participant for whom the Investigator decides to temporarily discontinue their IMP is to be 
discussed with the Sponsor Medical Monitor and, if applicable, be restarted on IMP as soon 
as possible.  
A participant must be prematurely withdrawn from the trial (during the trial treatment or follow-
up periods) because of the following: 
• 
Withdrawal of informed consent 
• 
Investigator considers that for safety reasons it is in the best interest of the participant 
that he/she be withdrawn, including a concern that the participant has symptomatic TB 
and/or bacteriological failure/relapse and requires a change in TB treatment 
• 
Pregnancy 
• 
At the specific request of the Sponsor or termination of the trial by the Sponsor 
• 
Lost to follow-up 
• 
When Phenotypic DST and / or whole genome sequencing (WGS) results on baseline 
samples become available, any results that are discordant with the screening molecular 
test results used to qualify a participant’s eligibility for the trial will be reviewed by the 
Sponsor Medical Monitor in consultation with the Investigator to determine whether that 
participant is unlikely to respond to treatment and should therefore be removed from the 
trial and given alternative treatment.  If a participant is removed from the trial for such a 
reason, they will be classified as a late exclusion. 
A participant may withdraw from the trial at any time at his/her request (withdrawal of consent), 
or may be withdrawn at any time at the discretion of the Investigator for safety, behavioural, 
compliance or administrative issues.  
When a participant withdraws consent from the trial, no additional follow-up visits will be 
performed. 
Participants who withdraw from the trial after having received IMP will not be replaced.  
All participants withdrawn from trial and who received at least one dose of IMP will be 
requested to return for an Early Withdrawal visit and the applicable safety Follow-Up visits, as 
per the Synopsis Flow Chart and Procedures (Section 1.2 footnote c), as well as Table 5. 
5.4.1 
Early Withdrawal 
In case of early withdrawal during the treatment or follow-up period, all efforts shall be made 
to complete the Early Withdrawal assessments.  At the Early Withdrawal visit the following 
information will be collected and procedures performed: 
• 
Sputum sample collection x 2 (one EMS brought from home and one spot at the research 
site under the coaching and observation of the trial staff).  If no EMS was provided by the 
participant, 2 spot samples may be collected at the site, at least 30 minutes apart. 
• 
Urine pregnancy test (women of child bearing potential, whether they are sexually active 
or not) 
• 
Laboratory safety sampling (including male reproductive hormone tests); 
• 
Single 12-lead ECG 
• 
TB Symptoms Profile 
• 
Patient Reported Health Status Questionnaire 
• 
Vital signs 
• 
Full physical examination, including weight 
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• 
Ophthalmology examination, if required as described in Table 5 
• 
IMP compliance check (if participant on IMP) 
• 
Concomitant medications 
• 
Adverse events 
Once a participant has been withdrawn early from the trial, they will be requested to attend 
follow-up visits as described in Table 5: 
Table 5: Follow-up Visits Required for Early Withdrawal Participants 
Treatment 
Duration at 
EWD visit 
Ophthalmology 
Examination at 
EWDa 
Ophthalmology 
Examination  
 
Visit 3 months 
after EWD Visita 
Week 52  
(Month12) 
Follow-up 
Visit 
Week 104 
(Month 24) 
Follow-up 
Visit 
≤ 14 days 
Not required 
Not required 
Required 
Required 
15 days to      
≤ 12 weeks 
Not required 
Required 
Required 
Required 
> 12 weeks  
Required 
Required 
Required, if 
not already 
performed 
Required 
a. If an additional visit is required for an ophthalmology examination after EWD, only the 
ophthalmology examination will be performed at this visit, and it will occur 3 months after 
the EWD visit date. 
The Weeks 52 and 104 visits will be performed to collect SAE information (including 
verification of survival) and participant reported TB outcome information.  This visit may be 
telephonic, a home or a site visit at Weeks 52 and/or Week 104 after the participants’ start of 
treatment date. 
5.4.2 
Unscheduled Visits 
Any visit which is conducted in addition to those required by the Synopsis Flow Chart and 
Procedures (Section 1.2), should be considered unscheduled regardless of the reason for the 
visit. The assessments which are undertaken as part of an Unscheduled visit should be as 
clinically indicated.  
The following situation/s would require an unscheduled visit/s: 
• 
For any medical reason, as determined by the investigator or participant. 
• 
If both sputum samples (EMS and spot) at Week 8 or later are contaminated, the 
participant should return for an unscheduled visit/s to give additional sputum samples 
or to document that the participant is not able to produce sputum. 
• 
If after having converted to culture negative, the participant has a MTB confirmed 
positive culture at or after the last visit of the treatment period (Week 17 or Week 26), 
the participant should return for an unscheduled visit/s to provide additional sputum 
samples, at a minimum of 7 days apart, or to document that the participant is not able 
to produce sputum sample.  
Determination of the participant’s primary outcome status requires sputum culture results at 
the following time-points during the trial:  
o End of Follow-up Period (Week 52 and 104) 
o Early Withdrawal, if applicable 
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At least one of the following criteria should be met at these time-points to confirm a 
participant’s primary outcome status: 
 
o two sequential negative sputum culture results; or  
o two sequential positive sputum culture results; or  
o has been unable to produce sputum after documentation of two negative 
sputum cultures with no intervening positive and the participant is clinically 
asymptomatic 
Should the participant’s primary outcome not meet any of the above criteria, the Investigator 
should continue to recall the participant for a Unscheduled visit to collect sputum samples until 
the criteria is met and the primary outcome can be determined. 
Additional sputum samples: Two samples at each visit – ideally, one EMS and one spot 
sputum at the research site under the coaching and observation of the trial staff. If no EMS 
was provided by the participant, 2 spot sputum samples may be collected on site, at least 30 
minutes apart. Additional sputum samples should be collected at least 7 days after the 
previous sample.  
Table 
6: 
Summary 
of 
Scenarios 
Requiring 
Unscheduled 
Visits 
for 
Mycobacteriology Testing 
Time-point 
Scenario 
Unscheduled 
Visit/s 
Required? 
Comment 
Week 8 or later 
Both sputum 
cultures are 
contaminated 
Yes 
Provide additional samples until 
a positive or negative result is 
reported, or it is confirmed that 
the participant is unable to 
produce sputum 
At or after the 
last treatment 
visit (Week 17 
or Week 26) 
Previously 
converted to culture 
negative but now 
has an MTB-positive 
culture 
Yes 
Provide additional samples at 
least 7 days after the previous 
sample until the result is 
confirmed, or it is confirmed that 
the participant is unable to 
produce sputum.  
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Time-point 
Scenario 
Unscheduled 
Visit/s 
Required? 
Comment 
End of Follow-
up Period 
(Week 52 and 
104)  
Early 
Withdrawal, if 
applicable 
Participant’s primary 
outcome status 
cannot be confirmed 
by: 
Two sequential 
negative sputum 
culture results; or   
two sequential 
positive sputum 
culture results; 
or has been unable 
to produce sputum 
after documentation 
of two negative 
sputum cultures with 
no intervening 
positive and are 
clinically 
asymptomatic 
Yes 
Provide additional samples at 
least 7 days after the previous 
sample until one of the criteria is 
met and the primary outcome 
status can be determined.  
 
If the Investigator is unsure of the outcome in any of the above scenarios the Investigator 
should contact the Sponsor Medical Monitor to discuss and agree on how the participant is to 
be managed. 
5.4.3 
Lost-to-Follow-up 
Every reasonable attempt must be made to minimise Lost-to-Follow-up (LTFU) participants.  
A minimum of three contact attempts (telephonic/home visit) will be made for participants who 
do not arrive for their scheduled trial visits. If these attempts are unsuccessful the participant 
will be considered LTFU.  All attempts to contact the participant must be clearly documented 
in the participant’s source documents. 
5.4.4 
Early Withdrawal due to TB 
Ultimately it is the Investigator’s decision whether a participant requires early withdrawal from 
the trial due to a concern that the participant has symptomatic worsening of TB and/or 
bacteriological failure/relapse.  
Early withdrawal is usually not indicated for a single positive culture.  Should a participant have 
a single positive culture result after being culture negative, the Investigator is to evaluate 
whether the participant has signs and symptoms suggestive of active inadequately treated TB 
and whether it is in the participants best interest that he/she be withdrawn. Prior to early 
withdrawal of a participant due to TB, the Investigator must discuss the participant with the 
Sponsor Medical Monitor, unless the Investigator cannot contact the Sponsor Medical Monitor 
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and considers that early withdrawal must occur immediately due to immediate safety concerns 
with respect to the participant. 
If the Investigator decides to withdraw a participant due to TB, additional sputum samples may 
need to be collected to ensure the participant’s outcome status as determined in Section 5.5. 
All early withdrawn participants who are confirmed sputum positive (two sequential sputum 
positive cultures) and/or have symptomatic TB will require further TB treatment. These 
participants will be referred to their applicable DS/DR local community TB clinics for standard 
anti-tuberculosis chemotherapy according to National TB Treatment Guidelines.  
The participants will be provided with a referral letter from the Investigator to take with them 
to their National Treatment Program (NTP) clinic and the referral letter, at a minimum, should 
include 
all 
treatment 
received 
by 
the 
participant 
and 
information 
about 
any 
suspected/confirmed adverse event/reaction related to any of the trial IMP’s and or 
concomitant medications.  A follow-up call should be made by the trial site staff to the clinic to 
ensure the participant attended the NTP clinic.  
5.5 
Participant Progress Definitions 
Table 7: Participant Progress Definitions 
Status 
Treatment 
Follow-Up 
Screen Failure 
Participants from whom informed consent is obtained and is 
documented in writing (i.e., participant signs an informed consent 
form) but who are not randomized 
Completed 
Treatment / 
Completed 
Follow-Up* 
Participants who complete 
the full course of IMP 
Participants who complete all follow-up 
visits 
Completed 
Treatment / 
Discontinued 
Follow-Up 
Participants who complete 
the full course of IMP 
Participants who do not complete all 
applicable follow-up visits, regardless 
of the reason (excluding LTFU) 
Completed 
Treatment / Lost 
to Follow-Up 
Participants who complete 
the full course of IMP 
Participants who are unable to be 
contacted on or before their final visit 
Discontinued 
Treatment / 
Completed FU 
Participants who 
discontinue IMP prior to 
completion of the protocol-
defined treatment course 
Participants who complete all 
applicable follow-up visits 
Discontinued 
Treatment / 
Discontinued 
Follow-Up** 
Participants who 
discontinue IMP prior to 
completion of the protocol-
defined treatment course 
Participants who do not complete all 
applicable follow-up visits, regardless 
of the reason (excluding LTFU) 
Lost to Follow-
Up 
Participants who are unable to be contacted on or before their final 
treatment visit and it cannot be confirmed whether treatment was 
completed 
* 
Note that this includes treatment failures who complete all applicable follow-up visits 
** 
Early Withdrawal 
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5.6 
Trial Stopping Rules 
There are no trial specific stopping rules.  
The trial or parts of the trial can be stopped by the Sponsor on advice from the Data Safety 
and Monitoring Committee (DSMC) after their review of applicable trial data.  In addition, the 
Sponsor has the right to stop the trial or a specific trial site at any time, although this should 
only occur after consultation between the involved parties.  Should this occur, the local and 
central Ethics Committee/Institutional Review Board (EC/IRB) and Regulatory Authorities will 
be informed.   
Should a trial site be closed prematurely, all trial materials (except source documentation that 
must remain at the site) will be returned to the Sponsor or applicable vendor.   The Investigator 
will retain all other documents until notification given by the Sponsor for destruction.  
Participants currently on trial IMP will receive an appropriate regimen and all participants will 
be referred to their applicable DS-TB/DR-TB NTP clinic. 
6.0 
Treatment 
6.1 
IMP Administration  
6.1.1 
Instructions for Dosing of Test Regimen (BPaMZ):  
• 
Treatment will be orally administered once daily, to be taken during breakfast, with a 
full glass of water (approximately 240 ml), for 17 weeks (4 months) or 26 weeks (6 
months). 
 
6.1.2 
Instructions for Dosing Control Treatment Regimen (HRZE/HR): 
• 
To be taken with a glass of water (approximately 240 ml). 
• 
HRZE or HR should not be taken with a meal (generally, no closer to meals than 1 
hour before or 2 hours after a meal) in the following dosing schemes. 
HRZE/HR treatment will be administered orally once daily to DS-TB participants as follows: 
Weight Band 
Weight Range 
Number of tablets per 
weight band 
1 
30-39 kg 
2 
2 
40-54 kg 
3 
3 
55-70 kg 
4 
4 
≥ 71 kg 
5 
 
The participant’s weight at the Screening (HRZE) and Week 8 (HR) visits will be used to 
determine which weight band and dose to administer. 
 
A daily supplement of Vitamin B6 will be provided by the trial site to participants randomised 
to the HRZE/HR treatment arm, per each country’s National TB Treatment Guideline.   
6.2 
Participant Compliance 
During site clinic visits, the IMP will be administered by the Investigator(s)/designated site 
personnel and when possible, the check for IMP compliance via the hand-and-mouth 
procedure (both the hand and the mouth of the participant will be checked to ensure that the 
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participant has swallowed the IMP). During the trial, sites will be responsible for ensuring 
participants are taking IMP correctly and are fully trained on how the IMP is to be taken, as 
well as to check the IMP cards for unused tablets in the containers at each visit during the 
treatment phase.  
6.3 
Treatment Modification(s) 
The importance of adherence to the treatment schedule will be reinforced at each visit.  Non-
adherence should prompt the Investigator to identify and address the cause(s) (e.g. side 
effects).  
 
Participants that do not take: 
 
• 
Up to 7 consecutive doses of IMP doses: restart IMP, no extension of IMP required. 
• 
If more than 7 to ≤ 35 consecutive doses of IMP: restart IMP and extend the IMP 
treatment by the number of consecutive doses missed. The final treatment visit 
should also be pushed out to the date of last dose. It is not necessary to have an 
unscheduled visit at the time when the end of treatment visit would have been.   
• 
If more than 35 consecutive doses of IMP, discontinue IMP and withdraw participant 
from the trial. 
• 
If the participant misses a total (sum) of 56 cumulative missed doses, discontinue the 
IMP and withdraw the participant from the trial. 
• 
If more than 7 to ≤ 35 consecutive doses are missed, these must be made up with 
the same treatment combination or dose that was missed. 
Any participant for whom the trial IMP is discontinued (including for non-adherence) will be 
discussed with the Sponsor Medical Monitor and, if applicable, the participant will be restarted 
on trial IMP as soon as possible.  
6.4 
IMP Packaging and Labelling 
The complete formulations of the IMP, bedaquiline and pretomanid, are found in the respective 
Investigator Brochures.[8, 15] The complete formulations of moxifloxacin, pyrazinamide, 
HRZE/HR are found in the Package Inserts.[19, 20, 22, 40]  
The IMP will be packaged in weekly or bi-weekly cards as follows: 
Week 1 to 8 Cards: Dispensed Weekly 
IMP 
Strength 
Number of tablets 
Abbreviation 
Bedaquiline 
100 mg 
14 
B 
Pretomanid 
200 mg 
7 
Pa 
Moxifloxacin 
400 mg 
7 
M 
Pyrazinamide 
500 mg 
21 
Z 
 
Week 9 to 17/26 Cards: Dispensed Weekly 
IMP 
Strength 
Number of tablets 
Abbreviation 
Bedaquiline 
100 mg 
7 
B 
Pretomanid 
200 mg 
7 
Pa 
Moxifloxacin 
400 mg 
7 
M 
Pyrazinamide 
500 mg 
21 
Z 
 
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Control (HRZE/HR) Group: Dispensed Bi-weekly 
Weight Band 
Weight Range 
Number of tablets 
per weight band 
Number of tablets 
in each card 
1 
30-39 kg 
2 
28 
2 
40-54 kg 
3 
42 
3 
55-70 kg 
4 
56 
4 
≥71 kg 
5 
70 
 
A daily supplement of Vitamin B6 will be provided by the trial site to participants randomised 
to the HRZE/HR treatment arm, per each country’s National TB Treatment Guideline. 
The packaging of each weekly and biweekly cards will be labelled with, at a minimum, the 
following information: 
• 
Name of Sponsor 
• 
Name of medication 
• 
Dosage, quantity and method of administration  
• 
Reference/lot number 
• 
The statement “For Clinical Trial Use Only” 
• 
Space for completion of name of Investigator and site number 
• 
MedID: medication identification number 
• 
Storage conditions 
• 
Period of use 
• 
The statement “Keep out of reach of children” 
• 
Expiry date 
• 
Directions for use 
• 
Space for completion of participant number and visit/date dispensed 
6.5 
Blinding and Procedures for Breaking the Blind 
As this is an open label trial there is no need for blinding or procedures to break the blind. The 
trial participants, the site staff, Sponsor, and CROs will not be blinded to treatment assignment.  
6.6 
Handling, Storage and Accountability  
The Investigator or designee must confirm that the appropriate temperature conditions as per 
details on IMP labelling, have been maintained during transit for all trial IMP received and any 
discrepancies are reported and resolved before use of the trial IMP. 
Only participants randomised in the trial may receive trial IMP and only authorized site staff 
may supply or administer trial IMP. All trial IMP’s must be stored in a secure, environmentally 
controlled, and monitored (manual or automated) area in accordance with the labelled storage 
conditions with access limited to the Investigator and authorized site staff. 
The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for trial IMP accountability, reconciliation, and record maintenance (i.e., receipt, 
reconciliation, and final disposition records).  Upon completion or termination of the trial, all 
unused and/or partially used IMPs must either be returned to Sponsor (or designated vendor: 
who will arrange for destruction) or destroyed at site as agreed by the Sponsor, after final 
accountability has been confirmed. 
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The Investigator/designee will immediately inform the Sponsor of any quality issues arising 
with respect to the trial IMP. The Sponsor will take whatever action is required should such a 
situation arise. 
Further guidance and information for the handling, storage, accountability and final disposition 
of unused trial IMPs are provided in the Pharmacy Manual. 
7.0 
Trial Variables and Procedures 
The Synopsis Flowchart and Procedures in (Section 1.2) should be referenced for timing, 
sequence of assessments, and specific procedures. 
7.1 
Demographic and Background Variables and Procedures 
The following demographic and background variables will be collected: 
• 
Written Informed Consent 
• 
Visit dates 
• 
Participant disposition 
• 
Demography (date of birth, race and gender) 
• 
Inclusion and exclusion criteria 
• 
Clinically significant medical and TB treatment history (including past and current TB 
diagnosis, smoking and alcohol use) 
• 
Screening coached spot sputum samples: 
 
o Smear microscopy for acid-fast bacilli 
o Rapid molecular tests for isoniazid, rifampicin, fluoroquinolones resistance (Hain 
MTBDRplus and HainMTBRsl) 
o Liquid Culture (MGIT) for Mycobacterium tuberculosis (MTB), followed by a 
speciation test to detect presence or absence of MTB and obtain time to positivity 
(TTP) when positive. 
 
• 
Urine pregnancy test: women of childbearing potential only, whether they are sexually 
active or not (non-childbearing potential for a female participant is defined as having 
bilateral oophorectomy, bilateral tubal ligation and/or hysterectomy or has been 
postmenopausal with a history of no menses for at least 12 consecutive months). 
• 
Serology: HIV and CD4 count.  Where required by regulatory authorities or ethics 
committees, a separate (EC/IRB approved) HIV informed consent form will be obtained 
from participants: 
 
o Prior to HIV testing and on receipt of the results, participants will be counselled on 
HIV by trained counsellors if they have indicated as such on the HIV consent form. If 
requested by the participant, HIV counselling that is provided to the participant by 
the trial site should be clearly documented in the participant’s medical 
records/source.  Participants have the right to decline to know or receive their HIV 
test results. This decision should be clearly documented in the participant’s medical 
records/source.   
• 
Karnofsky Score (Appendix 5). Only for HIV positive participants. 
• 
Chest X-Ray: A chest X-ray digital image within 6 months prior to or during the 
Screening visit, will be obtained and read locally by the Investigator or designee.  Digital 
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images will be provided to the Sponsor; this process will be documented in the Chest X-
Ray / Radiology Manual.  The investigator is responsible for review and analysis of the 
chest X-ray for participant’s inclusion. 
• 
Method of birth control: male and female participants and their sexual partners 
• 
IMP details: randomization 
• 
IMP compliance and actual dosing 
• 
Concomitant medications 
7.2 
Efficacy Variables and Procedures 
Two spot sputum samples are collected, one EMS brought from home or collected in the 
hospital ward (only if the participant is hospitalised) and one spot sputum sample collected at 
the research site under the coaching and observation of the trial staff or, if no EMS sample 
was provided by the participant, 2 samples may be collected on site at least 30 minutes apart. 
The mycobacteriology sampling methodology and requirements will be described in a 
separate document, the Mycobacteriology Laboratory Manual, which will be provided prior to 
the trial start. Sputum samples may not be obtained by induction. 
The following analyses will be performed: 
• 
Liquid culture (MGIT), to detect presence or absence of MTB and obtain the TTP 
followed by a speciation test when applicable, to confirm MTB. 
 
Using these observed variables, the following derived variables will be assessed for evaluation 
of the efficacy endpoints: 
• 
Bacteriologic failure/relapse 
• 
Time to sputum culture conversion 
• 
Number of participants with sputum culture conversion 
 
Every effort must be made to collect sputum samples. However, in general, the inability to 
produce sputum is treated as being equivalent to having a negative culture (favourable) result.  
A participant who never achieves culture negative status due to the inability to produce 
sputum, but has completed Week 17 or Week 26 and post treatment completion follow-up 
(Weeks 39 to 104) and is without clinical or biological evidence of relapse, will be considered 
to have a favourable outcome. 
TB Symptoms Profile:  
• 
The TB Symptoms Profile will record participants’ ratings of the severity of common TB 
symptoms.  
 
Patient Reported Health Status Variables and Procedures:  
• 
The Patient Reported Health Status variables will be collected at the time points 
described in the Synopsis Flow Chart and Procedures (Section 1.2). Patient Reported 
Health Status will be collected using the EQ-5D-5L Health Questionnaire. This 
descriptive system consists of five health-related quality of life dimensions, each of which 
will be recorded using five levels of severity.  
 
Methodology: The Patient Reported Health Status methodology and requirements will be 
described in a separate trial Participant Questionnaires Guideline which will be provided 
prior to the trial start. 
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7.3 
Safety and Tolerability Assessments 
The following safety and tolerability variables will be collected at the time points described in 
the Synopsis Flow Chart and Procedures (Section 1.2) and assessed for evaluation of the 
safety endpoints: 
• 
The safety laboratory sampling methodology and requirements will be described in a 
separate document, the Safety Laboratory Manual, which will be provided prior to the 
trial start. The following analyses will be performed: 
 
o Full Blood Count (haemoglobin, haematocrit, red blood cell count, white blood 
cell count with differential, platelet count) 
o Clinical Chemistry (albumin, serum urea, creatinine, direct, indirect and total 
bilirubin, uric acid, total protein, ALP, AST, ALT, lipase, phosphate, sodium, 
potassium, calcium (corrected for albumin), chloride, magnesium, glucose, 
bicarbonate/CO2, creatine phosphokinase (CPK). GGT is only routinely included 
at the Screening visit (Day -9 to -1).  
o When managing participants with elevated liver enzymes at an Unscheduled visit, 
the investigator can request additional tests, in addition to the repeat LFT [e.g. 
Gamma Glutamyl Transferase (GGT), screening for Hepatitis A, B, C; to assist in 
ruling out other causes of a dysfunctional liver test (e.g. alcohol induced hepatic 
cell injury, hepatobiliary disease, hepatic viral infection)]. 
o Hepatitis A, B and C serology test to be performed at Day 1 (baseline) or where 
available, the backup PK sample at Day 1 (pre-dose) will be used to obtain a 
hepatitis A, B and C serology result for all participants already enrolled prior to 
Russia Protocol V3.0 
o Urinalysis (pH, specific gravity, protein, glucose, micro-albumin, ketones, 
bilirubin, creatinine, nitrite, sodium, urobilinogen, blood, leukocytes). Microscopy 
will be completed as follow up to abnormal urinalysis per discretion of Investigator 
• 
12-lead ECG: 
o Investigator assessment: normal or abnormal 
o Central cardiologist assessment: heart rate, PR interval, RR interval, QT, corrected 
QT Interval (QTc) (QTcB and QTcF), QRS. 
o Methodology: 
 
Timing (Synopsis Flow Chart and Procedures, Section 1.2) and registration 
technique for ECGs will be standardized for all participants and will be described 
in a separate document which will be provided prior to the trial start 
 
ECGs are to be recorded for 10 seconds 
 
ECGs are to be performed during a single visit 
 
ECGs should be done before any phlebotomy when both included in a visit 
 
For each participant, the ECGs should, to every extent possible, be collected at 
approximately the same time of day (+/- 1 hours) and in the same fed/fast state 
throughout the trial (e.g. 4 hours after lunch) 
o ECGs to be performed prior to pre- and post-dose PK sampling as described below: 
• 
Day 1: pre-dose (within 2 hours prior to dosing) 
• 
Week 2: pre-dose (within 2 hours prior to dosing), 1.5–3 hours post-dose and 4-6 
hours post-dose 
• 
Week 8: pre-dose (within 2 hours prior to dosing), 1.5–3 hours post-dose and 4-6 
hours post-dose 
• 
Week 12: pre-dose (within 2 hours prior to dosing)  
• 
Week 17 or at early withdrawal if prior to week 17: pre-dose (within 2 hours prior 
to dosing) and 1.5–3 hours post-dose 
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• 
Vital signs: 
o Vital signs (should be done before any phlebotomy in light clothing and with no 
shoes) 
o Systolic and diastolic blood pressure (mmHg) to be measured in a supine position 
(after 5 minutes of rest) using an appropriately sized cuff, and using the same type of 
sphygmomanometer, if possible by the same observer, at each relevant visit 
o Heart rate (beats per minute) 
o Respiratory rate (breaths per minute)  
o Axillary body temperature (°C) 
• 
Physical Examination:  
o Height (m) is measured at the screening visit only 
o Full (complete) and limited (gross neurological, pulmonary, cardiovascular and 
abdominal) examinations will be performed and any clinically significant findings will 
be recorded 
o Weight (kg) (in light clothing and with no shoes) 
o Using the variables of weight and height, the body mass index (BMI) will be 
calculated 
• 
Ophthalmology Slit Lamp Examination: 
o To be done by an Ophthalmologist trained on Age-Related Eye Disease Scale 2 
(AREDS2) assessment. The ophthalmology slit lamp methodology and requirements 
will be described in a separate document, the Ophthalmology Guideline. The 
following analyses will be performed: AREDS2 opacity typing and grading. 
• 
Adverse events 
• 
Investigator assessment:  
o The Investigator will review the participant status at specified visits in the Synopsis 
Flow Chart and Procedures (Section 1.2), including any time the Investigator 
determines that the participant fulfils the criteria for the primary outcome of treatment 
failure. The Investigator will assess whether TB treatment is considered a “success” 
or “failure”.  If it is considered a failure, the Investigator should specify if the 
assessment is based on bacteriology and/or clinical deterioration and/or radiological 
deterioration. 
7.4 
PK Variables and Procedures 
Plasma concentrations from sparse sampling (Synopsis Flow Chart and Procedures, 
Section 1.2) will be used to update population PK models for bedaquiline and its M2 
metabolite, pretomanid, moxifloxacin and pyrazinamide to further evaluate the effects of 
covariates on model parameters in this trial population. 
 
PK data from the current trial may be combined with prior data to enhance this population PK 
analysis. The models will be used to estimate individual exposure metrics (e.g., Cmin, Cmax, 
AUCτ, Cmean, and time above minimum inhibitory concentration) for subsequent analyses 
exploring relationships between drug exposure and efficacy and safety endpoints. 
 
If IMP is not administered during Week 2, 8 and or 17, then only a single PK sample is 
required to be obtained at any time during the visit assessment. 
7.5 
Mycobacteriology Characterization Variable and Procedures 
 
• 
Day 1 (Baseline) sputum sample (or any positive sample from Screening to Week 4, if 
the baseline cultures are contaminated or negative); 
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• 
MTB confirmed positive cultures (after the participant has previously converted to 
negative) at or after the last visit of the treatment period (Week 17 or Week 26) or visits 
with positive cultures, during the post-treatment follow-up period. 
• 
Refer to the Mycobacteriology Laboratory Manual for full details. 
 
Mycobacterial Characterization - MTB isolates (from the first MTB positive culture) will be 
processed for: 
 
• 
Rapid molecular tests for fluoroquinolones, injectables, isoniazid and rifampicin 
resistance (only on MTB positive cultures in the follow-up period); 
• 
Minimum Inhibitory Concentration (MIC) against bedaquiline, pretomanid and 
moxifloxacin  
• 
Drug Susceptibility Testing for streptomycin, rifampicin, isoniazid, ethambutol, 
moxifloxacin and pyrazinamide in liquid culture; 
• 
Extraction of organismal (MTB) DNA for whole genome sequencing (WGS), and the 
comparison of sequences from baseline and relapse isolates. 
 
If the participant’s culture converts to negative and has a MTB positive culture at or after the 
last visit of the treatment period (Week 17 and Week 26), the MTB cultures will be tested at 
the trial mycobacteriology laboratories using Hain MTBDRplus and HainMTBRsl to detect 
resistance to isoniazid, rifampicin, fluoroquinolones and injectables. 
 
All MTB isolates must be stored be stored at the local mycobacteriology laboratories, until trial 
closure. In addition, MTB isolates as well as extracted MTB DNA from the applicable baseline 
and follow-up cultures will be stored at the central mycobacteriology laboratory for potential 
further work to advance new assay tools and understanding of MTB as a pathogen for a 
maximum of 5 years after trial closure.  
 
 
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8.0 
Adverse Events 
8.1 
Definitions 
8.1.1 
Adverse Event (AE) 
Any untoward medical occurrence in a clinical investigation participant, temporally associated 
with the use of a trial treatment whether or not considered related to trial treatment. An AE can 
therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease (new or exacerbated) temporally associated with the use of a trial 
treatment, whether or not related to the trial treatment. 
8.1.2 
Serious Adverse Event (SAE) 
Any untoward medical occurrence that at any dose: 
• 
Results in death 
• 
Is life threatening (any event in which the participant was at risk of death at the time of 
the event; it does not refer to an event, which hypothetically might have caused death 
if it were more severe) 
• 
Requires inpatient hospitalisation or prolongation of existing hospitalisation; In general, 
hospitalisation signifies that the participant has been detained (usually involving at 
least an overnight stay) at the hospital or emergency ward for observation and/or 
treatment that would not have been appropriate in the physician’s office or outpatient 
setting. Complications that occur during hospitalisation are AEs. If a complication 
prolongs hospitalisation or fulfils any other serious criteria, the event is serious. When 
in doubt as to whether “hospitalisation” occurred, or was necessary, the AE should be 
considered serious. Hospitalisation for elective treatment of a pre-existing condition 
that did not worsen from baseline is not considered an AE. 
• 
Results in persistent or significant disability/incapacity; the term disability means a 
substantial disruption of a person’s ability to conduct normal life functions. This 
definition is not intended to include experiences of relatively minor medical significance 
such as uncomplicated headache, nausea, vomiting, diarrhoea, influenza, and 
accidental trauma (e.g., sprained ankle) which may interfere with or prevent everyday 
life functions but do not constitute a substantial disruption. 
• 
Is a congenital anomaly/birth defect; or 
• 
Is a medically important event 
Note:  Medical and scientific judgment should be exercised in deciding which is a medically 
important event that may not be immediately life-threatening or result in death or 
hospitalisation but may jeopardize the participant or may require medical or surgical 
intervention to prevent one of the outcomes listed above.   
Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias or convulsions that do not result in hospitalisation, or the 
development of drug dependency or drug abuse. A “suspected transmission of infectious 
agent by a medicinal product” is also considered a serious adverse event under the SAE 
criterion “Other medically important condition”.     
8.1.3 
Attribution/Causality 
• 
The Investigator is obligated to assess the relationship between trial treatment and 
each occurrence of each AE/SAE 
• 
The Investigator will use clinical judgment to determine the relationship 
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• 
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to trial IMP administration will 
be considered and investigated 
• 
The Investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment 
• 
For each AE/SAE, the Investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality 
• 
There may be situations in which an SAE has occurred and the Investigator has 
minimal information to include in the initial report to the Sponsor/designee. However, 
it is very important that the Investigator always assesses causality for every event 
before the initial transmission of the SAE data to the Sponsor/designee. 
• 
The Investigator may change his/her opinion of causality in light of follow-up 
information and send a SAE follow-up report with the updated causality assessment 
Table 8: Adverse Events Attribution/Causality Ratings 
Relatedness Rating 
Definition 
Not Related 
An AE, which is not related to the use of the drug. 
Unlikely 
An AE for which an alternative explanation is more likely, e.g., 
concomitant drug(s) or concomitant disease(s), and/or the 
relationship in time suggests that a causal relationship is 
unlikely. 
Possible 
An AE, which might be due to the use of the drug.  An 
alternative explanation, e.g., concomitant drug(s) or 
concomitant disease(s), is inconclusive.  The relationship in 
time is reasonable; therefore, the causal relationship cannot be 
excluded. 
Probable 
An AE, which might be due to the use of the drug.  The 
relationship in time is suggestive, e.g., confirmed by de-
challenge.  An alternative explanation is less likely, e.g., 
concomitant drug(s) or concomitant disease(s). 
Certain 
An AE, which is listed as a possible adverse reaction and 
cannot be reasonably explained by an alternative explanation, 
e.g., concomitant drug(s) or concomitant disease(s).   
 
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8.1.4 
Severity 
Table 9: Definitions for Adverse Event Severity Gradings 
Grade 
Severity Rating 
Definition 
GRADE 1 
Mild 
Transient or mild discomfort (< 48 hours); no medical 
intervention/therapy required. 
GRADE 2 
Moderate 
Mild to moderate limitation in activity - some 
assistance may be needed; no or minimal medical 
intervention/therapy required. 
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. 
 
See Appendix 2 for full DMID Toxicity Tables. Above ratings should be used to estimate the 
grade for abnormalities NOT found elsewhere in the Toxicity Tables. 
8.2 
Reporting 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about AE 
occurrences. 
All AEs will be collected by the Investigator from the time a participant signs the Informed 
Consent Form through to their Week 104 follow-up visit. The exception to this is early 
withdrawal participants who will only have SAEs collected from their time of early withdrawal 
to their Week 104 follow-up visit at the timepoints specified in the Synopsis Flow Chart and 
Procedures (Section 1.2) and recorded in the CRF.   
Medical occurrences that begin after obtaining informed consent will be recorded as AEs. If 
an AE started before signing of the informed consent, but is ongoing at trial start, it should be 
recorded as medical history.  If the pre-existing medical occurrence worsens during the trial, 
an AE will be recorded. 
All SAEs will be recorded and reported to the Sponsor or designee within 24 hours of the 
information becoming known to the Investigator, as noted in the SAE reporting guidelines. The 
Investigator will submit any updated SAE data to the Sponsor within 24 hours of information 
becoming known to the Investigator.  
The Sponsor/Investigator/designee will inform Regulatory Authorities and/or EC/IRB of all 
SAEs in accordance with local requirements and ICH guidelines for GCP. 
The Sponsor/designee will forward Safety Notification letters to the Investigator for submission 
to the EC/IRB. 
Investigators are not obligated to actively seek AE or SAE information in former trial 
participants. However, if the Investigator learns of any SAE, including a death, at any time 
after a participant has been discharged from the trial, and he/she considers the event to be 
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reasonably related to the trial IMP or trial participation, the Investigator must promptly notify 
the Sponsor, EC/IRB and regulatory authorities in an expedited basis, in accordance with local 
requirements and ICH GCP Guidelines. 
8.2.1 
Follow up of Adverse Events 
All AEs will be followed until: 
• 
Satisfactory clinical resolution or stabilization; or 
• 
The end of the follow-up period; and  
• 
All queries on these AEs have been resolved.   
Certain long-term AEs cannot be followed until resolution within the setting of this protocol. In 
these cases, follow-up will be the responsibility of the Investigator.  However, this will have to 
be agreed upon with the Sponsor Medical Monitor. 
The Investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor or 
representative to elucidate the nature and/or causality of the AE or SAE as fully as possible. 
This may include additional laboratory tests or investigations, histopathological examinations, 
or consultation with other health care professionals.  The Investigator should contact the 
Sponsor/designee to discuss appropriate medical follow-up if consultation is required.  
If a participant dies during participation in the trial or during a recognized follow-up period, the 
Investigator will provide the Sponsor/representative with a copy of any post-mortem findings, 
including histopathology. 
New or updated SAE information will be recorded in the originally completed CRF and 
submitted to the Sponsor within 24 hours of receipt, per the eCRF completion guidelines. 
8.2.2 
Clinical Laboratory Adverse Events 
Changes in the results of the clinical laboratory assessment results and which the Investigator 
determines are clinically significant will be reported as AEs.  It is the Investigators’ 
responsibility to review the results of all laboratory tests as they become available.  This review 
must be documented by the Investigators’ dated signature on the laboratory report.  For each 
abnormal laboratory test result, the Investigator needs to ascertain and document if this is a 
clinically significant change from baseline for that individual participant.  This determination, 
however, does not necessarily need to be made the first time an abnormal value is observed.  
The Investigator may repeat the laboratory test or request additional tests to verify the results 
of the original laboratory tests.  If this laboratory value is determined by the Investigator to be 
a clinically significant change from baseline for that participant, it is considered to be an AE. 
8.2.3 
Disease Symptoms During Trial 
Symptoms of the disease under trial (Tuberculosis) experienced by the participant while on 
the trial will be assessed by the Investigator.  If the symptom has: 
o worsened while the participant is in the trial; and  
o the Investigator assesses it as clinically significant; 
it will be recorded as an adverse event. If there is: 
o no change; and  
o the Investigator assesses the symptom as due to the participant’s TB; and  
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o not clinically significant; 
it will not be recorded as an AE and this will be noted in the participant’s source documentation. 
All TB related symptoms that meet SAE criteria will be recorded and reported as a SAE. 
8.2.4 
Overdose 
Overdose of the IMP experienced by the participant while on the trial, will be assessed by the 
Investigator to determine whether the overdose led to an adverse event, including if the taking 
of the suspected medicine led to suicidal intention and subsequent overdose of the suspected 
medicine, or other medication. In this case it will be recorded as an adverse event. If it does 
not lead to an adverse event, it will not be recorded as an AE and this will be noted in the 
participant’s source documentation. 
8.2.5 
Drug Interaction 
If the Investigator becomes aware that the participant has experienced a drug interaction 
which has resulted in an adverse event, it will be recorded as an adverse event. 
8.2.6 
Pregnancy 
The Investigator will immediately notify the Sponsor of any pregnancy that is discovered during 
IMP administration or which started during IMP administration.  Pregnancy forms will be 
completed for all pregnancies reported during the clinical trial, as defined below. In addition, 
the Investigator will report to the Sponsor any follow up information regarding the outcome of 
the pregnancy, including perinatal and neonatal outcome.  Infants will be followed-up for 6 
months.   
All women of childbearing potential will be instructed to contact the investigator immediately if 
they suspect they might be pregnant (for example, missed or late menses) at any time during 
the trial. 
If a pregnancy is suspected while the participant is receiving IMP, the IMP will be withheld 
immediately until the result of the pregnancy test is known.  If pregnancy is confirmed, the IMP 
will be permanently discontinued in an appropriate manner and the participant withdrawn from 
the trial and referred to the NTP for further management.  
Protocol-required procedures for trial discontinuation and follow-up will be performed unless 
contraindicated by the pregnancy. 
Pregnancy reporting will follow the same timelines for a SAE (see above). Instructions and 
forms will be provided separately. SAE reporting will also occur if the pregnancy outcome is a 
congenital anomaly.  This will follow the reporting procedures described above for SAE 
reporting. 
8.3 
Monitoring for Specific Toxicities  
Monitoring for specific toxicities is based upon target organs as defined in the preclinical 
toxicity studies of the Investigator’s Brochures[8, 15] and Package Inserts.[19, 20, 22, 40] 
AEs still ongoing at the end of the treatment period in the trial will be followed until satisfactory 
clinical resolution or stabilization, or until the end of the follow-up period and until all queries 
on these AEs have been resolved.   
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Grade 3 and Grade 4 laboratory abnormalities, and laboratory abnormalities considered 
clinically significant should be followed until satisfactory resolution or stabilization. 
Note: For Grade 3 or 4 laboratory toxicities, participants should have a confirmatory 
measurement within 48 hours, where possible. The recommendations for managing 
participants below assumes that the laboratory abnormalities of concern have been 
confirmed. 
 
8.3.1 
ALT, AST and Bilirubin Elevations 
The Investigator should refer to the Hepatotoxicity Management Guideline, to appropriately 
monitor significant elevations of AST, ALT or Bilirubin. A separate Hepatoxicity Management 
Guideline document has been developed to aid investigators in the management of 
participants. 
When managing participants with elevated liver enzymes at an Unscheduled visit, the 
investigator should request additional tests, in addition to the repeat LFT [e.g. Gamma 
Glutamyl Transferase (GGT), screening for Hepatitis A, B, C; to assist in ruling out other 
causes of a dysfunctional liver test (e.g. alcohol induced hepatic cell injury, hepatobiliary 
disease, hepatic viral infection)]. 
8.3.2 
Lipase 
Grade 3 (> 2.0 to ≤ 5.0 x ULN) or Grade 4 (> 5.0 x ULN): 
• 
Contact the Sponsor Medical Monitor to review. Participants with confirmed Grade 3 
or 4 elevations of lipase, the Investigator should consider pausing the full regimen, 
pending further evaluation. 
8.3.3 
Musculoskeletal System and Cardiac Muscle Myalgia 
Grade 2 (muscle tenderness at a site other than sites of injection and/or venepuncture or with 
moderate impairment of activity) or Grade 3 (severe muscle tenderness with marked 
impairment of activity) or Grade 4 (frank myonecrosis): 
• 
Participants with Grade 2 signs and symptoms should be followed closely. Participants 
with Grade 3 or 4 signs and symptoms should be discussed with the Sponsor Medical 
Monitor to consider pausing trial IMP, pending further evaluation. 
8.3.4 
Cardiac Rhythm Disturbances 
Cardiac rhythm disturbances that are Grade 3 (recurrent, persistent, symptomatic arrhythmia 
requiring treatment) or Grade 4 (unstable dysrhythmia requiring treatment): 
• 
Participants should be monitored closely.  The Investigator should discuss with the 
Sponsor Medical Monitor to consider pausing the full regimen, pending further 
evaluation. 
QTc prolongation  
If QTcF is equal to or greater than 500 msec, the ECG should be repeated and serum 
electrolytes should be evaluated. If the second ECG also has a QTcF of > 500 msec, the 
Sponsor Medical Monitor should be consulted to consider pausing the full regimen, pending 
further evaluation. 
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New left bundle branch block (LBBB) or Mobitz type 2 or complete heart block. Recordings 
with artifacts that interfere with the interpretation of the ECG should be repeated to confirm 
the findings. If the finding is from the centralized ECG machine reading the result is to be 
checked and confirmed by the Investigator.  If this is confirmed by the Investigator, dosing is 
to be paused until the reading has been confirmed by the central cardiologist and the 
participant is to be treated per the Investigator’s clinical judgment. If it is confirmed by the 
central cardiologist, the participant is to be withdrawn from the full regimen.  Contact Sponsor 
Medical Monitor to review.  
8.4 
Safety Monitoring by Data Monitoring Committee 
A Data Safety Monitoring Committee (DSMC) will be appointed for the trial. The primary 
responsibility of the DSMC will be to act in an advisory capacity to the Sponsor to safeguard 
the interests of trial participants by monitoring participant safety, assess participant risk versus 
benefit, and assess data quality and general evaluation of the trial progress. Its activities will 
be delineated in a DSMC Charter that will define the membership, responsibilities and the 
scope and frequency of data reviews.  
The DSMC will operate on a conflict-free basis independently of the Sponsor and the trial 
team. It will comprise at least 3 voting members that include at least 2 clinicians and one 
statistician.   
The DSMC may have an organizational meeting prior to commencement of the trial. The 
DSMC will have meetings where it will review unblinded data during a closed session. These 
meetings will be planned at regular intervals.  
The Sponsor or the DSMC may convene ad hoc meetings based on rates of SAEs and/or to 
review results of the futility analysis, or if safety concerns arise during the trial.  After its 
assessment, the DSMC will recommend to the Sponsor continuation, modification or 
termination of the clinical trial.  
9.0 
Statistical Analysis 
The statistical analysis plan (SAP), which will contain details of the analyses specified in this 
section, will be written and signed off prior to the interim analysis. 
There will be 3 data analyses and trial reports generated for this trial:  
 
1. When all participants have completed 8 weeks (2 months) of treatment from 
baseline.  
2. When all participants have completed 52 weeks (12 months) follow-up from start of 
therapy. 
3. When all participants have completed 104 weeks (24 months) follow-up from start of 
therapy.  
9.1 
Analysis Populations 
There will be three main analyses of the primary efficacy endpoint: An intent to treat (ITT) 
analysis; a modified intent to treat (mITT) analysis and a per protocol (PP) analysis 
• 
The ITT population is defined as all randomized participants excluding late screening 
failures. Late screening failures are participants withdrawn from treatment because 
they were found to be ineligible (late exclusions from the trial), based on data collected 
prior to randomization. 
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• 
The mITT population is defined as the ITT population with extra exclusions (described 
in the SAP). 
• 
The PP population is defined as the mITT population with extra exclusions (described 
in the SAP). 
• 
The mITT analysis will be considered primary, with consistent findings required from 
the other main analysis populations to support the primary conclusion. 
9.2 
Sample Size 
For the primary endpoint, time-to-culture conversion at 8 weeks,150 participants per arm (DS-
TB participants) will provide at more than 90% power (5% 2-sided significance) to detect a 
hazard ratio (HR) of at least 2 assuming 50% of control participants are culture negative by 8 
weeks. If only 25% of the control arm remain culture positive at 8 weeks, then this sample size 
will still retain more than 90% power to detect a HR of least 2.  This sample size also allows 
for one planned interim analysis of the primary endpoint (See Section 9.4.1) 
For the key secondary endpoint of clinical outcome at 12 months from randomization, 150 
patients per arm will provide 74% power based on assumptions using data from the largest 
most recent and completed phase 3 TB treatment trial which used the same control arm.[41]  
That is, assuming 16% unfavourable (see Section 9.4.2) in the control arm and 13% 
unassessable (see Section 9.6) at 52 weeks post randomization. A 12% margin of non-
inferiority was chosen to preserve at least 75% of the estimated control arm effect against 
placebo (estimated to be 54%)[41, 42] which is considered an acceptable proportion on which to 
declare non-inferiority of the test regimen. 
9.3 
Interim Analyses 
There is one planned interim efficacy analysis which will occur after approximately 60 
assessable participants have been randomised to the control arm and have reached the 8-
week primary endpoint. Time to culture negative status in liquid media up to 8 weeks will be 
analysed using a Cox regression model, censoring for death and lost to follow up/withdrawal 
to estimate the hazard ratio (HR). Following a review of these interim findings, the following 
considerations will be given to modify the trial objectives and sample size: 
If the observed HR (time to culture negativity, experimental arm vs. HRZE control arm) is >2, 
the sample size may be increased to adequately power the trial on the key secondary efficacy 
endpoint (clinical and microbiological outcome at 52 weeks from randomization), which will 
then become the primary efficacy endpoint. The trial efficacy objectives will be updated as 
follows: 
- 
Primary Objective 
To determine the incidence of bacteriologic failure or relapse or clinical failure at 52 
weeks from the start of treatment / randomisation.  
- 
Secondary Objectives 
To evaluate the time to culture negativity over 8 weeks, from the start of treatment / 
randomisation. 
All other trial objectives will remain unchanged. 
To achieve 90% power and overall 5% 2-sided significance after adjusting for the 
interim analysis, this will mean increasing the sample size to 225 participants per randomised 
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arm, i.e., to a total of 450 DS-TB participants (and up to 225 DR-TB participants). This 
adaptation is based on the Multi-arm Multi-stage (MAMS) framework [46,47,48] and full details 
are provided in the Statistical Analysis Plan.  
9.4 
Primary and Secondary Efficacy Endpoint Analysis 
9.4.1 
Primary Efficacy Endpoint, Time to Culture Conversion at 8 Weeks 
The primary analysis will be conducted using culture results from liquid culture (MGIT) media. 
Participants will be classified as being culture positive, culture negative, dead or unassessable 
at 8 weeks.  The proportion culture negative will be those classified as being culture negative 
divided by the total considered culture negative, culture positive or have died. This proportion 
will be estimated from the Kaplan Meier estimates from the time to culture conversion to 
negative status analysis and groups compared using a hazard ratio and 95% confidence 
interval. 
Non-inferiority of the key secondary endpoint of clinical outcome will be assessed using the 
upper bound of the one-sided 97.5% confidence interval for the difference between the 
proportion of participants who are classified as having an unfavourable status on the 
intervention less the control regimen.  If the upper bound of the one-sided 97.5% confidence 
limit for this difference in proportions is less than 12% (the margin of inferiority) the intervention 
will be non-inferior to the control arm. 
9.4.2 
Key Secondary Efficacy Endpoint, Clinical Outcome at 52 Weeks from 
Randomization  
For the key secondary endpoint of clinical outcome (bacteriologic failure or relapse or clinical 
failure), participants will be classified as having a favourable, unfavourable or unassessable 
outcome status which will be defined in detail in the SAP.  In general, participants achieving 
and maintaining culture negative status without any additional treatment will be considered 
favourable; participants who fail on treatment or relapse in follow-up will be considered 
unfavourable and participants who are not assessable (and who have not already been 
declared as unfavourable) will be considered unassessable and excluded from the analysis. 
9.4.3 
Other Secondary Efficacy Endpoints 
The secondary efficacy endpoints and analyses are as follows are: 
• 
Clinical outcome (bacteriologic failure or relapse or clinical failure) at 104 weeks from the 
start of therapy.  
• 
Proportion of participants with sputum culture conversion to negative status in liquid culture 
(MGIT) at 4, 6, 12 and 17 weeks to be explored as a potential biomarker of outcome at 
52 weeks from start of therapy. 
• 
Change from baseline in weight will be summarised and presented. 
• 
Proportion of participants experiencing a change from baseline in TB symptoms. 
• 
Change from baseline in Patient Reported Health Status will be summarised and 
presented. 
9.5 
Safety and Tolerability Assessments 
The incidence of all-cause mortality will be summarized. All adverse events will be coded using 
the Medical Dictionary for Regulatory Activities (MedDRA) and will be presented by Preferred 
Term within each MedDRA System Organ Class (SOC). 
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Treatment-emergent adverse events (TEAEs) are defined as any AE occurring or worsening 
with an onset date on or after the date of the first dose of the study medication and within 14 
days after the date of the last dose. Any adverse event that started beyond this timeframe and 
assessed as possibly related to study drug is considered treatment-emergent.  
The incidence of the following events will be summarized for further medical analysis: 
o Incidence of TEAEs; 
o Incidence of TEAEs by Severity; 
o Incidence of TEAEs by DMID toxicity grade; 
o Incidence of Drug-Related TEAEs; 
o Incidence of Serious TEAEs; 
o Incidence of TEAEs Leading to Early Withdrawal; 
o Incidence of TEAEs leading to Death. 
9.6 
Pharmacokinetics 
For each analyte and each scheduled sampling time/window, the plasma concentration will 
be summarized by descriptive statistics including the mean, SD, coefficient of variation (CV), 
median, minimum, maximum, geometric mean and geometric CV (%). 
In addition, mean and/or median concentration-versus-time graphs will be provided, with error 
bars and/or scatter plots as appropriate. 
Plasma concentrations from sparse sampling will be used to update existing population PK 
models and derive exposure metrics (e.g., Cmin, Cmax, AUC) for bedaquiline and its M2 
metabolite, pretomanid, moxifloxacin, and pyrazinamide. Effects of baseline covariates on 
exposure will be assessed; so, too, will the effects of concomitant medications including ART, 
as feasible. Data from other trials may be included to enhance the model-based analysis.  
Detailed plans for the PopPK analysis will be outlined in a separate modelling plan, and results 
will be reported in separate modelling report. 
9.7 
Pharmacokinetics/Pharmacodynamics 
Relationships will be explored between drug exposure and efficacy and safety endpoints. 
These exploratory PK/PD analyses may include HIV status as a covariate. Planning details 
and results will be included in the separate modelling plan and report. 
10.0 Records Management 
10.1 Data Collection 
All relevant CRF/eCRF pages will be completed for each participant who receives any amount 
of IMP, depending on visits attended.  For screening failure participants, specific eCRF pages 
will be completed as described in the eCRF Completion Guidelines. For participants who are 
prematurely withdrawn, all the visits the participant attended including withdrawal and follow-
up visits need to be completed. 
10.2 Source Documents 
Source documents are defined as all information in original records and certified copies of 
original records of clinical findings, observations, or other activities in a clinical trial necessary 
for the reconstruction and evaluation of the trial.  Source documents will include, but are not 
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limited to, progress notes, in-patient hospital records, electronic data, screening logs, and 
recorded data from automated instruments. 
All source documents pertaining to this trial will be maintained by the Investigators.  The 
Investigator 
must 
permit 
trial 
related 
monitoring, 
audits, 
Independent 
Ethics 
Committee/Institutional Review Board (EC/IRB) review and regulatory inspections providing 
authorized personnel direct access to source documents, including documents required to 
confirm inclusion/exclusion and relevant in-patient records while participants are on trial 
treatment. 
10.3 File Management at the Trial Centre 
It is the responsibility of the Investigators to ensure that the trial centre files are maintained in 
accordance with International Good Clinical Practice Guidelines and the ethical principles that 
have their origin in the Declaration of Helsinki. 
10.4 Records Retention at the Trial Centre 
The Investigator is obliged to retain records and data from the trial for safety reasons and for 
audit and inspection after trial completion.  The essential documents should be retained for 
not less than 2 years after the last approval of a marketing application and until there are no 
pending or contemplated marketing applications or at least 2 years have elapsed since the 
formal discontinuation of clinical development of the IMP.  Investigator should notify the 
Sponsor/designees prior to destroying any records pertaining to the trial. 
 
 
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11.0 Quality Control and Assurance  
11.1 Site Procedures 
The Investigator undertakes to perform the clinical trial in accordance with this protocol, local 
regulations, International GCP, and the ethical principles that have their origin in the 
Declaration of Helsinki. 
The Investigator undertakes to complete the CRFs according to the Sponsor’s requirements, 
in a timely, accurate and legible manner. CRF entries will be verifiable to source 
documentation other than the CRF. 
Site Standard Operating Procedures (SOPs), where available, will be adhered to for all clinical 
and bioanalytical activities relevant to the quality of the trial.  Participant compliance will be 
monitored throughout the trial. 
The Investigator will sign and date any analysis results (e.g., laboratory, ECG, etc.) to verify 
that the results have been reviewed. 
The Investigator may appoint other sub-Investigators to assist with the trial. However, the 
Investigator maintains responsibility for the trial and will supervise the sub-Investigators. 
Written EC/IRB approval of the trial will be obtained prior to involvement in the trial. 
The Investigator will ensure that all site personnel are adequately trained in GCP, local 
regulations, the protocol, IBs/package inserts and all trial procedures and requirements. 
11.2 Monitoring 
The Investigator is responsible for the validity of all data collected at the clinical site and must 
accept the various monitoring procedures employed by the Sponsor.  The purpose of 
monitoring is to verify that the rights and well-being of human participants are protected; that 
trial data are accurate, complete and verifiable with source data; and that the trial is conducted 
in compliance with the protocol, International GCP, the ethical principles that have their origin 
in the Declaration of Helsinki and the applicable regulatory requirements.  
Monitors assigned by the Sponsor will conduct regular site visits before, during and after the 
trial for monitoring various aspects of the trial, and to assure appropriate conduct of the trial in 
accordance with ICH GCP.  Visits will take place usually within a predetermined interval, but 
this may vary during the trial.  The Investigator and site staff will allow the trial monitor and 
authorized representatives of the Sponsor to (1) inspect all CRFs, written informed consent 
documents and corresponding source documents (e.g., original medical records), patient 
records and laboratory raw data, site SOPs, training records, facilities and other trial related 
systems/processes, and (2) access clinical supplies, dispensing and storage areas.  The 
Investigator and site staff should also (1) agree to assist with monitoring activities if requested 
and (2) provide adequate time and space for monitoring visits.  
The monitor will query any missing, confusing, spurious, or otherwise ambiguous data with 
the Investigator.  All queries should be resolved in a timely manner.  A monitoring log will be 
maintained recording each visit, the reason for the visit, the monitor’s signature and 
Investigator or designee’s confirmation signature. 
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11.3 Protocol Deviations 
A protocol deviation is any noncompliance with the clinical trial protocol and GCP 
requirements. The noncompliance may be either on the part of the participant, the Investigator, 
or the trial site staff. Because of deviations, corrective actions are to be developed by the site 
and implemented promptly.  
It is the responsibility of the site to use continuous vigilance to identify and report deviations. 
All deviations must be addressed in trial source documents and reported to Sponsor/designee. 
Protocol deviations must be sent to the local IRB per their guidelines. The site PI/trial staff is 
responsible for knowing and adhering to their IRB requirements. 
11.4 Auditing 
For compliance with International GCP and regulatory agency guidelines, it may be necessary 
for Sponsor-authorized Quality Assurance personnel and/or authorized personnel from an 
external regulatory agency to conduct an audit or inspection of the investigational site.  The 
purpose of an audit is to assess the quality of data about accuracy, adequacy and consistency, 
and to assure that trials are in accordance with the guidelines.  Having the highest quality data 
from trials is an essential aspect of drug development.  
The Investigator and site staff will be given sufficient notice to prepare for such visits, which 
will usually last between one and two days and may be conducted at any stage during the 
trial.  The audit will involve the review of all trial-related documentation required by GCP to be 
maintained by each site; drug storage, dispensing and return; all trial-related supplies; and 
source documents against the CRFs to assure the adequacy and accuracy of the information 
which has been recorded, including the verification of any AEs which have occurred. The 
auditors or inspectors may also review site SOPs, training records, site facilities and other trial 
related systems/processes. 
In the event of the site being notified of a Regulatory Inspection, the Sponsor will help with 
preparation.  It is essential that the Sponsor be notified of the inspection as soon as possible. 
 
 
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12.0 Ethics and Regulatory 
12.1 Basic Principles 
This research will be carried out in accordance with International GCP, the ethical principles 
that have their origin in the Declaration of Helsinki and the applicable regulatory requirements. 
12.2 Independent Ethics Committee/Institutional Review Board (EC/IRB) 
Review 
The protocol and required trial related documents will be reviewed by the sites respective 
EC/IRB.  The trial will not start until the EC/IRB has approved the protocol, written informed 
consent, any written information to be provided to the participant or any modification thereof, 
plus any other trial related documents required for review.  The EC/IRB shall be constituted 
and shall operate in accordance with International GCP, the ethical principles that have their 
origin in the Declaration of Helsinki. The Investigator will maintain an accurate and complete 
record of all submissions made to, and responses from the IRB/EC.  The records should be 
filed in the Investigator’s Trial File, and copies will be sent to the Sponsor. 
12.3 Regulatory Authorities 
The Regulatory Authorities will receive the protocol, amendments, reports on SAEs, and the 
Integrated Clinical Trial Report according to national regulations.  As required by local 
legislation, written approval will be obtained from the Regulatory Authorities prior to 
commencement of the trial and implementation of e.g. amendments as applicable. 
12.4 Informed Consent 
Written informed consent will be obtained from all participants (or legally acceptable 
representative) before any trial-related procedures (including any screening or pre-treatment 
procedures) are performed.  Investigators may discuss the availability of the trial and the 
opportunity for entry with a potential participant without first obtaining consent.  However, 
informed consent must be obtained and documented prior to initiation of any procedures that 
are performed solely for determining eligibility for research, including withdrawal from current 
medication(s).  When this is done in anticipation of, or in preparation for, the research, it is 
part of the research. 
The Investigators have both ethical and legal responsibility to ensure that each participant 
being considered for inclusion in this trial is given a full explanation of the protocol.  Participants 
must be informed that their participation is voluntary.  The Investigator or his/her 
representative will explain the nature of the trial to the participant or his/her legally authorized 
representative and answer all questions regarding the trial. This shall be documented on a 
written informed consent form that shall be approved by the same EC/IRB responsible for 
approval of this protocol.  Each informed consent form shall include the elements required by 
the international GCP and must adhere to the ethical principles that have their origin in the 
Declaration of Helsinki.  
The trial will be included and updated in the appropriate Country registry and referenced in 
the informed consent forms (ICF). 
Once the appropriate essential information has been provided to the participant and fully 
explained by the Investigators (or qualified designees) and it is felt that the participant 
understands the implications of participating, the EC/IRB approved written ICF will be signed 
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and dated by both the participant and the person obtaining consent (Investigators or 
designees), and by any other parties required by the EC/IRB. Ongoing participants must be 
re-consented to the most current version of the ICF(s) during their participation in the trial. 
The original signed ICFs will be kept with the trial records and a copy of ICF will be provided 
to the participant or the participant’s legally authorized representative.  Another copy of the 
signed ICF and a source document identifying the trial and recording the dates of participation 
will be placed in the participant’s medical record. 
The monitor will inspect the original completed ICFs for all participants. 
12.5 Confidentiality 
All site staff, the Sponsor, and any Sponsor representatives will preserve the confidentiality of 
all participants taking part in the trial, in accordance with International GCP, applicable local 
legislation/regulations.  Subject to the requirement for source data verification by the trial 
personnel by reference to the participant’s notes, confidentiality of all participant identities will 
be maintained.  Unique identifiers will be used on the CRF and in all trial correspondence, as 
permitted.  No material bearing a participant’s name will be kept on file by the Sponsor. The 
written informed consent will contain a clause granting permission for review of the 
participants’ source data by the Sponsor or designees. 
 
 
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13.0 Publication Policy 
The definition of publication for this purpose is any public presentation of the data emerging 
from this trial.  
All unpublished information given to the Investigator by the Sponsor shall not be published or 
disclosed to a third party, other than to the responsible EC/IRB, within the understanding of 
the confidentiality of their nature, without the prior written consent of the Sponsor. 
Results of this research will be submitted for publication as soon as feasible upon completion 
of the trial in the form of a joint publication(s) between Sponsor and Investigator(s), including 
site clinical and laboratory Investigators, as appropriate. Publication and authorship will be in 
accord with the International Association of Journal Editors.[43]  
Because the trial is funded, in whole or in part, by the Bill and Melinda Gates Foundation (the 
“Foundation”), all peer-reviewed published research relating to the Trial must comply with the 
Foundation’s 
Open 
Access 
Policy 
as 
described 
from 
time 
to 
time 
at 
http://www.gatesfoundation.org/How-We-Work/General-Information/Open-Access-Policy 
. 
Specifically, (a) all peer-reviewed published research relating to the trial must be submitted for 
publication by TB Alliance through the Chronos Open Access Publishing Service established 
by the Foundation to ensure the immediate and unrestricted access and reuse of all peer-
reviewed published research funded, in whole or in part, by the Foundation without any 
embargo period, and (b) all data underlying the peer-reviewed published research results must 
be immediately made accessible and open to the public in accordance with the Foundation’s 
Open Access Policy. 
 
14.0 Protocol Amendment Policy 
Any change to the protocol will be affected by means of a protocol amendment.  Any changes 
which affect participant safety or welfare will be submitted to the EC/IRB and Regulatory 
Authorities prior to implementation.  The Investigator, EC/IRB, and Sponsor must agree on all 
amendments.  No amendment will be implemented until approved by the relevant authorities 
and/or EC/IRB and signed by all required parties.  Exceptions to this are when the Investigator 
considers that the participant’s safety is compromised.  
Protocol amendments detailing minor administrative changes should be submitted by the 
Investigator to the EC/IRB and Regulatory Authorities, either for notification purposes or 
approval as appropriate. 
 
15.0 Sponsor, Financial Aspects, Insurance and Indemnity 
The trial Sponsor is the TB Alliance (TBA).  The TB Alliance is a not for profit, product 
development partnership accelerating the discovery and development of new TB drugs that 
will shorten treatment, be effective against susceptible and resistant strains, be compatible 
with antiretroviral therapies for those HIV-TB participants currently on such therapies and 
improve treatment of latent infection. 
The TB Alliance works with public and private partners worldwide.  It is committed to ensuring 
that approved new regimens are affordable, adopted and available to those who need them. 
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Confidential 
Page 85 of 101 
The TB Alliance operates with funding mainly from the Bill & Melinda Gates Foundation, the 
Netherlands Ministry of Foreign Affairs (DGIS), the United Kingdom Department for 
International Development (DFID), and the United States Agency for International 
Development (USAID). 
The participants will not receive any incentives for their involvement in the trial.  The Sponsor 
has made provision to reimburse the participants for out-of-pocket expenses such as travelling 
to and from the trial site and other miscellaneous costs as a result of their trial participation. 
The Sponsor certifies that it has liability insurance coverage for itself and will provide an 
associated certificate upon request.  The insurance does not relieve the Investigators of the 
obligation to maintain their own liability insurance as required by applicable law. The Sponsor 
does not assume any obligation for the medical treatment of other injuries and illnesses.
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Protocol Version: Russia V3.0 / 1 OCT 2019, Incorporating Protocol V4.0 / 30 SEP 2019 
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CONFIDENTIAL 
Page 86 of 101 
16.0 References 
1. 
Maggi N, Pasqualucci CR, Ballotta R, Sensi P. Rifampicin: a new orally active 
rifamycin. Chemotherapy. 1966;11(5):285-292. 
2. 
Jindani A, Aber VR, Edwards EA, Mitchison DA. The early bactericidal activity of drugs 
in patients with pulmonary tuberculosis. Am Rev Respir Dis. 1980;121(6):939-949. 
3. 
Dietze R, Teixeira L, Rocha LM, Palaci M, Johnson JL, Wells C, et al. Safety and 
bactericidal activity of rifalazil in patients with pulmonary tuberculosis. Antimicrob 
Agents Chemother. 2001;45(7):1972-1976. 
4. 
Donald PR, Sirgel FA, Venter A, Parkin DP, Seifart HI, van de Wal BW, et al. Early 
bactericidal activity of antituberculosis agents. Expert Rev Anti Infect Ther. 
2003;1(1):141-155. 
5. 
Johnson JL, Hadad DJ, Boom WH, Daley CL, Peloquin CA, Eisenach KD, et al. Early 
and extended early bactericidal activity of levofloxacin, gatifloxacin and moxifloxacin 
in pulmonary tuberculosis. Int J Tuberc Lung Dis. 2006;10(6):605-612. 
6. 
Rustomjee R, Diacon AH, Allen J, Venter A, Reddy C, Patientia RF, et al. Early 
bactericidal activity and pharmacokinetics of the diarylquinoline TMC207 in treatment 
of pulmonary tuberculosis. Antimicrob Agents Chemother. 2008;52(8):2831-2835. 
7. 
Package insert: Sirturo.  Janssen Therapeutics, September 2014 Available at: 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/204384s000lbl.pdf. 
8. 
Investigator’s Brochure: TMC207 (bedaquiline).  Edition 10. Janssen Research and 
Development, 02 Dec 2016. 
9. 
Koul A, Dendouga N, Vergauwen K, Molenberghs B, Vranckx L, Willebrords R, et al. 
Diarylquinolines target subunit c of mycobacterial ATP synthase. Nat Chem Biol. 
2007;3(6):323-324. 
10. 
Andries K, Verhasselt P, Guillemont J, Gohlmann HW, Neefs JM, Winkler H, et al. A 
diarylquinoline drug active on the ATP synthase of Mycobacterium tuberculosis. 
Science. 2005;307(5707):223-227. 
11. 
Huitric E, Verhasselt P, Andries K, Hoffner SE. In vitro antimycobacterial spectrum of 
a 
diarylquinoline 
ATP 
synthase 
inhibitor. 
Antimicrob 
Agents 
Chemother. 
2007;51(11):4202-4204. 
12. 
Koul A, Vranckx L, Dendouga N, Balemans W, Van den Wyngaert I, Vergauwen K, et 
al. Diarylquinolines are bactericidal for dormant mycobacteria as a result of disturbed 
ATP homeostasis. J Biol Chem. 2008;283(37):25273-25280. 
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Protocol Number: NC-008 (B-Pa-M-Z) 
Protocol Version: Russia V3.0 / 1 OCT 2019, Incorporating Protocol V4.0 / 30 SEP 2019 
Protocol Name: 
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CONFIDENTIAL 
Page 87 of 101 
13. 
Nuermberger E, Rosenthal I, Tyagi S, Williams KN, Almeida D, Peloquin CA, et al. 
Combination chemotherapy with the nitroimidazopyran PA-824 and first-line drugs in 
a murine model of tuberculosis. Antimicrob Agents Chemother. 2006;50(8):2621-2625. 
14. 
Nuermberger E, Tyagi S, Tasneen R, Williams KN, Almeida D, Rosenthal I, et al. 
Powerful bactericidal and sterilizing activity of a regimen containing PA-824, 
moxifloxacin, and pyrazinamide in a murine model of tuberculosis. Antimicrob Agents 
Chemother. 2008;52(4):1522-1524. 
15. 
Investigator's Brochure: Pretomanid (PA-824).  Global Alliance for TB Drug 
Development, 22 December 2016. 
16. 
Stover CK, Warrener P, VanDevanter DR, Sherman DR, Arain TM, Langhorne MH, et 
al. A small-molecule nitroimidazopyran drug candidate for the treatment of 
tuberculosis. Nature. 2000;405(6789):962-966. 
17. 
Lenaerts AJ, Gruppo V, Marietta KS, Johnson CM, Driscoll DK, Tompkins NM, et al. 
Preclinical testing of the nitroimidazopyran PA-824 for activity against Mycobacterium 
tuberculosis in a series of in vitro and in vivo models. Antimicrob Agents Chemother. 
2005;49(6):2294-2301. 
18. 
Tyagi S, Nuermberger E, Yoshimatsu T, Williams K, Rosenthal I, Lounis N, et al. 
Bactericidal activity of the nitroimidazopyran PA-824 in a murine model of tuberculosis. 
Antimicrob Agents Chemother. 2005;49(6):2289-2293. 
19. 
Package insert: Moxifloxacin.  MacLeods Pharmaceuticals Ltd., January 2014. 
20. 
Package insert: Pyrazinamide.  MacLeods Pharmaceuticals Ltd., November 2012. 
21. 
Zhang Y, Mitchison D. The curious characteristics of pyrazinamide: a review. Int J 
Tuberc Lung Dis. 2003;7(1):6-21. 
22. 
Package insert: HRZE Combination Tablets.  MacLeods Pharmaceuticals Ltd., 
September 2011. 
23. 
World Health Organization. Global tuberculosis report 2012.  2015. WHO Press, 
Geneva, Switzerland. 
24. 
Pym AS, Diacon AH, Tang S-J, Conradie F, Danilovits M, Chuchottaworn C, et al. 
Bedaquiline safety data in a broad patient population treated for drug-resistant TB 
including XDR-TB (C209 trial). Tuberculosis. 2016;47:394-402. 
25. 
Lee M, Lee J, Carroll MW, Choi H, Min S, Song T, et al. Linezolid for treatment of 
chronic extensively drug-resistant tuberculosis. N Engl J Med. 2012;367(16):1508-
1518. 
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Protocol Version: Russia V3.0 / 1 OCT 2019, Incorporating Protocol V4.0 / 30 SEP 2019 
Protocol Name: 
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CONFIDENTIAL 
Page 88 of 101 
26. 
A Phase 3 Trial Assessing the Safety and Efficacy of Bedaquiline Plus PA-824 Plus 
Linezolid in Subjects With Drug Resistant Pulmonary Tuberculosis. ClinicalTrials.gov,  
Available at: https://www.clinicaltrials.gov/ct2/show/NCT02333799, Updated 28 
February 2017. 
27. 
Mdluli K, Nuermberger E. Pre-Clinical Drug Combination Trials to Identify Novel 
Regimens for TB.  2009. in Recent Advances in TB Drug Development Symposium. 
40th Union World Conference, International Union Against TB and Lung Disease. 
Cancun, Mexico. 
28. 
Tasneen R, Li SY, Peloquin CA, Taylor D, Williams KN, Andries K, et al. Sterilizing 
activity of novel TMC207- and PA-824-containing regimens in a murine model of 
tuberculosis. Antimicrob Agents Chemother. 2011;55(12):5485-5492. 
29. 
Singh R, Manjunatha U, Boshoff HI, Ha YH, Niyomrattanakit P, Ledwidge R, et al. PA-
824 kills nonreplicating Mycobacterium tuberculosis by intracellular NO release. 
Science. 2008;322(5906):1392-1395. 
30. 
Manjunatha U, Boshoff HI, Barry CE. The mechanism of action of PA-824: Novel 
insights from transcriptional profiling. Commun Integr Biol. 2009;2(3):215-218. 
31. 
Manjunatha UH, Boshoff H, Dowd CS, Zhang L, Albert TJ, Norton JE, et al. 
Identification of a nitroimidazo-oxazine-specific protein involved in PA-824 resistance 
in Mycobacterium tuberculosis. Proc Natl Acad Sci U S A. 2006;103(2):431-436. 
32. 
Nuermberger E, Tyagi S, Williams KN, Rosenthal I, Bishai WR, Grosset JH. 
Rifapentine, moxifloxacin, or DNA vaccine improves treatment of latent tuberculosis in 
a mouse model. Am J Respir Crit Care Med. 2005;172(11):1452-1456. 
33. 
Tasneen R, Betoudji F, Tyagi S, Li SY, Williams K, Converse PJ, et al. Contribution of 
Oxazolidinones to the Efficacy of Novel Regimens Containing Bedaquiline and 
Pretomanid in a Mouse Model of Tuberculosis. Antimicrob Agents Chemother. 
2015;60(1):270-277. 
34. 
Diacon AH, Dawson R, du Bois J, Narunsky K, Venter A, Donald PR, et al. Phase II 
dose-ranging trial of the early bactericidal activity of PA-824. Antimicrob Agents 
Chemother. 2012;56(6):3027-3031. 
35. 
Burman WJ, Goldberg S, Johnson JL, Muzanye G, Engle M, Mosher AW, et al. 
Moxifloxacin versus ethambutol in the first 2 months of treatment for pulmonary 
tuberculosis. Am J Respir Crit Care Med. 2006;174(3):331-338. 
36. 
Rustomjee R, Lienhardt C, Kanyok T, Davies GR, Levin J, Mthiyane T, et al. A Phase 
II trial of the sterilising activities of ofloxacin, gatifloxacin and moxifloxacin in pulmonary 
tuberculosis. Int J Tuberc Lung Dis. 2008;12(2):128-138. 
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Protocol Version: Russia V3.0 / 1 OCT 2019, Incorporating Protocol V4.0 / 30 SEP 2019 
Protocol Name: 
SimpliciTB 
 
CONFIDENTIAL 
Page 89 of 101 
37. 
Conde MB, Efron A, Loredo C, De Souza GR, Graca NP, Cezar MC, et al. Moxifloxacin 
versus ethambutol in the initial treatment of tuberculosis: a double-blind, randomised, 
controlled phase II trial. Lancet. 2009;373(9670):1183-1189. 
38. 
Dorman SE, Johnson JL, Goldberg S, Muzanye G, Padayatchi N, Bozeman L, et al. 
Substitution of moxifloxacin for isoniazid during intensive phase treatment of 
pulmonary tuberculosis. Am J Respir Crit Care Med. 2009;180(3):273-280. 
39. 
Investigator's Brochure: Bayer HealthCare AG, moxifloxacin.  01 October 2011. 
40. 
Package insert: HR Combination Tablets.  MacLeods Pharmaceuticals Ltd., 
September 2011. 
41. 
Gillespie SH, Crook AM, McHugh TD, Mendel CM, Meredith SK, Murray SR, et al. 
Four-month moxifloxacin-based regimens for drug-sensitive tuberculosis. N Engl J 
Med. 2014;371(17):1577-1587. 
42. 
Tiemersma EW, van der Werf MJ, Borgdorff MW, Williams BG, Nagelkerke NJ. Natural 
history of tuberculosis: duration and fatality of untreated pulmonary tuberculosis in HIV 
negative patients: a systematic review. PLoS One. 2011;6(4):e17601. 
43. 
Recommendations for the Conduct, Reporting, Editing, and Publication of Scholarly 
work 
in 
Medical 
Journals. 
 
Available 
at: 
http://www.icmje.org/icmje-
recommendations.pdf, Updated December 2016. 
44.  
Reuben A (2004). “Hy’s Law”. Landmarks in Hepatology 39(2): 574-578. 
45. 
Temple 
RJ 
(2006). 
“Hy’s 
Law: 
predicting 
serious 
hepatotoxicity”. 
Pharmacoepidemoiology and Drug Safety 15: 241-243. 
46. 
Parmar, M.K., et al., Testing many treatments within a single protocol over 10 years at 
MRC Clinical Trials Unit at UCL: Multi-arm, multi-stage platform, umbrella and basket 
protocols. Clin Trials, 2017. 14(5): p. 451-461. 
47. 
Bratton, D.J., P.P. Phillips, and M.K. Parmar, A multi-arm multi-stage clinical trial 
design for binary outcomes with application to tuberculosis. BMC Med Res Methodol, 
2013. 13: p. 139. 
48. 
Royston, P., et al., Designs for clinical trials with time-to-event outcomes based on 
stopping guidelines for lack of benefit. Trials, 2011. 12: p. 81. 
 
 
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Protocol Version: Russia V3.0 / 1 OCT 2019, Incorporating Protocol V4.0 / 30 SEP 2019 
Protocol Name: 
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CONFIDENTIAL 
Page 90 of 101 
Appendices 
Appendix 1: The IUATLD Scale 
The IUATLD scale proposes five groups for reporting the results of reading smears for acid 
fast bacilli. They should be recorded as follows: 
FINDING 
RECORDING 
No acid-fast bacilli found in at least 100 fields 
negative 
1 to 9 acid-fast bacilli per 100 fields 
scanty positive 
10 to 99 acid-fast bacilli per 100 fields 
+ 
1 to 10 acid-fast bacilli per field in at least 50 fields 
++ 
More than 10 acid-fast bacilli per field in at least 20 fields 
+++ 
Reference: The Public Health Service National Tuberculosis Reference Laboratory and the 
National Laboratory Network. Minimum Requirements, Role and Operation in a Low-Income 
Country. International Union Against Tuberculosis and Lung Disease 1998. 
 
 
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CONFIDENTIAL 
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Appendix 2: Division of Microbiology and Infectious Disease (DMID) Toxicity 
Table 
Source:  U.S. National Institute of Allergy and Infectious Diseases, DMID, November 2007 
(Draft) 
ABBREVIATIONS:  Abbreviations utilized in the Table: 
ULN = Upper Limit of Normal 
LLN = Lower Limit of Normal 
Rx = Therapy 
Req = Required 
Mod = Moderate 
IV  = Intravenous 
ADL = Activities of Daily Living 
Dec = Decreased 
 
ESTIMATING SEVERITY GRADE 
For abnormalities NOT found elsewhere in the Toxicity Tables use the scale below to estimate 
grade of severity: 
Grade 
Severity Rating 
Definition 
GRADE 1 
Mild 
Transient or mild discomfort (< 48 hours); no medical 
intervention/therapy required. 
GRADE 2 
Moderate 
Mild to moderate limitation in activity - some assistance may be 
needed; no or minimal medical intervention/therapy required. 
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. 
 
SERIOUS OR LIFE-THREATENING AEs 
ANY clinical event deemed by the clinician to be serious or life-threatening should be 
considered a grade 4 event. Clinical events considered to be serious or life-threatening 
include, but are not limited to: seizures, coma, tetany, diabetic ketoacidosis, disseminated 
intravascular coagulation, diffuse petechiae, paralysis, acute psychosis, severe depression. 
COMMENTS REGARDING THE USE OF THESE TABLES 
• 
Standardized and commonly used toxicity tables (Division of Acquired Immune Deficiency 
Syndrome (AIDS), NCI’s Common Toxicity Criteria (CTC), and World Health Organization 
(WHO)) have been adapted for use by the DMID and modified to better meet the needs of 
participants in DMID trials. 
• 
For parameters not included in the following Toxicity Tables, sites should refer to the 
“Guide For Estimating Severity Grade” located above. 
• 
Criteria are generally grouped by body system. 
• 
Some protocols may have additional protocol specific grading criteria, which will 
supersede the use of these tables for specified criteria. 
 
 
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HEMATOLOGY 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Hemoglobin 
9.5 - 10.5 gm/dL 
8.0  - 9.4gm/dL 
6.5 - 7.9 gm/dL 
< 6.5 gm/dL 
Absolute 
Neutrophil Count 
1000-1500/mm3 
750-999/mm3 
500-749/mm3 
<500/mm3 
Platelets 
75,000- 
99,999/mm3 
50,000- 
74,999/mm3 
20,000- 
49,999/mm3 
<20,000/mm3 
WBCs 
11,000-13,000/ 
mm3 
13,000-15,000 
/mm3 
15,000- 
30,000/mm3 
>30,000 or <1,000 
/mm3 
% 
Polymorphonuclear 
Leucocytes + Band 
 
> 80% 
 
90 – 95% 
 
>95% 
 
---------- 
 
 
Abnormal Fibrinogen 
Low: 
100-200 
mg/dL High: 
400-600 mg/dL 
Low: 
<100 
mg/dL 
High: 
>600 mg/dL 
Low: 
< 50 mg/dL 
 
---------- 
Fibrinogen 
associated with 
gross bleeding 
or with 
disseminated 
coagulation 
Fibrin Split Product 
20-40 mcg/ml 
41-50 mcg/ml 
51-60 mcg/ml 
> 60 mcg/ml 
Prothrombin Time (PT) 
1.01 - 1.25 x ULN 
1.26-1.5 x ULN 
1.51 -3.0 x ULN 
>3 x ULN 
Activated 
Partial 
Thromboplastin 
1.01 -1.66 x ULN 
1.67 - 2.33 x ULN 
2.34 - 3 x ULN 
> 3 x ULN 
Methemoglobin 
5.0 - 9.9 % 
10.0 - 14.9 % 
15.0 - 19.9% 
> 20.0 % 
 
CHEMISTRIES 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
 
Hyponatremia 
 
130-135 
mEq/L 
 
123-129 mEq/L 
 
116-122 mEq/L 
< 116 mEq/L or 
abnormal sodium with 
mental status 
changes or seizures 
 
Hypernatremia 
 
146-150 
mEq/L 
 
151-157 mEq/L 
 
158-165 mEq/L 
> 165 mEq/L or 
abnormal sodium with 
mental status 
changes or seizures 
 
 
Hypokalemia 
 
 
3.0 
- 
3.4
mEq/L 
 
 
2.5 - 2.9 mEq/L 
2.0 - 2.4 mEq/L or 
intensive 
replacement 
therapy or 
hospitalization 
required 
 
< 2.0 mEq/L or 
abnormal potassium with 
paresis, ileus or life-
threatening arrhythmia 
 
Hyperkalemia 
 
5.6 
- 
6.0
mEq/L 
 
6.1 - 6.5 mEq/L 
 
6.6 - 7.0 mEq/l 
> 7.0 mEq/L or 
abnormal potassium 
with life- threatening 
arrhythmia 
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Hypoglycemia 
 
55-64 mg/dL
 
40-54 mg/dL 
 
30-39 mg/dL 
<30 mg/dL or 
abnormal glucose with 
mental status changes 
or coma 
Hyperglycemia 
(non-fasting and no 
prior diabetes) 
 
116 
- 
160
mg/dL 
 
161- 250 mg/dL 
 
251 - 500 mg/dL 
> 500 mg/dL or 
abnormal glucose with 
ketoacidosis or seizures 
Hypocalcemia 
(corrected 
for 
albumin) 
 
8.4 
- 
7.8
mg/dL 
 
7.7 - 7.0 mg/dL 
 
6.9 - 6.1 mg/dL 
< 6.1 mg/dL or 
abnormal calcium with 
life threatening 
Hypercalcemia 
(correct for albumin) 
 
10.6 
- 
11.5
mg/dL 
11.6 - 12.5 
mg/dL 
 
12.6 - 13.5 mg/dL 
> 13.5 mg/dL or 
abnormal calcium with 
life threatening 
arrhythmia 
 
Hypomagnesemia 
 
1.4 
- 
1.2
mEq/L 
 
1.1 - 0.9 mEq/L 
 
0.8 - 0.6 mEq/L 
< 0.6 mEq/L or 
abnormal 
magnesium with life- 
threatening 
 
Hypophosphatemia 
 
2.0 
- 
2.4
mg/dL 
1.5 -1.9 mg/dL 
or replacement 
Rx required 
1.0 
-1.4 
mg/dL 
intensive therapy or 
hospitalization 
required 
< 1.0 mg/dL or 
abnormal phosphate 
with life- threatening 
arrhythmia 
Hyperbilirubinemia 
(when accompanied 
by any increase in 
other liver function 
 
 
1.1 - <1.25 x
ULN 
 
1.25 - <1.5 x 
ULN 
 
 
1.5 – 1.75 x ULN 
 
 
> 1.75 x ULN 
Hyperbilirubinemia 
(when 
other 
liver 
function are in the 
normal range) 
 
1.1 - <1.5 x
ULN 
 
1.5 - <2.0 x ULN 
 
2.0 – 3.0 x ULN 
 
> 3.0 x ULN 
BUN 
1.25 - 2.5 x
ULN 
2.6 - 5 x ULN 
5.1 - 10 x ULN 
> 10 x ULN 
Hyperuricemia (uric 
acid) 
7.5 
– 
10.0
mg/dL 
10.1 – 12.0 
mg/dL 
12.1 – 15.0 mg/dL 
>15.0 mg/dL 
Creatinine 
1.1 - 1.5 x
ULN 
1.6 - 3.0 x ULN 
3.1 - 6 x ULN 
> 6 x ULN or 
dialysis 
required 
 
ENZYMES 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
AST (SGOT) 
1.1 - <2.0 x ULN 
2.0 – <3.0 x ULN 
3.0 – 8.0 x ULN 
> 8 x ULN 
ALT (SGPT) 
1.1 - <2.0 x ULN 
2.0 – <3.0 x ULN 
3.0 – 8.0 x ULN 
> 8 x ULN 
GGT 
1.1 - <2.0 x ULN 
2.0 – <3.0 x ULN 
3.0 – 8.0 x ULN 
> 8 x ULN 
Alkaline Phosphatase 
1.1 - <2.0 x ULN 
2.0 – <3.0 x ULN 
3.0 – 8.0 x ULN 
> 8 x ULN 
Amylase 
1.1 - 1.5 x ULN 
1.6 - 2.0 x ULN 
2.1 - 5.0 x ULN 
> 5.1 x ULN 
Lipase 
1.1 - 1.5 x ULN 
1.6 - 2.0 x ULN 
2.1 - 5.0 x ULN 
> 5.1 x ULN 
 
 
 
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CONFIDENTIAL 
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URINALYSIS 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
 
Proteinuria 
1+ or 200 mg - 
1 
gm 
loss/day 
2-3+ or 1- 2 
gm 
loss/day 
4+ or 2-3.5 
gm 
loss/day 
nephrotic 
syndrome or > 
3.5 gm loss/day 
 
Hematuria 
 
microscopic only 
<10 rbc/hpf 
 
gross, no clots 
>10 rbc/hpf 
gross, with or 
without clots, 
OR red blood 
cell casts 
obstructive 
or required 
transfusion 
 
CARDIOVASCULAR 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Cardiac Rhythm 
 
asymptomatic, 
transient signs, no 
Rx required 
recurrent/persistent 
; symptomatic Rx 
required 
unstable 
dysrythmia; 
hospitalization 
and 
treatment 
required 
Hypertension 
transient increase 
> 20 mm/Hg; 
no treatment 
recurrent, chronic 
increase 
> 
20mm/Hg. 
/treatment required 
acute 
treatment 
required; 
outpatienttreatm 
ent 
or 
hospitalization 
possible 
end 
organ 
damage 
or 
hospitalization 
required 
Hypotension 
transient 
orthostatic 
hypotension 
with heart rate 
increased 
by 
<20 beat/min or 
decreased 
by 
<10 
mm 
Hg 
systolic BP, No 
treatment 
required 
symptoms due to 
orthostatic 
hypotension or BP 
decreased by <20 
mm 
Hg 
systolic; 
correctable with oral 
fluid treatment 
requires IV fluids; 
no hospitalization 
required 
mean 
arterial 
pressure <60mm/ 
Hg or end organ 
damage or shock; 
requires 
hospitalization 
and vasopressor 
treatment 
Pericarditis 
minimal effusion 
mild/moderate 
asymptomatic 
effusion, 
no 
treatment 
symptomatic 
effusion; pain; EKG 
changes 
tamponade; 
pericardiocentesis 
or 
surgery 
required 
Hemorrhage, 
Blood Loss 
microscopic/occult mild, no transfusion 
gross blood loss; 
1-2 
units 
transfused 
massive 
blood loss; > 
3 
units 
transfused 
 
 
 
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CONFIDENTIAL 
Page 95 of 101 
RESPIRATORY 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
 
Cough 
Transient 
- 
no 
treatment 
persistent cough; 
treatment 
responsive 
Paroxysmal 
cough; 
uncontrolled with 
treatment 
 
-------------------- 
 
Bronchospasm, 
Acute 
transient; no 
treatment; 70% 
- 
80% FEV1 of 
peak flow 
requires treatment; 
normalizes with 
bronchodilator; 
FEV1 
50% - 70% (of 
peak flow) 
no normalization 
with 
bronchodilator;FEV1 
25% - 50% of 
peak flow; or 
retractions 
present 
cyanosis: FEV1 
< 25% of peak 
flow or 
intubation 
necessary 
Dyspnea 
dyspnea on exertion 
dyspnea 
with 
normal 
activity 
dyspnea at rest 
dyspnea 
requiring 
Oxygen 
therapy 
 
GASTROINTESTINAL 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Nausea 
mild 
or 
transient; 
maintains 
reasonable 
intake 
moderate 
discomfort; intake 
decreased 
significantly; some 
activity limited 
no 
significant 
intake; requires 
IV fluids 
hospitalization 
required; 
Vomiting 
1 episode in 
24 hours 
2-5 episodes in 24 
hours 
>6 episodes in 
24 
hours or 
needing 
IV 
fluids 
physiologic 
consequences 
requiring 
hospitalization 
or 
requiring 
parenteral nutrition 
Constipation 
requiring stool 
softener 
or 
dietary 
modification 
requiring laxatives 
obstipation 
requiring 
manual 
evacuation or 
enema 
obstruction or toxic 
megacolon 
Diarrhea 
mild or transient; 
3- 
4 
loose 
stools/day 
or 
mild 
diarrhea 
last < 1 week 
moderate 
or 
persistent; 5-7 loose 
stools/day 
or 
diarrhea lasting >1 
week 
>7 
loose 
stools/day 
or 
bloody diarrhea; 
or 
orthostatic 
hypotension 
or 
electrolyte 
imbalance or >2L 
IV fluids required 
hypotensive shock 
or 
physiologic 
consequences 
requiring 
hospitalization 
Oral 
Discomfort/Dysphagia 
mild discomfort; 
no 
difficulty 
swallowing 
some limits on 
eating/drinking 
eating/talking 
very 
limited; 
unable 
to 
swallow 
solid 
foods 
unable to drink 
fluids; requires IV 
fluids 
 
 
 
834 of 852


TB Alliance 
Protocol Number: NC-008 (B-Pa-M-Z) 
Protocol Version: Russia V3.0 / 1 OCT 2019, Incorporating Protocol V4.0 / 30 SEP 2019 
Protocol Name: 
SimpliciTB 
 
CONFIDENTIAL 
Page 96 of 101 
NEUROLOGICAL 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Neuro-Cerebellar 
slight incoordination 
dysdiadochokinesis 
intention tremor, 
dysmetria, slurred 
speech; 
nystagmus 
locomotor ataxia 
incapacitated 
Psychiatric 
mild anxiety or 
depression 
moderate anxiety 
or 
depression; 
therapy required; 
change in normal 
routine 
severe 
mood 
changes 
requiring 
therapy; or suicidal 
ideation; 
or 
aggressive ideation 
acute 
psychosis 
requiring 
hospitalization;  or 
suicidal 
gesture/attempt 
or 
hallucinations 
Muscle Strength 
Subjective 
weakness 
no 
objective 
symptoms/ signs 
mild 
objective 
signs/symptoms 
no 
decrease in 
function 
objective 
weakness function 
limited 
paralysis 
Paresthesia 
(burning, 
tingling, etc.) 
mild discomfort; no 
treatment required 
moderate 
discomfort; non- 
narcotic 
analgesia 
required 
severe discomfort; 
or 
narcotic 
analgesia required 
with 
symptomatic 
improvement 
incapacitating; 
or 
not responsive to 
narcotic analgesia 
Neuro-sensory 
mild impairment in 
sensation 
(decreased 
sensation, 
e.g., 
vibratory, 
pinprick, 
hot/cold 
in 
great 
toes) in focal area or 
symmetrical 
distribution; 
or 
change 
in 
taste, 
smell, vision and/or 
hearing 
moderate 
impairment (mod 
decreased 
sensation, 
e.g., 
vibratory, 
pinprick, hot/cold 
to ankles) and/or 
joint position or 
mild 
impairment 
that 
is 
not 
symmetrical 
severe impairment 
(decreased or loss 
of 
sensation 
to 
knees or wrists) or 
loss of sensation of 
at least mod degree 
in multiple different 
body 
areas (i.e., 
upper 
and lower 
extremities) 
sensory 
loss 
involves limbs and 
trunk; paralysis; or 
seizures 
 
MUSCULOSKELETAL 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Arthralgia 
(joint pain) 
mild pain not 
interfering with 
function 
moderate 
pain, 
analgesics and/or pain 
interfering with function 
but not with activities of 
daily living 
severe pain; pain 
and/or analgesics 
interfering 
with 
activities of daily 
living 
disabling pain 
Arthritis 
mild 
pain 
with 
inflammation, 
erythema or joint 
swelling – but not 
interfering 
with 
function 
moderate 
pain 
with 
inflammation, erythema 
or 
joint 
swelling 
– 
interfering with function, 
but not with activities of 
daily living 
severe pain with 
inflammation, 
erythema or joint 
swelling 
–and 
interfering 
with 
activities of daily 
living 
permanent and/or 
disabling 
joint 
destruction 
Myalgia 
myalgia 
with 
no 
limitation of activity 
muscle tenderness (at 
other than injection site) 
or 
with 
moderate 
impairment of activity 
severe 
muscle 
tenderness 
with 
marked impairment 
of activity 
frank 
myonecrosis 
 
 
835 of 852


TB Alliance 
Protocol Number: NC-008 (B-Pa-M-Z) 
Protocol Version: Russia V3.0 / 1 OCT 2019, Incorporating Protocol V4.0 / 30 SEP 2019 
Protocol Name: 
SimpliciTB 
 
CONFIDENTIAL 
Page 97 of 101 
SKIN 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Mucocutaneous 
erythema; pruritus 
diffuse, maculo 
papular rash, dry 
desquamation 
vesiculation 
or 
moist 
desquamation or 
ulceration 
exfoliative dermatitis, 
mucous 
membrane 
involvement 
or 
erythema, multiforme 
or 
suspected 
Stevens- Johnson or 
necrosis 
requiring 
surgery 
Induration 
< 15mm 
15-30 mm 
>30mm 
 
Erythema 
< 15mm 
15-30 mm 
>30mm 
 
Edema 
< 15mm 
15-30 mm 
>30mm 
 
Rash 
at 
Injection Site 
< 15mm 
15-30 mm 
>30mm 
 
Pruritus 
slight itching 
at 
injection 
site 
moderate itching at 
injection extremity 
itching 
over 
entire body 
 
 
SYSTEMIC 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
 
Allergic Reaction 
 
pruritus without rash 
 
localized urticaria 
generalized 
urticaria; 
angioedema 
 
anaphylaxis 
 
Headache 
mild, 
no 
treatment 
required 
transient, 
moderate; 
treatment required 
severe; responds to 
initial 
narcotic 
therapy 
intractable; 
requires repeated 
narcotic therapy 
Fever: oral 
37.7 - 38.5 C 
or 
100.0 
- 
38.6 - 39.5 C 
or 
101.6 
- 
39.6 - 40.5 C or 103 
- 105 F 
> 40 C or > 105 F 
 
Fatigue 
normal 
activity 
reduced 
< 
48 
hours 
normal 
activity 
decreased 
25- 
50% 
> 48 hours 
normal 
activity 
decreased > 50% 
can’t work 
unable to care 
for self 
 
 
 
 
 
 
836 of 852


TB Alliance 
Protocol Number: NC-008 (B-Pa-M-Z) 
Protocol Version: Russia V3.0 / 1 OCT 2019, Incorporating Protocol V4.0 / 30 SEP 2019 
Protocol Name: 
SimpliciTB 
 
CONFIDENTIAL 
Page 98 of 101 
Appendix 3: Who Clinical Staging of HIV/AIDS for Adults and Adolescents  
Primary HIV Infection 
Asymptomatic 
Acute retroviral syndrome 
Clinical Stage 1 
Asymptomatic 
Persistent generalized lymphadenopathy 
Clinical Stage 2 
Moderate unexplained weight loss (<10% of presumed or measured body weight) 
Recurrent respiratory infections (sinusitis, tonsillitis, otitis media, and pharyngitis) 
Herpes zoster 
Angular cheilitis 
Recurrent oral ulceration 
Papular pruritic eruptions 
Seborrheic dermatitis 
Fungal nail infections 
Clinical Stage 3 
Unexplained severe weight loss (>10% of presumed or measured body weight) 
Unexplained chronic diarrhea for >1 month 
Unexplained persistent fever for >1 month (>37.6ºC, intermittent or constant) 
Persistent oral candidiasis (thrush) 
Oral hairy leukoplakia 
Pulmonary tuberculosis (current) 
Severe presumed bacterial infections (e.g., pneumonia, empyema, pyomyositis, 
bone or joint infection, meningitis, bacteremia) 
Acute necrotizing ulcerative stomatitis, gingivitis, or periodontitis 
Unexplained anemia (hemoglobin <8 g/dL) 
Neutropenia (neutrophils <500 cells/µL) 
Chronic thrombocytopenia (platelets <50,000 cells/µL) 
Clinical Stage 4 
HIV wasting syndrome 
Pneumocystis pneumonia 
Recurrent severe bacterial pneumonia 
Chronic herpes simplex infection (orolabial, genital, or anorectal site for >1 month or 
visceral herpes at any site) 
Esophageal candidiasis (or candidiasis of trachea, bronchi, or lungs) 
Extrapulmonary tuberculosis 
Kaposi sarcoma 
Cytomegalovirus infection (retinitis or infection of other organs) 
Central nervous system toxoplasmosis 
HIV encephalopathy 
Cryptococcosis, extrapulmonary (including meningitis) 
Disseminated nontuberculosis mycobacteria infection 
Progressive multifocal leukoencephalopathy 
Candida of the trachea, bronchi, or lungs 
Chronic cryptosporidiosis (with diarrhea) 
Chronic isosporiasis 
Disseminated mycosis (e.g., histoplasmosis, coccidioidomycosis, penicilliosis) 
Recurrent nontyphoidal Salmonella bacteremia 
Lymphoma (cerebral or B-cell non-Hodgkin) 
Invasive cervical carcinoma 
837 of 852


TB Alliance 
Protocol Number: NC-008 (B-Pa-M-Z) 
Protocol Version: Russia V3.0 / 1 OCT 2019, Incorporating Protocol V4.0 / 30 SEP 2019 
Protocol Name: 
SimpliciTB 
 
CONFIDENTIAL 
Page 99 of 101 
Atypical disseminated leishmaniasis 
Symptomatic HIV-associated nephropathy 
Symptomatic HIV-associated cardiomyopathy 
Reactivation of American trypanosomiasis (meningoencephalitis or myocarditis) 
 
REF: World Health Organization. WHO Case Definitions of HIV for Surveillance and Revised Clinical Staging and Immunological 
Classification of HIV-Related Disease in Adults and Children; 2007 
Vital Signs 
The following abnormalities will be defined for vital signs: 
Abnormality Code 
Vital Signs Parameter 
 
Pulse 
DBP 
SBP 
RR 
Abnormalities on actual values 
“Abnormally low” 
≤ 50 bpm 
≤ 50 mmHg 
≤ 90 mm Hg 
<12 
Breaths per minute 
“Grade 1 or mild” 
- 
> 90 mmHg-
<100 mmHg 
> 140 mmHg-
<160 mmHg 
17-20 
Breaths per minute 
“Grade 2 or moderate” 
- 
≥ 100 mmHg-
<110 mmHg 
≥ 160 mmHg-
<180 mmHg 
21-25 
Breaths per minute 
“Grade 3 or severe” 
- 
≥ 110 mmHg 
≥ 180 mmHg 
>25 
Breaths per minute 
“Abnormally 
high 
or 
Grade 4” 
≥ 120 bpm 
- 
- 
Intubation 
 
 
838 of 852


TB Alliance 
Protocol Number: NC-008 (B-Pa-M-Z) 
Protocol Version: Russia V3.0 / 1 OCT 2019, Incorporating Protocol V4.0 / 30 SEP 2019 
Protocol Name: 
SimpliciTB 
 
CONFIDENTIAL 
Page 100 of 101 
Appendix 4: Cardiovascular Safety 
CARDIOVASCULAR 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Cardiac 
Rhythm 
 
asymptomatic, 
transient signs, 
no Rx required 
recurrent/persistent; 
symptomatic Rx 
required 
unstable 
dysrythmia; 
hospitalization and 
treatment required 
Hypertension 
transient increase 
> 20 mm/Hg; no 
treatment 
recurrent, 
chronic 
increase > 
20mm/Hg. 
/treatment 
required 
acute treatment 
required; outpatient 
treatment or 
hospitalization 
possible 
end organ 
damage or 
hospitalization 
required 
Hypotension 
transient 
orthostatic 
hypotension with 
heart rate 
increased by <20 
beat/min or 
decreased by <10 
mm Hg systolic BP, 
no treatment 
required. 
symptoms due 
to orthostatic 
hypotension or 
BP decreased 
by <20 mm Hg 
systolic; 
correctable with 
oral fluid 
treatment 
requires IV fluids; 
no hospitalization 
required 
mean arterial 
pressure <60mm/ 
Hg or end organ 
damage or shock; 
requires 
hospitalization and 
vasopressor 
treatment 
Pericarditis 
minimal effusion 
mild/moderate 
asymptomatic 
effusion, no 
treatment 
symptomatic 
effusion; pain; EKG 
changes 
tamponade; 
pericardiocentesis 
or surgery 
required 
Hemorrhage, 
Blood Loss 
microscopic/occult 
mild, no 
transfusion 
gross blood loss; 1-
2 units transfused 
massive blood 
loss; > 3 units 
transfused 
All-important abnormalities from the ECG readings will be reported. 
The percentage of participants with increases in QTc of <30, 30-60, or > 60 ms from baseline 
will also be tabulated at each time point. 
Abnormality Code 
ECG parameter 
 
HR 
PR 
QRS 
QTcorrected 
Abnormalities on actual values 
“Abnormally low” 
≤ 50 bpm 
NAP 
≤ 50 ms 
- 
“Abnormally high” 
≥ 120 bpm 
≥ 210 ms 
≥ 120 ms 
- 
“]450 ms, 480 ms] 
- 
- 
- 
450 ms < QTc ≤ 480 ms 
“]480 ms, 500 ms] 
- 
- 
- 
480 ms < QTc ≤ 500 ms 
“More than 500 ms 
- 
- 
- 
QTc > 500 ms 
Abnormalities on changes from baseline 
“[30; 60] ms” 
- 
- 
- 
[30; 60] ms 
“> 60 ms” 
- 
- 
- 
> 60 ms 
 
 
 
839 of 852


TB Alliance 
Protocol Number: NC-008 (B-Pa-M-Z) 
Protocol Version: Russia V3.0 / 1 OCT 2019, Incorporating Protocol V4.0 / 30 SEP 2019 
Protocol Name: 
SimpliciTB 
 
CONFIDENTIAL 
Page 101 of 101 
Appendix 5: Karnofsky Performance Status Scale Definitions Rating (%) Criteria 
Description 
% 
Able to carry on normal activity 
and to work; no special care 
needed. 
Normal no complaints; no evidence of disease. 
100 
Able to carry on normal activity; minor signs or 
symptoms of disease. 
90 
Normal activity with effort; some signs or 
symptoms of disease.  
80 
Unable to work; able to live at 
home and care for most 
personal 
needs; 
varying 
amount of assistance needed. 
Cares for self; unable to carry on normal activity 
or to do active work. 
70 
Requires occasional assistance, but is able to 
care for most of his personal needs. 
60 
Requires considerable assistance and frequent 
medical care.  
50 
Unable to care for self; requires 
equivalent of institutional or 
hospital care; disease may be 
progressing rapidly. 
Disabled; requires special care and assistance. 
40 
Severely disabled; hospital admission is indicated 
although death not imminent. 
30 
Very sick; hospital admission necessary; active 
supportive treatment necessary. 
20 
Moribund; fatal processes progressing rapidly. 
10 
Dead 
0 
 
Ref: Oxford Textbook of Palliative Medicine, Oxford University Press.  1993; 109. 
 
 
 
840 of 852


TB Alliance 
Protocol Number: NC-008 
Protocol Amendment No.: Russia Amendment 2 / 01-Oct-2019 
Protocol Name: SimpliciTB 
Protocol Amendment 
or Administrative Change 
TMP-C-SOP01-C V1.0 30-Nov-2018 
CONFIDENTIAL 
This document is proprietary and shall not be reproduced without prior written permission from TB Alliance. 
Trial Number 
Trial Name
NC-008 
SimpliciTB 
X Protocol Russia Amendment Number 2 Dated 01/OCT/2019, Incorporating Protocol V4.0 Dated 30/SEP/2019 
 Protocol Administrative Change Number _ _, Dated _ _/_ _ _/_ _ _ _ 
Summary - Protocol section changed 
Does amendment / 
administrative change 
affect any of the 
elements listed? 
YES
NO
A 
Purpose of trial 
X 
B 
Design of trial 
X 
C 
Informed consent 
X 
D 
Recruitment procedure 
X 
E 
Measures of efficacy 
X 
F 
Schedule of samples 
X 
G 
Addition or deletion of tests or measures 
X 
H 
Number of participants 
X 
I 
Age range of participants 
X 
J 
Inclusion criteria 
X 
K 
Exclusion criteria 
X 
L 
Safety monitoring 
X 
M 
Duration of exposure to the investigational medicinal product(s) 
N 
Change of posology of the investigational medicinal product(s) 
X 
O 
Change of comparator 
X 
P 
Statistical analysis 
X 
1 of 12
841 of 852


TB Alliance 
Protocol Number: NC-008 
Protocol Amendment No.: Russia Amendment 2 / 01-Oct-2019 
Protocol Name: SimpliciTB 
Protocol Amendment 
or Administrative Change 
TMP-C-SOP01-C V1.0 30-Nov-2018 
CONFIDENTIAL 
This document is proprietary and shall not be reproduced without prior written permission from TB Alliance. 
Reasons for Protocol Amendment or Administrative Change: 
1 
Change: 
TB Alliance logo has been changed on page 1, due to updated company logo that was implemented in Jul 2019. 
2 
Clarify:  
Per Memo #3, Slit lamp ophthalmic examination to be performed at Week 17 and 26 for the 4-month treatment arm, and 
only at  Week 26 for the 6-month treatment arms (Section 1.2, Synopsis Flow Chart and Procedures update, only) to  
ensure consistency with protocol Section 1.2 Flow Chart and Procedures footnote p. 
3 
Clarify:  
Per Memo #5, ECG to be performed at Week 12 (Section 1.2, Synopsis Flow Chart and Procedures update, only) to ensure 
consistency with the protocol Section 1.2 Flow Chart and Procedures footnote n, and Section 7.3 Safety and Tolerability 
Assessments. 
4 
Clarify:  
Per Memo #6, Male Reproductive Hormone testing to be performed at the end of each 4 and 6-month treatment period 
(Section 1.2, Synopsis Flow Chart and Procedures update, only) in alignment with the protocol intention to perform this 
assessment at the end of each treatment period. 
5 
Clarify:  
Per Memo #7, Male Reproductive Hormone testing to be performed at the early withdrawal visit (Section 1.2, Synopsis Flow 
Chart and Procedures update, only), to ensure consistency with the Section 5.4.1 Early Withdrawal. 
6 
Clarify:  
Per Memo #8, pregnancy testing is to be performed on all female participants of childbearing potential.  Females of non- 
 
 
childbearing potential are: Female participant or male participants  female sexual partner  bilateral oophorectomy, bilateral 
tubal ligation and/or hysterectomy or has been postmenopausal with a history of no menses for at least 12 consecutive 
months (Inclusion criteria #5.1.7 updated, only), to ensure consistency with the Section 1.2 Synopsis and Flow Chart and 
Procedures footnote k, Section 5.4.1 Early Withdrawal (urine pregnancy test) and Section 7.1 Demographic and Background 
Variables and Procedures (urine pregnancy test). 
7 
Change: 
should (changed from 
 (Section 1.2, Synopsis Flow Chart and Procedures footnote l; Section 7.3 Safety and  
Tolerability Assessments; Section 8.3.1 ALT, AST and Bilirubin Elevations) to improve safety monitoring and management 
of participants. 
8 
Add: 
Hepatitis A, B and C serology test to be performed at Day 1 (baseline) or where available, the backup PK sample at Day 1 
(pre-dose) will be used to obtain a hepatitis A, B and C serology result for all participants already enrolled prior to Protocol 
V4.0, to improve safety monitoring and management of participants (Section 1.2, Synopsis Flow Chart and Procedures 
footnote l; Section 7.3 Safety and Tolerability Assessments). 
9 
Add: 
Where available, the backup PK sample at Day 1 (pre-dose) will be used to obtain a hepatitis A, B and C result for all  
participants already enrolled prior to Protocol V4.0 , to improve safety monitoring and management of participants (Section 
1.2, Synopsis Flow Chart and Procedures footnote s). 
10 
Add: 
/ or whole genome sequencing (WGS) results on baseline samples become available, any 
results that are discordant with the screening molecular test results
wording updated, as Phenotypic DST results are 
2 of 12
842 of 852


TB Alliance 
Protocol Number: NC-008 
Protocol Amendment No.: Russia Amendment 2 / 01-Oct-2019 
Protocol Name: SimpliciTB 
Protocol Amendment 
or Administrative Change 
TMP-C-SOP01-C V1.0 30-Nov-2018 
CONFIDENTIAL 
This document is proprietary and shall not be reproduced without prior written permission from TB Alliance. 
more readily available when this review and decision needs to be made, on an ongoing basis (Section 5.1.5 
Inclusion Criteria and 5.4 Treatment Discontinuation and/or Early Withdrawal). 
11 
Change: 
Treatment-emergent adverse events (TEAEs) are defined as any AE occurring or worsening with an onset date on or after 
the date of the first dose of the study medication and within 14 days after the date of the last dose, changed from 
the last scheduled visit / assessment / measurement
in Section 9.5 Safety and Tolerability Assessments, to be consistent 
with the Statistical Analysis Plan (SAP) definition of  TEAEs. 
# 
Section 
Previous Text 
Version 3.0, dated 14-Jan-19 
Amended Text 
Version 4.0, dated 30-Sep-19 
Additional text - bold font. Deleted text  strike-
through. 
Reason for 
Change 
Insert 
reason # 
from table 
above 
1 
Page 1, title 
page 
1 
2 
Section 1.2 
Synopsis Flow 
Chart and 
Procedures 
X-mark present at Week 17 for the 6-month 
treatment arms 
X-mark has been removed from Week 17 for the
6-month treatment arms, for the Ophthalmic
examination assessment
2 
3 
Section 1.2 
Synopsis Flow 
Chart and 
Procedures 
X-mark not present 
X-mark has been included at Week 12, for the
assessment of the 12-lead ECG
3 
4 
Section 1.2 
Synopsis Flow 
Chart and 
Procedures 
X-marks present at Week 17 for the 6-month 
treatment arms, and at Week 26 for the 4-month 
treatment arm 
X-mark has been included at Week 17 for the 4-
month and at Week 26 for the 6-month treatment
arms, for the assessment of the Male Reproductive
Hormone Tests
4 
5 
Section 1.2 
Synopsis Flow 
Chart and 
Procedures 
X-mark not present 
X-mark has been included at Early Withdrawal,
for the assessment of the Male Reproductive
Hormone Tests
5 
3 of 12
843 of 852


 
 
TB Alliance 
Protocol Number: NC-008 
Protocol Amendment No.: Russia Amendment 2 / 01-Oct-2019 
Protocol Name: SimpliciTB 
Protocol Amendment 
or Administrative Change 
 
TMP-C-SOP01-C V1.0 30-Nov-2018 
CONFIDENTIAL 
This document is proprietary and shall not be reproduced without prior written permission from TB Alliance. 
# 
Section 
Previous Text 
Version 3.0, dated 14-Jan-19 
 
Amended Text 
Version 4.0, dated 30-Sep-19 
Additional text - bold font. Deleted text  strike-
through. 
Reason for 
Change 
Insert 
reason # 
from table 
above 
6 
Inclusion 
Criteria #5.1.7 
a. Participant - not heterosexually active or 
practice sexual abstinence; or 
b. Female participant or male participants female 
sexual partner  bilateral oophorectomy, 
bilateral tubal ligation and/or hysterectomy or 
has been postmenopausal with a history of no 
menses for at least 12 consecutive months; or 
c. Male participant or female participants male 
sexual partner - vasectomised or has had a 
bilateral orchidectomy at least three months 
prior to screening; 
 
a. Participant - not heterosexually active or practice 
sexual abstinence; or 
b. Female participant or male participants female 
sexual partner  bilateral oophorectomy, bilateral 
tubal ligation and/or hysterectomy or has been 
postmenopausal with a history of no menses for 
at least 12 consecutive months; or 
c. Male participant or female participants male 
sexual partner - vasectomised or has had a 
bilateral orchidectomy at least three months prior 
to screening; 
 
6 
7 
Section 1.2, 
Synopsis Flow 
Chart and 
Procedures 
footnote l; 
Section 7.3 
Safety and 
Tolerability 
Assessments; 
Section 8.3.1 
ALT, AST and 
Bilirubin 
Elevations 
When managing participants with elevated liver 
enzymes at an Unscheduled visit, the investigator 
should request additional tests, in addition to the 
repeat LFT [e.g. Gamma Glutamyl Transferase 
(GGT), screening for Hepatitis A, B, C; to assist in 
ruling out other causes of a dysfunctional liver test 
(e.g. alcohol induced hepatic cell injury, 
hepatobiliary disease, hepatic viral infection)]. 
 
When managing participants with elevated liver 
enzymes at an Unscheduled visit, the investigator 
can should request additional tests, in addition to 
the repeat LFT [e.g. Gamma Glutamyl Transferase 
(GGT), screening for Hepatitis A, B, C; to assist in 
ruling out other causes of a dysfunctional liver test 
(e.g. alcohol induced hepatic cell injury, 
hepatobiliary disease, hepatic viral infection)]. 
 
7 
4 of 12
844 of 852


TB Alliance 
Protocol Number: NC-008 
Protocol Amendment No.: Russia Amendment 2 / 01-Oct-2019 
Protocol Name: SimpliciTB 
Protocol Amendment 
or Administrative Change 
TMP-C-SOP01-C V1.0 30-Nov-2018 
CONFIDENTIAL 
This document is proprietary and shall not be reproduced without prior written permission from TB Alliance. 
# 
Section 
Previous Text 
Version 3.0, dated 14-Jan-19 
Amended Text 
Version 4.0, dated 30-Sep-19 
Additional text - bold font. Deleted text  strike-
through. 
Reason for 
Change 
Insert 
reason # 
from table 
above 
8 
Section 1.2, 
Synopsis Flow 
Chart and 
Procedures 
footnote l; 
Section 7.3 
Safety and 
Tolerability 
Assessments 
No previous text 
Hepatitis A, B and C serology test to be
performed at Day 1 (baseline) or where available, 
the backup PK sample at Day 1 (pre-dose) will be 
used to obtain a hepatitis A, B and C serology 
result for all participants already enrolled prior 
to Protocol V4.0 
8 
9 
Section 1.2, 
Synopsis Flow 
Chart and 
Procedures 
footnote s 
No previous text 
Where available, the backup PK sample at Day 1 
(pre-dose) will be used to obtain a hepatitis 
serology result for all participants already 
enrolled prior to Protocol V4.0 
9 
10 
Section 5.1.5 
Inclusion 
Criteria and 
5.4 Treatment 
Discontinuatio
n and/or Early 
Withdrawal 
When Phenotypic DST and whole genome 
sequencing (WGS) results on baseline samples 
become available, any results that are discordant 
with the screening molecular test results used to 
eligibility for the trial will be 
reviewed by the Sponsor Medical Monitor in 
consultation with the Investigator to determine 
whether that participant is unlikely to respond to 
treatment and should therefore be removed from 
the trial and given alternative treatment.  If a 
participant is removed from the trial for such a 
reason, they will be classified as a late exclusion. 
When Phenotypic DST and / or whole genome 
sequencing (WGS) results on baseline samples 
become available, any results that are discordant 
with the screening molecular test results used to 
reviewed by the Sponsor Medical Monitor in 
consultation with the Investigator to determine 
whether that participant is unlikely to respond to 
treatment and should therefore be removed from the 
trial and given alternative treatment.  If a participant 
is removed from the trial for such a reason, they will 
be classified as a late exclusion. 
10 
5 of 12
845 of 852


 
 
TB Alliance 
Protocol Number: NC-008 
Protocol Amendment No.: Russia Amendment 2 / 01-Oct-2019 
Protocol Name: SimpliciTB 
Protocol Amendment 
or Administrative Change 
 
TMP-C-SOP01-C V1.0 30-Nov-2018 
CONFIDENTIAL 
This document is proprietary and shall not be reproduced without prior written permission from TB Alliance. 
# 
Section 
Previous Text 
Version 3.0, dated 14-Jan-19 
 
Amended Text 
Version 4.0, dated 30-Sep-19 
Additional text - bold font. Deleted text  strike-
through. 
Reason for 
Change 
Insert 
reason # 
from table 
above 
11  
Section 9.5 
Safety and 
Tolerability 
Assessments 
Treatment-emergent adverse events (TEAEs) are 
defined as AEs which started at or after the first 
administration of IMP and includes those events 
started prior to the first administration of IMP but 
which worsened after the first intake.  Adverse 
events starting after the last administration of IMP 
until the last scheduled 
visit/assessment/measurement will be regarded as 
treatment-emergent. 
Treatment-emergent adverse events (TEAEs) are 
defined as AEs which started at or after the first 
administration of IMP and includes those events 
started prior to the first administration of IMP but 
which worsened after the first intake.  Adverse 
events starting after the last administration of IMP 
until the last scheduled 
visit/assessment/measurement will be regarded as 
treatment-emergent. any AE occurring or 
worsening with an onset date on or after the date 
of the first dose of the study medication and 
within 14 days after the date of the last dose. 
Any adverse event that started beyond this 
timeframe and assessed as possibly related to 
study drug is considered treatment-emergent 
 
11 
 
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TB Alliance 
Protocol Number: NC-008 
Protocol Amendment No.: Russia Amendment 2 / 01-Oct-2019 
Protocol Name: SimpliciTB 
Protocol Amendment 
or Administrative Change 
 
TMP-C-SOP01-C V1.0 30-Nov-2018 
CONFIDENTIAL 
This document is proprietary and shall not be reproduced without prior written permission from TB Alliance. 
Sponsor 
I agree to the terms of this Protocol Amendment or Administrative Change. 
Signature of Study Physician 
 
Printed name 
 
Date 
Principal Investigator 
I hereby confirm I have read the above Protocol Amendment or Protocol Administrative Change and agree to conduct this clinical trial as 
outlined in the above. I will provide copies of the Protocol Amendment or Protocol Administrative Change and access to all of the information 
required to conduct the clinical trial according to the above Protocol Amendment or Protocol Administrative Change to the site personnel under 
my supervision. I will discuss this material with them and ensure they are fully informed on all trial requirements.  
Signature of Principal Investigator 
 
Printed name 
 
Date 
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SAP_001.pdf: 
TB Alliance 
 
Clinical Trial Report 
NC-008-(B-Pa-M-Z) 
 
SimpliciTB 
CONFIDENTIAL 
 
 
16.1.9 
Documentation of Statistical Methods 
SimpliciTB SAP, Version 3.0, 26MAY2021 
SimpliciTB SAP, Note to File 1 for SAP Version 3.0, 11NOV2021 
SimpliciTB SAP, Note to File 2 for SAP Version 3.0, 11NOV2021 
SimpliciTB SAP, Note to File 3 for SAP Version 3.0, 11NOV2021 
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$e85941cce780$1CEF3513A3394750B91A6EFB4C6311B1.docx  
Page 1 of 38 
 
 
 
 
CONFIDENTIAL 
 
Protocol Title
 
An Open-Label, Partially Randomised Trial to Evaluate the Efficacy, Safety and Tolerability of a 4-
month Treatment of Bedaquiline plus Pretomanid plus Moxifloxacin plus Pyrazinamide (BPaMZ) 
Compared to a 6-month Treatment of HRZE/HR (Control) in Adult Participants with Drug-
Sensitive Smear-Positive Pulmonary Tuberculosis (DS-TB) and a 6-month Treatment of BPaMZ in 
Adult Participants with Drug Resistant, Smear-Positive Pulmonary Tuberculosis (DR-TB). 
 
Protocol Name and Number: SimpliciTB NC-008 (B-Pa-M-Z) 
 
Statistical Analysis Plan 
Version 3.0  
Dated 26th May 2021 
 
 
Author name:
Lindsay Thompson
Author position:
Statistician, UCL
Author signature and date:
 
 
 
 
Approval name:
Morounfolu Olugbosi
Approval position:
Study Physician, TB Alliance 
Approval signature and date:
 
 
 
 
 
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Version History: 
 
Version Number/Date 
Change 
0.1 / 15June2018 
1st draft circulated  
0.2 / 27June2018 
2nd draft AC discussed with CM 
0.3 / 28June2018 
3rd draft circulated  
0.4 / 29June2018 
4th draft circulated following comments from CM and MO 
0.5 / 13August2018 
5th draft circulated following rework by CM 
0.6 / 31Augut2018 
6th draft circulated to wider group 
1.0 / 07November2018 
Version 1.0 following external review 
1.1 / 15March2019 
Updated to include details of interim analysis;  
1.2 / 11April2019 
Updated following comments on v1.1 
1.3 / 25April2019 
Updated following comments on v1.2 
1.4 / 10May2019 
Updated following comments on v1.3 
1.5 / 17May2019 
Updated following comments on v1.4 
2.1 / 25June2020 
Adding COVID clause 
Adding minor clarification to the text 
2.2 / 24 September 2020 Combining efficacy and safety SAP information 
2.3 / 01 December 2020 
Incorporation of comments after online review  
2.4 / 10 December 2020 
Incorporation of comments following review meeting 
2.5 / 22 March 2020 
New draft following internal review. Circulated to TBA. 
2.6 / 21 May 2021 
New draft following review with TBA. 
3.0 / 26 May 2021 
Version 3.0 following the combination of the efficacy and safety SAPs 
 
 
 
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List of Abbreviations 
AE  
Adverse Event  
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
ANC 
Absolute Neutrophil Count 
AREDS2 
Age Related Eye Disease Scale 2 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
B 
Bedaquiline 
BLQ 
Below the Limit of Quantitation 
BMI 
Body Mass Index 
BPaMZ 
Combination of Bedaquiline plus Pretomanid plus Moxifloxacin plus Pyrazinamide 
CPK 
Creatinine Phosphokinase 
DMID 
Division of Microbiology and Infectious Disease 
DSMC 
Data Safety Monitoring Committee 
DR-TB 
Drug-resistant tuberculosis 
DS-TB 
Drug-sensitive tuberculosis 
ECG 
Electrocardiogram 
(e)CRF 
(electronic) Case Report Form 
GGT 
Gamma-glutamyl Transferase 
HeR 
Heart Rate 
HIV  
Human Immunodeficiency Virus 
HGB 
Hemoglobin 
HRZE 
Isoniazid, Rifampicin, Pyrazinamide, Ethambutol 
HR 
Isoniazid plus Rifampicin combination tablet 
ITT 
Intent to Treat 
IMP 
Investigational Medication Product 
IWRS 
MeDRA 
Interactive Web Response System 
Medical Dictionary for Regulatory Activities 
mITT 
Modified Intent to Treat 
MDR-TB 
Multi Drug Resistant Tuberculosis 
MGIT™ 
Mycobacterial Growth Indicator Tube 
Pa 
Pretomanid 
PD 
Pharmacodynamic 
PP 
Per Protocol 
PK 
PT 
Pharmacokinetic 
Preferred term 
PR 
PR interval – time from start of P wave to start of QRS complex on ECG 
QT 
QT interval – time from start of Q wave to end of T wave on ECG 
QTc 
QT interval corrected for heart rate 
QTcB 
QT interval corrected for heart rate using Bazett’s formula 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
QRS 
QRS complex (ventricular depolarization) on ECG 
RBC 
Red Blood Cell 
RR 
RR interval – time between two QRS complexes on ECG 
SAP 
Statistical Analysis Plan 
SOC 
System Organ Class 
TB 
Tuberculosis 
TB-mITT 
TB Specific Modified Intent to Treat 
TEAE 
Treatment Emergent Adverse Event 
ULN 
Upper Limit of Normal 
WBC 
White Blood Cell 
XDR-TB 
Extensively Drug Resistant Tuberculosis 
 
 
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1. Introduction .............................................................................................. 8
1.1. 
Trial Intervention ..................................................................................................................... 9 
1.2. 
Randomisation, Stratification and Blinding ............................................................................. 9 
2. Outcome Measures ................................................................................... 9
2.1. 
Primary Efficacy Endpoint ....................................................................................................... 9 
2.2. 
Key Secondary Efficacy Endpoint ..........................................................................................10 
2.3. 
Secondary Safety and Tolerability Outcomes .......................................................................10 
2.3.1. 
All-cause mortality.........................................................................................................10 
2.3.2. 
Treatment emergent adverse events (TEAEs) ...............................................................10 
Incidence .......................................................................................................................10 
Severity ..........................................................................................................................10 
Drug relatedness ...........................................................................................................10 
Seriousness ....................................................................................................................11 
Leading to treatment discontinuation ..........................................................................11 
Leading to study discontinuation ..................................................................................11 
Leading to death ............................................................................................................11 
Liver-related, drug and liver-related and serious liver-related TEAEs ..........................11 
2.3.3. 
Clinical safety laboratory measurements ......................................................................11 
2.3.4. 
Electrocardiogram .........................................................................................................11 
2.3.5. 
Changes in male reproductive hormones .....................................................................11 
2.3.6. 
Changes in lens opacities...............................................................................................12 
2.3.7. 
Pharmacokinetics (PK) and Pharmacokinetics/Pharmacodynamics (PK/PD) ................12 
2.4. 
Other Secondary Efficacy Endpoints .....................................................................................12 
2.5. 
Exploratory Objectives ..........................................................................................................12 
2.5.1. 
Predictors of relapse free cure ......................................................................................12 
2.5.2. 
Subgroup analyses .........................................................................................................12 
3. Definitions and Data Handling Issues ...................................................... 12
3.1. 
Positive and Negative Status .................................................................................................12 
3.1.1. 
Positive culture ..............................................................................................................12 
3.1.2. 
Isolated Positive Cultures ..............................................................................................13 
3.1.3. 
Culture negative status .................................................................................................13 
3.1.4. 
Inability to Produce Sputum ..........................................................................................13 
3.2. 
Bacteriological failure, Relapse or Reinfection .....................................................................14 
3.3. 
Adequate Treatment .............................................................................................................14 
3.4. 
Determining Cause of Death .................................................................................................15 
3.5. 
Major Protocol Deviations for analysis .................................................................................15 
Table of Contents
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3.6. 
Trial Timings ..........................................................................................................................15 
3.7. 
General Statistical Considerations for Safety Analysis ..........................................................16 
3.8. 
Newly notable abnormalities ................................................................................................16 
4. Sample Size ............................................................................................. 16 
5. Analysis Populations ............................................................................... 17 
6. Endpoint definitions ................................................................................ 18 
6.1. 
Short term endpoints ............................................................................................................18 
6.1.1. 
mITT Population ............................................................................................................18 
 Unassessable status (late exclusions)............................................................................18 
6.2. 
Long term endpoints .............................................................................................................18 
Favourable status (all analysis populations) .................................................................................18 
6.2.1. 
mITT Population ............................................................................................................18 
 Unassessable status (late exclusions)............................................................................18 
 Unfavourable status ......................................................................................................19 
6.2.2. 
TB-mITT Population .......................................................................................................19 
 Unassessable status (additional exclusions from mITT) ................................................19 
 Unfavourable status ......................................................................................................20 
6.2.3. 
PP Population ................................................................................................................20 
 Unassessable status (additional exclusions from TB-mITT) ..........................................20 
 Unfavourable status ......................................................................................................21 
7. Efficacy Statistical Analysis ...................................................................... 21 
7.1. 
Primary Efficacy Endpoint .....................................................................................................21 
7.1.1. 
Sensitivity Analyses of Primary Efficacy Endpoint .........................................................22 
7.2. 
Secondary endpoints .............................................................................................................22 
7.2.1. 
Key Secondary Endpoint: Unfavourable Status at 12 months (Non-inferiority 
Comparison) ..................................................................................................................................22 
 Secondary Bayesian analysis of Unfavourable Status at 12 months .............................22 
 Sensitivity Analyses for Unfavourable Status at 12 months .........................................22 
7.2.2. 
Unfavourable Status at 24 months ................................................................................23 
7.2.3. 
Time to Unfavourable Status .........................................................................................23 
7.2.4. 
Time to Sputum Culture Conversion to Negative Status...............................................23 
7.2.5. 
Culture Conversion Status at 4, 6, 12 and 17 Weeks ....................................................23 
7.2.6. 
Adherence .....................................................................................................................23 
7.2.7. 
Weight and BMI .............................................................................................................23 
7.2.8. 
TB Symptoms .................................................................................................................23 
7.2.9. 
Patient Reported Health Status .....................................................................................23 
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7.2.10. 
Predictors of Favourable Status at 12 and 24 months ..................................................24 
7.3. 
Interim Analyses ....................................................................................................................24 
7.3.1. 
Overview ........................................................................................................................24 
7.3.2. 
Operating characteristics ..............................................................................................24 
7.3.3. 
Sample size calculation ..................................................................................................25 
7.3.4. 
Decision .........................................................................................................................25 
7.4. 
Subgroup Analyses ................................................................................................................25 
7.5. 
Minimum Inhibitory Concentrations .....................................................................................26 
8. Safety Statistical Analysis ........................................................................ 26 
8.1. 
All-cause mortality ................................................................................................................26 
8.2. 
Treatment emergent AEs (TEAEs) .........................................................................................26 
8.2.1. 
Incidence of TEAEs .........................................................................................................26 
8.2.2. 
Severity ..........................................................................................................................27 
8.2.3. 
Drug-related TEAEs ........................................................................................................27 
8.2.4. 
Serious TEAEs ................................................................................................................27 
8.2.5. 
TEAEs leading to treatment discontinuation or interruption ........................................27 
8.2.6. 
TEAE leading to study discontinuation ..........................................................................27 
8.2.7. 
TEAEs leading to death ..................................................................................................27 
8.2.8. 
Liver-related TEAE .........................................................................................................28 
 Liver and drug-related TEAEs ........................................................................................28 
 Serious liver-related TEAEs ............................................................................................28 
 Incidence of hepatotoxicity ...........................................................................................28 
 Predictors of hepatotoxicity ..........................................................................................28 
8.2.9. 
Additional TEAE summary .............................................................................................28 
8.3. 
Clinical Evaluation .................................................................................................................28 
8.3.1. 
Clinical Laboratory Evaluation .......................................................................................28 
8.3.2. 
Vital Sign Measurements ...............................................................................................29 
8.4. 
Electrocardiogram .................................................................................................................30 
8.5. 
Male Reproductive Hormone Tests .......................................................................................31 
8.6. 
Lens Opacity Tests .................................................................................................................31 
8.7. 
Pharmacokinetics/Pharmacodynamics .................................................................................31 
9. Participant Disposition ............................................................................ 31 
9.1. 
Participant Disposition ..........................................................................................................31 
9.2. 
Study protocol deviations .....................................................................................................32 
10. Demographics and baseline characteristics ............................................. 32 
10.1. Demographics ........................................................................................................................32 
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10.2. Baseline characteristics .........................................................................................................32 
10.3. Medical History .....................................................................................................................33 
10.4. Inclusion and Exclusion Criteria .............................................................................................33 
11. Treatment and Medications .................................................................... 33 
11.1. Prior and Concomitant Medications .....................................................................................33 
11.1.1. 
Prior Medications ..........................................................................................................33 
11.1.2. 
Concomitant Medications .............................................................................................33 
11.1.3. 
Concomitant Procedures ...............................................................................................34 
11.1.4. 
Study Treatment Exposure ............................................................................................34 
12. References .............................................................................................. 35 
13. Appendix ................................................................................................. 36 
13.1. Derived MGIT results per visit ...............................................................................................36 
13.2. Interpretation of Relapse/Reinfection using Whole Genome Sequence (WGS) ...................36 
13.3. TB-mITT population ...............................................................................................................37 
13.4. STATA code for interim analysis sample size ........................................................................38 
 
 
 
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1. Introduction 
This document outlines the statistical analysis for both efficacy and safety. This includes, but is not 
limited to, the efficacy primary endpoint, secondary efficacy and safety endpoints, populations, TB 
symptoms, EQ5D, adherence and weight. Summaries of plasma drug concentrations and PK 
parameters will also be described. 
 
SimpliciTB is a multi-centre, open-label, randomised clinical trial in drug sensitive tuberculosis (DS-TB). 
DS-TB participants should be sensitive to rifampicin and isoniazid and either newly diagnosed for 
tuberculosis (TB) or have a history of being untreated for at least 3 years after cure from a previous 
episode of TB. 
 
Participants who are drug resistant (DR-TB) will also be enrolled into the study and will receive the 
same experimental treatment, except that they will be treated for a longer period of time due to the 
high degree of pyrazinamide resistance expected in this group. These participants will not be 
randomised. DR-TB participants should be resistant to rifampicin or isoniazid. 
              
SimpliciTB will evaluate and support that, in addition to previous studies evaluated with BPaMZ, the 
drug regimen (BPaMZ) will be safe, effective, and well-tolerated and could potentially shorten the 
current treatment duration compared to standard HRZE/HR treatment for participants with DS-TB 
disease. This trial will also evaluate if this drug regimen (BPaMZ) given for 6 months will be safe and 
effective in DR-TB disease. All participants will be followed for 2 years after enrolment. 
 
For participants with DS-TB, the experimental arm (4BPaMZ) will be compared to the control arm 
(HRZE/HR) in all analyses (unless otherwise stated). There will be no formal comparisons for 
participants with DR-TB. 
 
While SimpliciTB is an open label study, only members of the Data Safety Monitoring Committee 
(DSMC) and the unblinded statistician(s) will have access to data grouped by study arm. Access to data 
grouped by study arm by investigators, CRO and TB Alliance study team should not occur. In addition, 
site staff will be strongly discouraged from attempting to aggregate data by treatment arm at a site 
level. In order to protect the safety of study participants, TB Alliance staff who do not work directly 
with study conduct will require access to aggregated safety data as part of study safety oversight and 
for the purpose of making strategic study decisions. In addition, if there are identified potential safety 
concerns that warrants a more frequent look at aggregated data compared to the DSMC meeting 
frequency, the medical monitoring team will require access to aggregated safety data. 
 
Note: The protocol refers to three analysis populations (ITT, mITT and PP). In this SAP these are 
referred to as mITT, TB-mITT and PP. There are also two additional analysis populations outlined in the 
SAP. This is described in Table 1.  
 
 
 
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Table 1: Analysis populations according to protocol and SAP 
Analysis Populations 
Protocol 
Statistical Analysis Plan 
All randomised* 
Intent to treat (ITT) 
Safety* 
Safety 
Intent to treat (ITT) 
Modified intent to treat (mITT) 
Modified intent to treat (mITT) 
TB-specific mITT (TB-mITT) 
Per protocol (PP) 
Per Protocol (PP) 
*Not formally defined in the protocol  
 
1.1. 
Trial Intervention 
Participants with DS-TB who are randomised to the intervention arm will receive: bedaquiline (200 mg 
daily for 8 weeks then 100 mg daily for 9 weeks); and pretomanid (200 mg daily), moxifloxacin (400 
mg daily) and pyrazinamide (1500 mg daily) for 17 weeks (4BPaMZ).  
 
Participants with DS-TB who are randomised to the control arm will receive the standard dose of 
isoniazid, rifampicin, pyrazinamide and ethambutol (HRZE) for 8 weeks followed by 18 weeks of 
isoniazid and rifampicin. This regimen will be administered according to weight band (HRZE/HR).  
 
Participants with DR-TB will be treated with bedaquiline (200 mg daily for 8 weeks then 100 mg daily 
for 18 weeks); and pretomanid (200 mg daily), moxifloxacin (400 mg daily) and pyrazinamide (1500 mg 
daily) for 26 weeks (6BPaMZ).  
 
1.2. 
Randomisation, Stratification and Blinding 
Eligible participants with DS-TB will be randomised in the ratio 1:1 using an interactive web response 
system and stratified according to: 
• 
HIV status (positive vs. negative) 
• 
Cavitation (yes vs. no) 
 
Participants, trial Investigators and staff, including laboratory staff, will not be blinded to treatment 
allocation during the treatment phase of the trial. See blinding plan for more detail. 
 
2. Outcome Measures 
 
2.1. 
Primary Efficacy Endpoint 
The primary efficacy endpoint will be time to culture negative status in liquid media, up to 8 weeks. 
This will be assessed for superiority.   The hypothesis is that the 4-month treatment regimen will be 
superior to control for participants with DS-TB.  A modified intent-to-treat (mITT) analysis will be 
performed (as defined in §6.1).  
 
 
 
 
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2.2. 
Key Secondary Efficacy Endpoint 
A key secondary efficacy endpoint will be the proportion of participants who have an unfavourable 
outcome at 12 months. This will be assessed for non-inferiority using the 12% margin. The difference 
in proportions of unfavourable status at 12 months post-randomisation (non-inferiority comparison) 
will be performed for participants with DS-TB for the mITT, TB-mITT and PP analysis populations (as 
defined in §6.1).   
 
2.3. 
Secondary Safety and Tolerability Outcomes 
All safety summaries in this section will be presented for all participants in the Safety population, as 
defined in §5, unless otherwise stated.  
 
Adverse event verbatim reported terms will be coded by system organ class (SOC) and preferred term 
(PT) using the latest version of MedDRA.  
Adverse events are defined as either:  
1. Treatment emergent adverse events (TEAEs) which are adverse events (AEs) which started or 
worsened on or after the first administration of IMP up to and including 14 days after the last 
study drug administration, or  
2. Post-treatment AEs which are AEs that start or worsen more than 14 days after the last 
administration of IMP. 
Secondary safety and tolerability outcomes are outlined below in §2.3.1-2.3.7. These data will be 
presented as descriptive analyses, and no inferential tests will be carried out. 
 
2.3.1. All-cause mortality  
The proportion of participants who died from any cause during the study. 
 
2.3.2. Treatment emergent adverse events (TEAEs)  
 
 Incidence 
The proportion of participants who experienced at least one treatment-emergent adverse event 
(TEAE). 
 
 Severity 
Of those experiencing at least one TEAE the highest grade experienced. The highest grade experienced 
is defined as the most extreme severity captured on the Adverse Event CRF page. The possible 
severities are ‘Grade 1: Mild,’ ‘Grade 2: Moderate,’ ‘Grade 3: Severe’, and ‘Grade 4: Potentially life-
threatening.’  
 
 Drug relatedness 
Proportion of participants experiencing at least one TEAE related to any study medication. A related 
AE is defined as ‘Possibly’, ‘Probably’, or ‘Certainly’ related to study medication. 
 
 
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 Seriousness 
Proportion of participants experiencing at least one serious TEAE. A serious AE (SAE) is defined as any 
untoward medical occurrence that at any dose results in death, is life-threatening, is a congenital 
anomaly/birth defect, requires in-participant hospitalisation or prolongation, results in significant 
disability/incapacity, or is a medically important event. 
 Leading to treatment discontinuation 
Proportion of participants experiencing a TEAE that lead to treatment discontinuation. This will be AEs 
where action taken with study treatment is ‘Permanently Discontinued’ for BPaMZ or HRZE/HR. 
 
 Leading to study discontinuation 
Proportion of participants experiencing a TEAE that lead to study discontinuation. This will be AEs 
where action taken with study treatment is ‘Withdrawn from Study’. 
 
 Leading to death 
Proportion of participants experiencing a TEAE that lead to death. This will be AEs where the answer 
to ‘Outcome’ on the AE form is ‘Fatal’. 
 
 Liver-related, drug and liver-related and serious liver-related TEAEs 
The proportion of participants experiencing liver related, drug and liver related and serious liver 
related TEAEs. Liver related AEs are those where the preferred term specifies ‘Hepatic’ Drug and liver 
related are those AEs that are liver related and related to a drug and serious liver related TEAEs are 
those that are liver related and the AE is considered serious (as described in § 2.3.2.4). 
 
2.3.3. Clinical safety laboratory measurements 
The incidence of newly notable (an abnormality observed post baseline that meets the notable criteria) 
grade 3 or 4 severity for laboratory parameters according to DMID grading. Participants are considered 
to have notable laboratory abnormalities if his/her response falls within the specified definitions (see 
Table 3 in §8.3.1) at least once during the treatment period.  
 
2.3.4. Electrocardiogram  
The electrocardiogram (ECG) results (heart rate, RR interval, PR interval, QRS interval, QT interval and 
QTc interval), which are read by a central cardiology service, observed measurements and change from 
baseline. QT/QTc intervals, maximum change from baseline, will be categorised according to §8.4 
below. The ECG results will be considered at baseline, week 8, week 17, week 26, week 39 and early 
withdrawal in all participants. 
 
2.3.5. Changes in male reproductive hormones  
The change in male reproductive hormones (testosterone, follicle-stimulating hormone (FSH), 
luteinizing hormone (LH) and Inhibin B) for all male participants in all treatment groups from baseline 
to end of treatment visit (week 17 or week 26 depending on treatment group) and week 39.  
 
 
 
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2.3.6. Changes in lens opacities 
The change (increase or decrease) in lens opacity (cortical, nuclear and posterior subcapsular) from 
baseline to end of treatment (week 17 or week 26), week 39 and early withdrawal in all participants. 
 
2.3.7. Pharmacokinetics (PK) and Pharmacokinetics/Pharmacodynamics (PK/PD) 
This SAP provides descriptive summaries of plasma drug concentrations and PK parameters only. Full 
details on the full analysis of PK and PK/PD data can be found in the PK/PD modelling SAP. 
 
2.4. 
Other Secondary Efficacy Endpoints 
Other secondary endpoints which will be analysed according to the populations specified: 
• 
Proportion of unfavourable at 24 months (mITT, TB-mITT and PP populations)  
• 
Time to unfavourable status (mITT, TB-mITT and PP populations) 
• 
Time to sputum culture conversion to negative status (mITT population) 
• 
Culture conversion status at 4, 6, 12 and 17 weeks (mITT population) 
• 
Change in weight from baseline (mITT population) 
• 
Change in TB symptoms from baseline (mITT population) 
• 
Change in participant reported health status from baseline (mITT population) 
• 
Adherence (TB-mITT population) 
• 
Baseline predictors of Favourable Status at 12 months (mITT population) 
 
2.5. 
Exploratory Objectives 
 
2.5.1. Predictors of relapse free cure 
Evaluate whether any of the secondary efficacy endpoints as outlined in §2.4 predict relapse free cure 
at 12 months post randomisation. Potential predictors will include, but are not limited to, baseline 
variables (see §7.4), culture negative status at weeks 4, 6, 8, 12 and 17 as well as time to culture 
negativity (as a continuous variable).  
 
2.5.2. Subgroup analyses 
Subgroup analyses will be carried out and analysed for the key secondary efficacy endpoint (as 
described in §2.2 for the TB-mITT population). These subgroups are described in §7.4. 
 
3. Definitions and Data Handling Issues 
 
3.1. 
Positive and Negative Status 
 
3.1.1. Positive culture  
 
Positive culture refers to the culture being positive for Mycobacterium Tuberculosis (M.tb).  The MGIT 
culture results that are positive with contamination, contaminated, or with no result will be treated as 
missing.    
 
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Two sputum samples per visit are collected at each visit throughout treatment and follow-up.  The 
culture result for a given visit is established using all samples obtained for that visit. A positive culture 
takes precedence over a negative or contaminated culture at the same visit and a negative culture 
takes precedence over a contaminated culture at the same visit (Appendix §13.1). 
 
3.1.2. Isolated Positive Cultures 
It is known that occasionally participants produce sputum samples that are “isolated positives,” that 
is, a positive culture preceded by a series of negative cultures and followed thereafter by at least two 
negative cultures without an intervening positive result.  This phenomenon may be the result of a 
sealed cavity breaking down or laboratory contamination and does not in itself signify that the 
participant is relapsing. In the event of a single positive culture result occurring in a participant who 
has previously been classified as having culture negative status (in the absence of any retreatment), 
the participant will not be classified as a recurrence unless a second positive culture result is obtained 
at a separate visit (at least 7 days apart), without an intervening negative culture or unless the 
participant is lost to follow up or completes the study (and is unable to be brought back) before two 
negative cultures are obtained.  As there is a higher incidence of isolated positives with liquid culture 
and sometimes even serial “isolated positives” [1], the clinical condition of the participant will also be 
considered in deciding whether the participant has an unfavourable outcome and re-treatment is 
indicated. 
 
For example, if a participant after being culture negative has two positive cultures in a row, but is 
deemed to be doing well clinically, the investigator may choose to leave the participant untreated on 
clinical grounds.  In such a case, so long as two consecutive negative cultures are eventually obtained 
in the absence of treatment, the participant will not be classified as an unfavourable outcome (defined 
below). 
 
3.1.3. Culture negative status  
Culture negative status is achieved when a participant produces at least two negative culture results 
at different visits (at least 7 days apart) without an intervening positive culture result for M.tb.  The 
date of the first negative culture (date of collection of culture) of these two is the date at which culture 
negative status was obtained.  Once obtained, culture negative status continues until there are two 
positive cultures at different visits (at least 7 days apart), without an intervening negative culture, or 
until there is a single positive culture not followed by two negative cultures.  Culture negative status 
can be achieved at any time during treatment or follow-up but before any re-treatment. Culture 
negative status can be re-established. A single culture result or inability to produce sputum (see §3.1.4) 
at 8 weeks will be sufficient to count that participant as having data for endpoint classification. 
 
Participants with two contaminated or missing samples at a given visit (from month 2 onwards) will be 
asked to return to produce two more sputum samples.  
 
3.1.4. Inability to Produce Sputum 
In general, inability to produce sputum is treated as being equivalent to having a negative culture result 
if no other sputum sample is produced at that visit.  This includes: 
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• 
the rare situation where a participant who never achieves culture negative status due to the 
inability to produce sputum, after TB has been confirmed on the applicable baseline sample, 
completes follow-up without clinical or microbiological evidence of relapse.   
• 
during the COVID-19 lockdown situation where this data is collected remotely/telephonically. 
 
In SimpliciTB, such participants will be considered to have a favourable outcome and an inability to 
produce sputum with no other sputum produced at that visit will be treated as a negative culture 
result. 
 
3.2. Bacteriological failure, Relapse or Reinfection 
Treatment failure is defined as being declared an unfavourable outcome at or before the end of 
treatment (either 4 or 6 months) or failing to attain culture negative status and being declared an 
unfavourable outcome (§6.2) or the participant is withdrawn at or before the end of treatment for 
clinical (TB) reasons including being re-treated (or changing from protocol treatment) for TB.   
 
Relapse or bacteriological relapse is defined as failing to maintain culture negative status or being 
declared an unfavourable outcome (§6.2) after the end of treatment (either 4 or 6 months) in those 
participants who attained culture negative status by the end of treatment and had culture conversion 
to positive status with an M.tb strain that is genetically identical to the infecting strain at baseline or 
after the end of treatment in those participants who attained culture negative status by the end of 
treatment and were withdrawn for clinical (TB) reasons, including being re-treated (or changing from 
protocol treatment) for TB.  Details are given in Appendix §13.2. 
 
Reinfection or bacteriological reinfection is defined as failing to maintain culture negative status or 
being declared an unfavourable outcome (including being withdrawn for clinical (TB) reasons including 
being re-treated or changing from protocol treatment for TB) after the end of treatment in those 
participants who attained culture negative status by the end of treatment and had culture conversion 
to positive status with a M.tb strain that is genetically different from the infecting strain at baseline. If 
reinfection cannot be distinguished from relapse, the participant will be assumed to have relapsed. A 
single positive sample will be sufficient for strain typing to compare to baseline. Full details are in 
Appendix §13.2. 
 
3.3. 
Adequate Treatment  
The definition of adequate treatment sets a limit for the amount of treatment missed.  Participants 
not taking the adequate amount of treatment by this definition will be excluded from the PP analysis 
(see §6.2.3). 
 
Participants allocated to a 4 month regimen, to meet the definition of adequate treatment they must 
have taken at least 96 doses (80%) of their allocated 119 day (17 weeks) treatment regimen within 175 
days of starting therapy (i.e. 17 weeks plus an allowable 56 day halt (including a maximum of 35 
consecutive days) as per the protocol).  
 
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Participants allocated to a 6 month regimen, to meet the definition of adequate treatment they must 
have taken at least 146 doses (80%) of their allocated 182 day (26 weeks) treatment regimen within 
238 days of starting therapy (i.e. 26 weeks plus an allowable 56 day halt (including a maximum of 35 
consecutive days) as per the protocol).  
 
Participants in the control arm are additionally required to have taken at least 80% of their allocated 
intensive treatment. 
 
3.4. 
Determining Cause of Death 
A list of all TB-related and non-TB-related deaths will be generated and approved by a review 
committee blind to randomised arm before database lock. Similarly, a list of violent or accidental 
deaths will be generated (see study Death Adjudication Manual). 
 
3.5. 
Major Protocol Deviations for Analysis  
A major protocol deviation for analysis is defined as a serious protocol deviation which is likely to affect 
to a significant degree the scientific value of the trial.  These participants will be included in the mITT 
and TB-mITT analyses, but not in the PP analysis (see §6.2). A list of all major protocol deviations for 
analysis (blinded to treatment arm) will be approved by a review committee prior to database lock.  
Note: participants attending a long term outcome visit outside the specified window will be evaluated 
and considered for potential major protocol violator. Visits within 2 weeks of the window opening will 
be considered minor protocol violators. 
 
3.6. 
Trial Timings 
Study Day 1 is defined as the date on which a participant is administered the first dose of the study 
medication. Other study days are defined relative to the Study Day 1 with Day 2 being the day after 
Study Day 1 and Day -1 being the day prior to Study Day 1. 
 
For all safety endpoints, baseline is defined as the last non-missing measurement prior to first dose of 
study treatment unless otherwise stated. 
 
In all analyses, visit date rather than day or week number will be used to define the timing of events.   
For participants treated with the 6-month regimens (HRZE/HR for DS-TB participants and 6mBPaMZ 
for DR-TB participants) this will be taken as a total of 26 weeks, i.e. 182 dosing days. For DS-TB 
participants randomised to 4 months of BPaMZ a total of 17 weeks (119 dosing days) is taken. As per 
the protocol, assessments should be collected as follows: 
 
• 
Within ± 3 days of scheduled visit from day 1 to week 8 
• 
Within ± 5 days of scheduled visit from week 12 to week 26 
• 
Within ± 14 days of scheduled visit during the follow-up phase at or after month 6 to month 
24. 
 
Unscheduled visits and visits outside of these windows will be slotted into windows as appropriate. 
Visits falling outside of the defined protocol visit windows will be put into separate visits so that all 
data, both collected at scheduled and unscheduled time points, are used. 
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The treatment period is defined as either 17 or 26 weeks from start of therapy depending on allocated 
treatment regimen. 
 
The follow-up period is defined as the period after the end of treatment to the end of follow-up. 
 
3.7. 
General Statistical Considerations for Safety Analysis 
 
If there are multiple assessments in a visit, the highest grade non-missing value within a visit will be 
used in the summaries, however all will be shown in the listings. If numeric data is beyond range of lab 
detectability and result is showed as “<XX” or “>XX” then the numeric XX value will be used for 
summary statistics. 
 
There will be no specific strategy to deal with missing data i.e. it will not be imputed. A complete case 
analysis will be performed. For example when modelling the data based on a specific outcome only 
participants with complete data will be included. 
 
Baseline is defined as last available measurement prior to dosing and post baseline abnormalities are 
included in the summary if the subject did not meet the abnormality criteria at baseline or toxicity 
grade at post baseline is higher than that on baseline. 
 
All statistical analyses tables, listings and figures will be produced using STATA Version 16.0 or higher. 
 
3.8. 
Newly notable abnormalities 
A newly notable laboratory abnormality is defined as an abnormality observed post baseline that 
meets the notable criteria in Table 3 and that did not exist at baseline. Participants can still meet the 
criteria for newly notable laboratory if the baseline value is missing. 
 
 
4. Sample Size 
For the primary endpoint, time-to-negative culture conversion at 8 weeks, 150 participants per arm 
(DS-TB participants) will provide more than 99% power (5% two-sided significance) to detect a hazard 
ratio (HR) of at least 2 (for 4BPaMZ vs. HRZE), assuming 50% of control participants are culture negative 
by 8 weeks. If only 25% of the control arm remain culture positive at 8 weeks, then this sample size 
will still retain more than 93% power to detect a HR of least 2. Note, non-randomised MDR participants 
will not be formally compared to any randomised group. 
 
For the key secondary efficacy endpoint of clinical outcome at 12 months from randomisation, 150 
participants per arm will provide 74% power at the two-sided 5% significance level based on 
assumptions using data from the largest most recently completed phase 3 TB treatment trial which 
used the same control arm [2]. That is, assuming 16% of participants in the control arm are 
unfavourable and 13% are unassessable at 12 months post randomisation. A non-inferiority margin of 
12% is chosen and justified below. 
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This trial aims to demonstrate that the experimental regimen administered for 4 months to 
participants with DS‐TB is not inferior to the standard 6-month control regimen using a non‐inferiority 
margin of 12%, chosen based on the following rationale. The best estimate for the treatment effect 
(also known as M1 in guidance documents for non‐inferiority trials) of the current standard treatment 
(HRZE) is derived from modern clinical trials of this treatment compared to historical, natural history 
trials. Based on the above reference, an estimate of the favourable rate observed with standard HRZE 
therapy of 84% is used. The WHO estimates that the case fatality rate for untreated smear positive 
pulmonary tuberculosis is 70%, and this estimate was confirmed in a systematic review in 2011 [3]. 
Therefore, an estimate of 30% for the favourable rate of placebo may be contrasted with the 84% 
favourable rate of the standard HRZE therapy. Based on these data, the best available point estimate 
for M1 (the overall treatment effect of HRZE, expressed as a risk difference) is 54%. A selection of 12% 
for M2 (the non‐inferiority margin) would represent less than 25% of the point estimate of M1, thus 
assuring that the lower bound of the NI margin preserves more than 75% of the estimated treatment 
effect of the HRZE regimen. 
 
5. Analysis Populations  
 
Analysis populations are: 
• 
The Intent to treat (ITT) population, defined as all participants who were enrolled, whether or 
not they started treatment.  
 
• 
The Safety population, defined as all enrolled participants who received at least one dose of 
study treatment. Participants will be analysed as to the treatment they actually received 
regardless of given allocation. 
 
• 
The Modified intent to treat (mITT) population, defined as all participants who were enrolled 
and started treatment, excluding any late screening failures.  
 
• 
The TB-specific modified intent to treat (TB-mITT) population, defined as the mITT population 
with additional exclusions (see below). 
 
• 
The Per-protocol (PP) population, defined as the TB-mITT population with additional 
exclusions (see below). 
 
For ITT, mITT, TB-mITT and PP; participants will be analysed as to the treatment they were randomised 
to receive.  
 
For short-term culture conversion endpoints, only the mITT population will be examined. 
 
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The TB-mITT population is unique to the TB field and is outlined here (with further details provided in 
Appendix §13.3). TB-mITT is a key analysis that has been used in the literature of long-term outcome 
trials of durable cure in TB, although it has generally been referred to simply as the ‘mITT analysis’.  
This analysis excludes participants based on data collected post-randomisation. A true mITT analysis, 
as recognised by regulatory authorities, does not exclude any participants due to missing data post-
enrollment.   
 
Thus, for the long-term endpoint of durable cure, the TB-mITT analysis will be considered primary for 
the purposes of publication, to allow comparison with the rest of the literature in the TB field.  
However, for regulatory purposes, we recognise that regulatory agencies will consider the mITT 
analysis primary. 
 
6. Endpoint definitions  
 
6.1. 
Short term endpoints 
 
6.1.1. mITT Population 
Participant status is defined in §3.1. 
 
 Unassessable status (late exclusions) 
1. Participants enrolled and later found to be ineligible because of a protocol violation at 
enrolment (based on data collected prior to enrolment).  
2. Participants without culture confirmation of M.tb at Day 1 (baseline) sputum samples (or 
screening or out to Week 4 if the baseline is contaminated or negative). These participants will 
be late exclusions from the study. 
 
6.2. 
Long term endpoints 
 
Favourable status (all analysis populations) 
Participants with culture negative status at the time of the endpoint (at 12 or at 24 months), who have 
not already been classified as having an unfavourable outcome and whose last positive culture result 
(“isolated positive culture”) was followed by at least two negative culture results. For participants who 
are missing culture status at the 12 month endpoint but who have a culture result at a future timepoint 
will be considered culture negative status at 12 months if both the previous and future culture results 
are negative. 
 
6.2.1. mITT Population  
 
 Unassessable status (late exclusions) 
1. Participants enrolled and later found to be ineligible because of a protocol violation at 
enrolment (based on data collected prior to enrolment).  
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2. Participants without culture confirmation of M.tb at Day 1 (baseline) sputum samples (or 
screening or out to Week 4 if the baseline is contaminated or negative). These participants will 
be late exclusions from the study. 
 
 Unfavourable status  
Participants in the mITT analysis population who do not reach the time of the endpoint (12 or 24 
months depending on the endpoint) or who are not culture negative status at the time of the endpoint 
(12 or 24 months) and whose last positive culture result (“isolated positive culture”) was not followed 
by at least two negative culture results. 
 
6.2.2. TB-mITT Population  
 
 Unassessable status (additional exclusions from mITT) 
In addition to those excluded from the mITT analysis (see §6.2.1.1), the following participants will be 
excluded: 
 
1. Participants who, having completed treatment, are lost to follow-up or withdrawn from the 
study, their last status being culture negative and their last positive culture result (“isolated 
positive culture”) followed by at least two negative culture results at different visits (at least 7 
days apart, without an intervening positive culture). 
 
2. Women who become pregnant during treatment and stop their allocated treatment.  
 
3. Participants with suspected/confirmed COVID-19 during treatment and who stop their 
allocated treatment. 
 
4. Participants who died during treatment from violent or accidental cause (e.g. road traffic 
accident). N.B.: This does not include death from suicide, which will be considered an 
unfavourable outcome.  
 
5. Participants who died during follow-up (after the end of treatment) with no evidence of failure 
or relapse of their TB, their last status being culture negative and their last positive culture 
result (“isolated positive culture”) followed by at least two negative culture results at different 
visits (at least 7 days apart). 
 
6. Participants who, after being classified as having culture negative status are deemed culture 
positive and are infected with a new strain that is different from that with which they were 
originally infected.  Reinfection will be defined specifically as a participant infected with a 
strain that is genetically different from the initial strain (see Appendix §13.2).  
 
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7. Participants who are able to produce sputum at the endpoint visit, but whose endpoint visit 
sputum samples are all contaminated or missing, who cannot be brought back for repeat 
cultures, provided their last positive culture was followed by at least two negative cultures.  
N.B.:  This does not apply to participants who are unable to produce sputum at the given 
endpoint (see §3.1.4), or to participants who are able to be brought back subsequently and 
produce negative cultures. 
 
Participants in categories 1-7 above who have already been classified as having an unfavourable 
outcome will not be excluded. 
 
 Unfavourable status  
 
1. Participants not classified as having achieved or maintained culture negative status when last 
seen, or 
 
2. Participants previously classified as having culture negative status who, following the end of 
treatment, have two positive cultures without an intervening negative culture (however, see 
§3.1.2 for an exception), or 
 
3. Participants who had a positive culture not followed by at least two negative cultures when 
last seen, or  
 
4. Participants dying from any cause during treatment, except from violent or accidental cause 
(e.g. road traffic accident), not including suicide (e.g., suicide will be considered an 
unfavourable outcome), or 
 
5. Participants definitely or possibly dying from TB related cause during the follow-up phase, or 
 
6. Participants requiring an extension of their treatment beyond that permitted by the protocol 
a restart or a change of treatment for any reason except reinfection or pregnancy, or 
 
7. Participants lost to follow up or withdrawn from the study before the end of treatment. 
 
6.2.3. PP Population  
 
 Unassessable status (additional exclusions from TB-mITT) 
In addition to those already excluded from the mITT (see §6.2.1.1) and the TB-mITT (see §6.2.2.1) 
analyses, the following participants will be excluded from the PP analysis: 
 
1. Participants lost to follow-up or withdrawn for reasons other than treatment failure (e.g. 
participant consent or relocation) before the end of treatment, unless they have already been 
classified as having an unfavourable outcome. 
 
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2. Participants whose treatment was modified or extended beyond what is permitted in the 
protocol for reasons other than an unfavourable therapeutic response to treatment (e.g. an 
adverse drug reaction), unless they have already been classified as having an unfavourable 
outcome. 
 
3. Participants not meeting the definition of having received an adequate amount of their 
allocated study regimen (see §3.3), provided this is not due to an unfavourable outcome. 
 
4. Participants who are classified as “major protocol deviations for analysis” (see §3.5), unless 
they have already been classified as having an unfavourable outcome on the basis of data 
obtained prior to the protocol deviation 
 
 Unfavourable status  
Points 1-6 in §6.2.2.2 Unfavourable status in the TB-mITT Population section above 
 
 
7. Efficacy Statistical Analysis 
All efficacy outcomes will be analysed for superiority with the exception of the proportion of 
participants who have an unfavourable outcome at 12 months and at 24 months. These will be 
analysed for non-inferiority with a non-inferiority margin of 12%.  
 
All superiority analyses for efficacy, apart from the interim analysis (see §7.3), will be two-sided and 
considered statistically significant at the 5% level. 
 
All efficacy analyses will be adjusted for the stratification variables (HIV status and cavitation) unless 
otherwise stated and considered primary. Unadjusted analyses will also be considered for key 
endpoints. 
 
Additional baseline covariates listed in §7.4 will be considered for a secondary adjusted analysis for 
key efficacy endpoints. 
 
7.1. 
Primary Efficacy Endpoint 
Time to culture negative status in liquid media over 8 weeks will be analysed using a Cox regression 
model, censoring for death and lost to follow up/withdrawal to estimate the hazard ratio. This model 
assumes proportional hazards. This means that the hazard rates for participant subgroups are 
proportional over time during participant follow-up. A program that tests the proportional hazards 
assumption in the Cox model (estat phtest for Stata) will be used.  In the case where there is adequate 
evidence that the proportional hazard assumptions are violated at the 5% level (i.e. p<0.05), then the 
restricted mean survival time method (RMST) will be used. Data will be described using Kaplan-Meier 
plots.  
 
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For the 8 week culture conversion endpoint the time will be taken from randomisation until the first 
occurrence of achieving culture negative status in liquid media over 8 weeks. For participants who do 
not achieve culture negative status, time will be taken from randomisation to 8 weeks (and censored). 
Participants who die or are lost to follow up/withdrawn will be considered as not achieving culture 
negative status unless they have achieved a culture negative status prior to death or being lost to 
follow up/withdrawn. The last known visit date will be taken for any participants who are missing the 
date of their 8-week visit. Participants negative at baseline (but eligible for the trial based on a positive 
result at screening) will not be included in this primary time-to-event analysis.  
 
7.1.1. Sensitivity Analyses of Primary Efficacy Endpoint 
As a sensitivity analysis for the primary efficacy endpoint, multiple imputation [under the missing at 
random (MAR) assumption] will be used to account for missing culture results at missing visits, defined 
as missing when there are no culture results for any sample at a visit. Note: a contaminated result will 
be considered as such, up to and including week 8, after which it will be considered missing (for 
statistical analysis purposes). A seed of 102079 will be used, and 20 imputed values will be created for 
each missing observation in the multiple imputation model. 
 
7.2. 
Secondary endpoints 
7.2.1. Key Secondary Endpoint: Unfavourable Status at 12 months (Non-inferiority Comparison) 
For the proportion of participants who have an unfavourable outcome at 12 or 24 months, non-
inferiority will be determined using the upper bound of the (two-sided) 95% confidence interval of the 
difference, relative to the 12% margin. If the upper bound of the two-sided 95% confidence limit for 
the difference (proportion with unfavourable outcome in the intervention arm less the proportion with 
unfavourable outcome in the control arm) is less than 12% (the margin of non-inferiority), the 
intervention will be considered to be non-inferior to the control arm on that comparison.   
 
The difference in proportions of an unfavourable status at 12 months will be analysed using the 
Cochran-Mantel-Haenszel test. 
 
 Secondary Bayesian analysis of Unfavourable Status at 12 months  
 
A Bayesian analysis of the key secondary endpoint will also be performed (as a secondary analysis) 
with the posterior distribution of the effect size graphed under different prior distributions (for 
example, sceptical, uninformative and optimistic). This analysis has advantages over a more standard 
frequentist analysis as direct probability statements can be made about the effect size and in addition, 
prior information about the size of the effect can be formally incorporated into the posterior 
estimation.  While the uninformative prior will yield similar results as a standard frequentist analysis 
(i.e. with a point estimate and confidence interval), the Bayesian analysis provides a more intuitive 
interpretation about the effect of the intervention compared to control.   
 
 Sensitivity Analyses for Unfavourable Status at 12 months 
The following sensitivity analyses on the key secondary endpoint are planned: 
 
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1. An analysis of participants in the TB-mITT and PP populations where reinfections are 
re-classified as unfavourable outcomes.   
2. An analysis of the TB-mITT and PP populations treating all deaths as unfavourable. 
 
7.2.2. Unfavourable Status at 24 months 
Unfavourable status at 24 months will be analysed as described in the first two paragraphs of §7.2.1 
for unfavourable status at 12 months. 
 
7.2.3.  Time to Unfavourable Status 
Time to an unfavourable outcome will be analysed using a Cox proportional-hazards regression 
analysis.  These analyses will be performed according to the mITT, TB-mITT and PP classifications. Time 
to event will be calculated in days from the date of enrolment up to the first date associated with the 
reason for unfavourable status or (if favourable) the date of the  12 months post randomisation visit 
or date last seen if they did not reach 12 month follow-up. Kaplan Meier plots will also be presented. 
 
7.2.4. Time to Sputum Culture Conversion to Negative Status  
For the mITT analysis population, time to culture negative status (first of two negative cultures without 
an intervening positive culture) will be analysed using survival analysis techniques, Kaplan Meier plots 
and Cox proportional hazard regression. 
 
7.2.5. Culture Conversion Status at 4, 6, 12 and 17 Weeks  
For the mITT analysis population, participants will be classified as being culture positive, culture 
negative, dead or unassessable at 4, 6, 12 and 17 weeks.   
 
7.2.6. Adherence 
The proportion of participants who have an adequate amount of treatment (see §3.3) will be 
tabulated. No formal comparisons will be performed.  
 
7.2.7. Weight and BMI 
Baseline weight and BMI and their change from baseline weight at week 8 and end of treatment and 
at 12 and 24 months after the end of therapy will be summarised by mean, median, IQR and range. 
 
7.2.8. TB Symptoms 
Each TB symptom will be summarised by n (%): none (0), mild (1), moderate (2), severe (3) at each visit 
collected as per the protocol: baseline, week 8, end of treatment, 12 and 24 months after the end of 
therapy.  
 
In addition, baseline and change from baseline score at each time point listed above for each symptom 
and for total symptom score will be summarised by mean, median, IQR and range. 
 
7.2.9. Participant Reported Health Status 
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Participant reported health status is measured by the 5 domains of EQ5D. These will be summarised 
at baseline, week 8, end of treatment and 12 month follow-up by randomised group. Change from 
baseline will be summarized at each follow-up assessment by mean, median, IQR and range. 
 
7.2.10. Predictors of Favourable Status at 12 and 24 months 
As an exploratory analysis, predictors of having a favourable outcome at 12 months and at 24 months 
will be investigated. Potential predictors will include, but are not limited to, baseline variables (see 
§7.4), culture negative status at weeks 4, 6, 8, 12 and 17 as well as time to culture negativity (as a 
continuous variable).  
 
7.3. 
Interim Analyses 
 
7.3.1. Overview 
There is one planned interim analysis for efficacy data. The interim analysis is based on an intermediate 
outcome of time to negative culture conversion status observed by 8 weeks. Following a review of 
these interim findings, consideration will be given to increase the sample size (pending funding 
availability) to adequately power the study on the key secondary 12-month clinical outcome. This 
would then become the primary efficacy endpoint. This adaptation is based on the Multi-arm Multi-
stage (MAMS) framework [4-6]. 
 
The interim analysis endpoint (I) is time to negative culture conversion status observed by 8 weeks in 
the mITT population. The final analysis endpoint (D) is favourable status at 12 months. Therefore, as 
the interim endpoint is not the same as the final analysis endpoint this is denoted as I ≠ D i.e. interim 
endpoint does not equal the final endpoint. 
 
For the interim analysis, a single culture result at week 8, with no available future culture data, is 
sufficient to classify culture negative status at that visit (see §3.1.3). If all culture results are 
contaminated at week 8 and no future culture data is available, then the week 7 result is sufficient to 
determine status at week 8. 
 
7.3.2. Operating characteristics 
The power at each stage has been maintained at a high level (> 0.9) to ensure an effective intervention 
has a high chance of proceeding beyond I (to minimise the chance of missing a result and not extending 
recruitment).  
 
A 10% significance level (p=0.1 one-sided) has been chosen for the first stage to allow in an event that 
the intervention seems to be performing poorly then the sample size will not be increased but stay as 
planned.  At the first stage there is less concern about extending recruitment if the observed interim 
result is false so a higher than the conventional 5% (2-sided) level is chosen.  But, the corresponding 
power has been chosen as 95% so that there is a high chance of proceeding to the 2nd (and final stage) 
if there is an indication of a treatment effect on the intermediate outcome measure. 
 
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Positive Predictive Value of the Control (PPVC) and of the Intervention (PPVE) were assumed 95%. 
Other values of PPVC were also considered to explore the sensitivity of the design on this assumed 
value. This is from a review of the literature and analyses on previously published TB trials [7]. 
 
Table 2 outlines the operating characteristics for both I and D. 
 
 
 
 
 
7.3.3. Sample size calculation 
The calculation was conducted in STATA using the NSTAGEBIN command (Appendix §13.4). 
 
Currently, no software allows for selection of a HR at the interim stage and risk difference at the final 
stage.  As such, the treatment effect in I was transformed from a HR to a risk difference for the sample 
size calculation.  Assuming a control event rate of 50%, a HR of 2 was equivalent to an absolute risk 
difference of 25%. 
 
7.3.4. Decision 
The interim analysis will occur after approximately 60 participants randomised to the control arm have 
reached the 8-week primary endpoint.  At the interim stage, a test on the risk difference between the 
two treatment arms on the I-outcome measure is carried out. The design and decision rule for the first 
stage was made based on target effect size of 2 on the hazard ratio scale. If the p-value of the test on 
the I-outcome is less than 0.1, accrual to both arms may continue to the final stage when a test on the 
D-outcome measure is carried out. Successfully moving to the final stage will mean increasing 
recruitment to 225 per arm i.e. to a total of 450 DS-TB participants and up to 225 DR-TB participants 
(if desired). This will adequately power the trial on the new primary endpoint in D with an overall 
power (both stages combined) of 86%. 
 
7.4. 
Subgroup Analyses 
As exploratory analyses to assess consistency of outcome, the following sub-group analyses (with tests 
for interaction) of the primary endpoint on the mITT analysis populations will be considered according 
to:  
• 
HIV status 
• 
Cavitation (images are to be reviewed in order for these data to be considered reliable) 
Table 2. Operating characteristics for interim and final analysis  
 
Interim (Phase 2) 
Final (Phase 3) 
Primary Outcome 
Culture negative status 
Favourable rate 
Follow-up length 
8 weeks 
12 months 
Significance level (1 sided) 
10% 
2.5% 
Power 
95% 
90% 
Control arm event rate 
50% 
84% 
Treatment effect under (H0) 
0% 
-12% (NI margin) 
Treatment effect under (H1) 
25%  
0% 
Allocation ratio (E:C) 
1:1 
1:1 
Attrition rate (LTFU rate) 
0% 
13% 
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• 
Age 
• 
Sex 
• 
Race 
• 
Region 
• 
Smoking status 
• 
Alcohol intake 
• 
Pyrazinamide resistance (pending numbers) 
• 
Bedaquiline resistance (pending numbers) 
• 
Time to positivity 
 
7.5. 
Minimum Inhibitory Concentrations 
Minimum inhibitory Concentrations (MICs) for all drugs will be tabulated separately. Baseline will be 
cross tabulated against end of treatment. If measured at multiple visits, end of treatment will be used. 
This is for descriptive purposes only. 
 
8. Safety Statistical Analysis 
 
All safety endpoints will be presented descriptively, and no inferential tests will be carried out. AE 
duration will be calculated as (Stop Date – Start Date) + 1. Partial dates for AEs will not be imputed. In 
the case where it is not possible to define an AE as treatment-emergent or not, the AE will be classified 
as treatment-emergent. 
At each level of participant summarisation, a participant is counted once within each PT and then each 
SOC if the participant reports one or more events. 
8.1. 
All-cause mortality 
A table will be presented that contains the cause of death as well as the following details about death 
(Yes/No): 
• 
Death was related to TB 
• 
Death due to treatment failure 
• 
Death was violent or accidental (excluding suicide) 
• 
Death was due to suicide 
 
 
8.2. 
Treatment emergent AEs (TEAEs) 
 
8.2.1. Incidence of TEAEs 
Summaries of the total number of TEAEs and the number and percentage of participants with at least 
one TEAE will be provided. 
 
 
 
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8.2.2. Severity 
A summary of TEAEs by maximum severity will be presented in a table. In the TEAE severity table, if a 
participant reported multiple occurrences of the same TEAE, only the most severe TEAE is presented. 
TEAEs that are missing severity will be presented in tables as ‘Severe’ but will be presented in the data 
listing with a missing severity. A separate table will be presented for ‘Grade 3: Severe’ or ‘Grade 4: 
Potentially life-threatening’ TEAEs. 
 
8.2.3. Drug-related TEAEs 
A summary of TEAEs by relationship to study treatment will be presented in a table by incidence of 
occurrence. The investigator will provide an assessment of the relationship of the event to the study 
treatment and specifically for bedaquiline, pretomanid, moxifloxacin, pyrazinamide, and HRZE/HR. The 
possible relationships are summarised as ‘Not Related’ (i.e. ‘Not Applicable’, ‘Not related’, ‘Unlikely’) 
and ‘Related’ (i.e. ‘Possibly’, ‘Probably’, and ‘Certainly’) in the table and their actual values (i.e. ‘Not 
Applicable’, ‘Not related’, ‘Unlikely’, ‘Possibly’, ‘Probably’, and ‘Certainly’) in the listing. In the TEAE 
relationship table, if a participant reports multiple occurrences of the same TEAE, only the most closely 
related occurrence will be presented. All TEAEs that have a missing relationship will be presented in 
the summary table as “Certainly” but will be presented in the data listing with a missing relationship. 
8.2.4. Serious TEAEs 
Treatment-emergent SAEs will be categorised and presented by SOC and PT in the same manner to 
that described in §8.2.1. The same summary will be repeated for Bedaquiline, Pretomanid, 
Moxifloxacin and Pyrazinamide separately. 
8.2.5. TEAEs leading to treatment discontinuation or interruption 
A summary of TEAEs with action taken with study treatment as ‘Permanently Discontinued’ for BPaMZ 
or HRZE/HR will be presented in a table. At each level of participant summarisation, a participant is 
counted once if the participant reported one or more events.   
The same presentation will be provided for interruption of BPaMZ or HRZE/HR (‘Action Taken with 
IMP’ is ‘Interrupted’). Data will be categorised and presented by SOC and PT in the same manner to 
that described in §8.2.1. 
 
8.2.6. TEAE leading to study discontinuation 
A summary of TEAEs where the answer to action taken’ is ‘Withdrawn from Study’ will be presented 
in a table. At each level of participant summarisation, a participant is counted once if the participant 
reported one or more events. Data will be categorised and presented by SOC and PT in the same 
manner to that described in §8.2.1. 
 
 
8.2.7. TEAEs leading to death 
A summary of TEAEs where the answer to ‘Outcome’ in the AE form is ‘Fatal’ will be presented in a 
table. Data will be categorized and presented by SOC and PT in the same manner to that described in 
§8.2.1. 
 
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8.2.8. Liver-related TEAE 
A summary of TEAEs that has preferred terms under “Hepatic disorders” according to MedDRA 
dictionary will be presented by SOC and PT in the same manner to that described in §8.2.1. In addition, 
any liver-related TEAE tables will be presented by region, sex, age (< vs. >median), previous alcohol 
intake and HIV status. 
 
 Liver and drug-related TEAEs 
A summary of liver-related TEAEs that are drug related (i.e. ‘Possibly’, ‘Probably’, and ‘Certainly’) will 
be presented by SOC and PT for treatment arm and drug in the same manner to that described in 
§8.2.1. 
 
 Serious liver-related TEAEs 
A summary of TEAEs that are liver related and serious (as described in § 2.3.2.4) will be presented by 
SOC and PT for treatment arm in the same manner to that described in §8.2.1. Liver enzyme profile 
plots will be provided for patients with treatment emergent serious adverse events that have toxicity 
grade 3 or higher for either AST, ALT, ALP or total bilirubin. 
 
 Incidence of hepatotoxicity 
Proportion of participants experiencing at least one liver function test (LFT; AST or ALT) that is ≥3 x 
ULN or at least one hepatic SAE (as described in §8.2.8). This will be summarised in a table by treatment 
arm (and combining the BPaMZ arms to give a BPaMZ total). In addition we will summarise for those 
who have had a hepatotoxicity what their hepatitis status (A, B and C) was at baseline, at the time of 
the event and the change from baseline to time of event. 
 
 Predictors of hepatotoxicity  
As an exploratory analysis, pending numbers, predictors of having a hepatotoxicity (binary outcome of 
at least one LFT ≥3xULN or not) will be investigated. Potential predictors will include, but are not 
limited to, baseline variables (see §7.4 with the addition of weight and BMI) and hepatitis (A, B or C) 
at baseline. Logistic regression will be used for this binary outcome. If this logistic regression analysis 
converges and shows any suggestion of a predictor then, pending numbers in each group an ordered 
logistic regression will be considered using the outcomes as described in Table 3 which lists notable 
criteria for AST and ALT. If there are no or very small numbers of patients with ≥8xULN then this may 
be combined with the ≥5-<8xULN group.  
 
8.2.9. Additional TEAE summary 
The number and percentage of participants with the following specific TEAEs will be presented: grade 
2, 3, or 4 myalgia, and grade 3 or 4 cardiac rhythm disturbances, grade 3 or 4 lipase, pancreatitis, 
peripheral neuropathy. 
 
All AEs will be presented in a listing, which will specify whether they are treatment emergent or not. 
8.3. 
Clinical Evaluation 
 
8.3.1. Clinical Laboratory Evaluation 
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A list of laboratory tests (haematology, clinical chemistry, and urinalysis) to be included in the analysis 
is presented in §7.3 of the protocol. Laboratory assessments done by a central laboratory will be 
summarised in tables. All summaries will be based on the units provided by the central laboratory, no 
conversion will be done.  The laboratory evaluations will be summarised for baseline, post-baseline, 
and change from baseline at week 8, end of treatment (week 17 or week 26), 52 week and 104 week 
FU.  
 
Laboratory values outside normal ranges will be identified, and the number and percentage of 
participants with at least one post-baseline abnormality will be summarised in shift tables comparing 
the baseline results to each post-baseline timepoint for those participants with results at both 
timepoints.  
 
The table below displays the general variables and thresholds of interest. Participants are considered 
to have notable laboratory abnormalities if his/her response falls within the specified definitions at 
least once during the treatment period.  
 
Table 3: Notable Criteria for Laboratory Data  
Lab Test Type 
Laboratory 
Variable 
SI 
Units 
Liver 
AST 
>3 x ULN and  ≤ 5 x ULN 
>5 x ULN and  ≤ 8 x ULN 
>8 x ULN 
 
ALT 
>3 x ULN and  ≤ 5 x ULN 
>5 x ULN and  ≤ 8 x ULN 
>8 x ULN 
Total Bilirubin  
>2 x ULN 
Alkaline Phosphatase (ALP) 
>2 x ULN 
Chemistry Labs 
Other: 
ALT or AST > 3 x ULN and total bilirubin > 2 x ULN  
ALT or AST > 3 x ULN and total bilirubin > 2 x ULN and ALP < 2 x ULN (potential 
Hy’s law case) 
 
Lipase 
>2xULN to ≤5XULN 
>5xULN 
 
 
8.3.2. Vital Sign Measurements 
Vital sign measurements include blood pressures (mmHg) (resting more than 5 minutes), and heart 
rate (bpm). These measurements will be summarised for baseline and change from baseline at week 
8, end of treatment (week17 or week 26), 12 and 24 month follow-up. Only the vital signs collected at 
the scheduled visits or time points will be included in the summary.  
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Abnormal vital sign assessment results will be identified, and the number and percentage of 
participants with at least one post-baseline abnormality will be summarised. General variables and 
thresholds of interest are outlined in appendix 3 of the protocol.  
8.4. 
Electrocardiogram 
All participants will have a standard 12-lead (ECG) assessment (heart rate (HeR), PR interval, RR 
interval, corrected QTcF intervals (adjusted using Fridericia’s correction) performed by a central 
cardiologist. All summaries will be based on the central cardiologist assessment.  
 
For all ECG parameters (HeR, PR, RR, QTcF), actual values and changes from measurement closest to 
and prior to dosing at each time point (week 8, end of treatment (week 17 or week 26), week 39 will 
be summarised using descriptive statistics by treatment group and time of collection. 
Post-baseline QTcF intervals will be classified into the following categories: 
• 
QTcF ≤ 450 msec 
• 
450 msec < QTcF ≤ 480 msec 
• 
480 msec < QTcF ≤ 500 msec 
• 
QTcF > 500 msec 
QTcF changes from baseline will be classified into the following categories: 
• 
increase > 0 msec and ≤ 30 msec, 
• 
increase >30 msec and ≤ 60 msec, and 
• 
increase > 60 msec. 
Number and percentage of notable maximum QTcF interval and change from baseline QTcF interval 
will be summarised.  
Interpreted ECG results based on CRF investigator assessment will be classified as “normal”, 
“abnormal, not clinically significant”, or “abnormal, clinically significant”. The number and percentages 
of participants with normal, abnormal not clinically significant, and abnormal clinically significant will 
be presented. In addition, shift tables will be provided to summarise the status changes from baseline 
to week 8, end of treatment, 12 and 24 month follow-up assessments.  
Patients with any QT or QTcF values >=500 that resulted in early withdrawal will be presented in a 
figure. 
 
 
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8.5. 
Male Reproductive Hormone Tests 
Descriptive summary statistics by treatment arm will be presented for each of testosterone, follicle-
stimulating hormone, luteinizing hormone, and inhibin B. These will only be presented for those 
participants who have had these tests carried out at an official timepoint. Any participant who has had 
these tests carried out outside the official windows will not be included. The timepoints are as follows: 
screening and baseline (Day 1) results to be displayed together taking the average of the two, end of 
treatment (week 17 or week 26) and week 39 follow-up. Change from baseline (average of screening 
and day 1) for each reproductive laboratory parameter will be presented at end of treatment (week 
17 or week 26) and 9 month follow-up by treatment arm. 
 
8.6. 
Lens Opacity Tests 
Descriptive summary statistics by treatment arm will be presented for Ophthalmology slit lamp 
examinations (lens opacity classification and grading) for each of cortical, nuclear and posterior 
subcapsular lens opacities at screening, baseline (Day 1), end of treatment (week 17 or week 26) and 
week 39 follow-up. Change from baseline for each lens opacity parameter will be presented at end of 
treatment (week 17 or week 26) and 6 month follow-up by treatment arm.   
 
8.7. 
Pharmacokinetics/Pharmacodynamics 
Descriptive statistics (n, arithmetic mean, standard deviation (SD), coefficient of variation (CV%), 
median, minimum and maximum, geometric mean and geometric CV (%)) will be used to summarise 
the plasma concentration at each scheduled sampling time/window per analyte. The geometric mean 
is obtained by computing the arithmetic mean of the logarithm-transformed values of concentration 
and then using the exponentiation to return the computation to the original scale. Geometric CV(%) is 
calculated as follows: CV (%)=Square root of [exp(𝜎𝜎ො2) – 1] * 100, where 𝜎𝜎ො2 denotes the variance of the 
log-transformed values.  
 
For a concentration value below the limit of quantitation (BLQ), a concentration value of zero is 
included for the computation of arithmetic mean and a concentration value of 50% the lower limit of 
quantitation (plasma LLOQ = x.xx units) is included for the computation of geometric mean. If 50% or 
more of the values are BLQ at one timepoint, the arithmetic mean and geometric mean is reported as 
BLQ. If the calculated arithmetic mean and/or geometric mean are less than LLOQ, the arithmetic mean 
and/or geometric mean are reported as BLQ.  
 
Derivation of PK/PD parameters described in the protocol Section 9.6 and 9.7 will be covered in a 
separate modelling SAP.  
 
9. Participant Disposition 
 
9.1. 
Participant Disposition 
Participant disposition for all participants who signed informed consent will be presented as follows: 
• 
No. of participants screened, screen failed, randomised, and received at least one dose of 
treatment.  
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• 
Of those receiving at least one dose, the number and proportion who completed the IMP, who 
discontinued IMP, who completed the study, who discontinued from the study. The reasons 
for discontinuation of IMP and study participation will also be summarised.  
 
9.2. 
Study protocol deviations 
All major deviations will be summarised by deviation type for all ITT participants.  
 
10. Demographics and baseline characteristics  
The following demographics and baseline characteristics will be summarised using the ITT population. 
Number and percentage will be reported, unless otherwise noted. 
10.1. 
Demographics 
Age (years), height (cm), weight (kg), and body mass index (BMI) (kg/m2) will be summarised as 
continuous variables. BMI is defined as the participant’s weight (kg) divided by the square of their 
height (m). The number and percentage of participants will be presented for categorical variables 
including race (Asian, Black or African American, White, Mixed Race, Native Hawaiian or Other Pacific 
Islander, Other), region (EMEA, EMEA (South Africa sites only), Asia, South America), and sex (male, 
female). 
10.2. 
Baseline characteristics 
• 
History of TB (type) (DS-TB, Mono-Resistant TB, MDR TB, PRE-XDR TB, XDR TB) 
• 
Current TB type (DS-TB, DR-TB) 
• 
Smoking status (never, current, former)  
• 
Alcohol status (never, current, former)  
• 
Screening mycobacteriology test result  
o Smear microscopy for acid-fast bacilli (AFB) (no AFB seen, scanty positive, 1+, 2+, 3+) 
o Rapid molecular tests for fluoroquinolones, aminoglycosides-cyclicpeptides, isoniazid, 
and rifampicin resistance (Hain assay MTBDRplus and MTBDRsl (sensitive, resistant, 
indeterminate, not done)) and MTB confirmed (Yes, No) 
o Liquid culture (MGIT) mycobacterium tuberculosis (MTB) result (negative, positive for 
MTB complex, positive for MTB complex with contamination, contaminated, no result) 
and time to positivity when positive. 
• 
Serology  
o HIV status (positive, negative as collected in CRF) 
o CD4 count (summary statistics) 
• 
Karnofsky performance status 
• 
Chest X-ray (normal, abnormal) 
o Cavities (none, unilateral, bilateral) 
• 
Ophthalmologic history  
o History of vision and/or eye disorders (yes, no) 
o Immediate family history of cataracts (yes, no) 
o History of prior eye surgery and/or trauma (yes, no) 
 
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10.3. 
Medical History 
Medical history will be coded using the latest version of Medical Dictionary for Drug Regulatory 
Activities (MedDRA). The number and percentage of participants with clinically significant 
medical/treatment history will be summarised by system organ class (SOC) and preferred term (PT). 
Percentages will be calculated based on number of participants in the ITT analysis set. 
10.4. 
Inclusion and Exclusion Criteria 
The inclusion and exclusion criteria can be referenced in the protocol, Sections 5.1 and 5.2, 
respectively. Any participant who violates the inclusion and/or exclusion criteria (screen failures as 
well as late screen failures) will be presented in a listing.  
 
 
11. Treatment and Medications 
 
11.1. 
Prior and Concomitant Medications 
For the purpose of inclusion in prior and/or concomitant medication summary tables, incomplete 
medication start and stop dates will be imputed as follows: 
Missing start dates will be handled as follows (where UK, UKN and UNKN indicate unknown or missing 
day, month and year respectively):  
• 
UK-MMM-YYYY: impute to 01-MMM-YYYY;  
• 
UK-UKN-YYYY: impute to 01-JAN-YYYY; 
• 
UK-UKN-UNKN: impute to date of initial screening. 
Missing stop dates will be handled as follows (where UK, UKN and UNKN indicate unknown or missing 
day, month and year respectively):  
• 
UK-MMM-YYYY: Assume the last day of the month; 
• 
UK-UKN-YYYY: Assume 31-DEC-YYYY; 
• 
UK-UKN-UNKN: Assume last day of study visit. 
All medications will be coded according to the latest version of World Health Organization drug 
dictionary. Summaries on prior and concomitant medication will be performed using the ITT set. Data 
on prior and concomitant medications will be presented in a listing. 
11.1.1. Prior Medications 
A prior medication is defined as any medication that has a stop date before the start of the study drug 
(prior to Day 1). Prior medications collected in the CRF will be classified as TB medications and non-TB 
medications. The number and percentages of participants with at least one prior medication will be 
summarised separately for TB medications and non-TB medications. Prior medications will be 
summarised by Anatomical Therapeutic Chemical classification 4 (ATC4) if used by >10% of 
participants. . 
11.1.2. Concomitant Medications 
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A concomitant medication is defined as any medication that has a stop date that is on or after the date 
of first dose of study treatment (Day 1). The number and percentages of participants with at least one 
concomitant medication will be summarised. Concomitant medication will also be summarised by 
ATC4 classification if used by >10% of participants.  
11.1.3. Concomitant Procedures 
A concomitant procedure is defined as any procedure that has a date that is on or after the date of 
first dose of study treatment (Day 1). The number and percentages of participants with at least one 
concomitant procedure will be summarised. Concomitant procedures will be summarised by MedDRA 
higher level term if carried out on >5% of participants.  
 
11.1.4. Study Treatment Exposure 
A participant’s drug exposure in days will be defined as (date of last dose - date of first dose +1). Drug 
exposure in weeks will be calculated by dividing the exposure in days by 7. The date of last dose is the 
last available date in the study medication page, if missing then the date of last dose in the disposition 
treatment page will be used. 
The duration of exposure to IMP and its category (4BPaMZ: <17 weeks, ≥17 weeks and 6BPaMZ: <17 
Weeks, ≥17 to <26 Weeks, ≥26 Weeks) by treatment will be summarised for all participants in the 
safety set and will be presented in a table by summary statistics. 
The following exposure parameters will be summarised according to the general methods: 
• 
HRZE-HR pause (number and percentage of participants with at least one dose pause and 
number of dose pauses, reason for dose pause). The HRZE-HR pause information will be 
retrieved from the CRF Exposure HRZE-HR Dosing pages indicated by a pause. 
• 
BPaMZ pause (number of participants with at least one dose pause and number of participants 
with at least one pause). The BPaMZ pause information will be retrieved from the CRF 
Exposure BPaMZ dosing pages indicated by a pause. 
 
 
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12. References 
1. 
Phillips, P.P.J., et al., A comparison of liquid and solid culture for determining relapse and 
durable cure in phase III TB trials for new regimens. BMC Med, 2017. 15(1): p. 207. 
2. 
Gillespie, S.H., et al., Four-month moxifloxacin-based regimens for drug-sensitive 
tuberculosis. N Engl J Med, 2014. 371(17): p. 1577-87. 
3. 
Tiemersma, E.W., et al., Natural history of tuberculosis: duration and fatality of untreated 
pulmonary tuberculosis in HIV negative patients: a systematic review. PLoS One, 2011. 6(4): 
p. e17601. 
4. 
Parmar, M.K., et al., Testing many treatments within a single protocol over 10 years at MRC 
Clinical Trials Unit at UCL: Multi-arm, multi-stage platform, umbrella and basket protocols. 
Clin Trials, 2017. 14(5): p. 451-461. 
5. 
Bratton, D.J., P.P. Phillips, and M.K. Parmar, A multi-arm multi-stage clinical trial design for 
binary outcomes with application to tuberculosis. BMC Med Res Methodol, 2013. 13: p. 139. 
6. 
Royston, P., et al., Designs for clinical trials with time-to-event outcomes based on stopping 
guidelines for lack of benefit. Trials, 2011. 12: p. 81. 
7. 
Bratton, D.J., Design issues and extensions of multi-arm multi-stage clinical trials. 2015, UCL 
(University College London). 
8. 
Jindani, A., et al., High-dose rifapentine with moxifloxacin for pulmonary tuberculosis. N Engl J 
Med, 2014. 371(17): p. 1599-608. 
9. 
Lienhardt, C., et al., Efficacy and safety of a 4-drug fixed-dose combination regimen 
compared with separate drugs for treatment of pulmonary tuberculosis: the Study C 
randomized controlled trial. JAMA, 2011. 305(14): p. 1415-23. 
 
 
 
 
 
 
 
 
 
 
 
 
 
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13. Appendix 
 
13.1. 
Derived MGIT results per visit  
 
Table A13.1: Derived MGIT results per visit  
Derived sample Culture 1 
(Visit X ) 
Derived Sample Culture 2    (Visit 
X) 
Final Derived Result               for 
Visit X 
Positive 
Missing/Negative/Contaminated 
Positive 
Negative 
Missing/Contaminated 
Negative 
Contaminated/missing 
Missing/Contaminated 
Missing 
 
13.2. 
Interpretation of Relapse/Reinfection using Whole Genome Sequence (WGS) 
The purpose of the WGS analysis is to determine if the two M. tuberculosis strains from a given 
participant (positive culture at baseline and at or after the end of treatment) can be considered the 
same (treatment failure/bacteriologic failure or relapse/bacteriological relapse), or different 
(reinfection/bacteriological reinfection).    
 
To do this, WGS of the two M. tuberculosis strains are compared, the number of SNPs/variants 
determined, and the criteria outlined below followed.   
 
These cut offs have been determined from previously published reports (REMoxTB [2]  and RIFAQUIN 
[8]  trials) that show a clear genetic distinction between relapse and reinfection cases of M.tb infection. 
 
≤12 SNPs different = Relapse 
 
≥100 SNPs different = Reinfection 
 
>12 and <100 SNPs different = Indeterminate   
 
 
Indeterminate results will be reviewed on case by case basis and are likely to be rare.   
 
Additional sequence analysis may be performed and/or additional samples may need to be tested.   
 
Any additional investigations will be documented on the ‘WGS Indeterminate Proforma’ which also 
includes the final conclusion of ‘relapse’ or reinfection’ based on this further review.  
 
A participant will be considered a relapse unless there is sufficient evidence to support a classification 
of reinfection. 
 
 
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13.3. 
TB-mITT population 
In the TB field, the combination of bacteriologic cure rates approaching 100% and required long-term 
follow up has meant that recorded negative outcomes are very much contaminated with the “noise” 
of missing data.   
 
There is a clear precedent for this analytic approach, and those trials also provide examples of why the 
inclusion of the losses to follow-up as unfavourable outcomes can affect the results. Data from the 
Priftin trial which led to accelerated approval of rifapentine and a trial conducted by the International 
Union Against TB & Lung Disease (IUATLD) in African and Asian sites illustrate the problems associated 
with classifying all losses to follow-up and deaths as having an unfavourable outcome [9]. In the Priftin 
trial bacteriological relapses occurred in 5% of participants on the rifampicin based regimen compared 
to 11% on the rifapentine based regimen.  Approximately one third of participants were lost to follow-
up and when this group combined with participants unassessable for other reasons were added to the 
bacteriological failures, the rates increased to 53% and 57% respectively.  The true bacteriological 
relapses were greatly outnumbered by these other groups. At the time of the licensing submission to 
the FDA it was recognised that because there were a substantial number of participants likely to be 
unassessable the main focus should be on the relapse rates.  In the final statistical report, the results 
were first reported excluding those unassessable and then assuming all losses follow-up had an 
unfavourable outcome and finally assuming all losses to follow-up had a favourable outcome. 
 
In a study conducted by the IUATLD the published failure/relapse rates 12 months after stopping 
treatment based on 1044 assessable participants were 5% for the control regimen and 10% and 14% 
in each of the experimental arms.  If the 311 unassessable participants were considered to have an 
unfavourable outcome these rates would have increased to 24%, 32% and 35%, respectively. The 311 
unassessable participants were not evenly distributed across the three trial arms. There were 42 
deaths, of which 20 occurred in one of the experimental arms (the more efficacious of the two) and 11 
in each of the other, a difference which was not considered to be due to the treatment, but due to 
chance.  There were also imbalances among those without a bacteriological assessment (7 in one arm 
versus 19 and 22 in the other two arms) and in the distribution of losses to follow-up. 
 
Hence the adaptation to this situation in publications, generally replacing what is usually considered 
mITT analyses in the TB field with TB-mITT analyses.   
 
 
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NC008_SimpliciTB Combined Statistical Analysis Plan v3.0.docx                                   
Page 38 of 38 
13.4. 
STATA code for interim analysis sample size 
 
nstagebin, nstage(2) arms(2 2) alpha(0.1 0.025) power(0.95 0.9) theta0(0 -0.12) theta1(0.25 0) 
ctrlp(0.5 0.84) ppvc(0.95) ppve(0.95) accrate(200 200) fu(0.27 1.0) extrat(0.075) ltfu(0 0.13) tunit(1) 
 
n-stage trial design                 version 1.0.1, 17 Jul 2014 
--------------------------------------------------------------- 
Sample size for a 2-arm 2-stage trial with binary outcome based 
on Bratton et al. (2013) BMC Med Res Meth 13:139 
--------------------------------------------------------------- 
 
Control arm I (D) event rate = 0.50 (0.84) 
Delay in observing I (D) outcome = 0.27 (1.0) years 
Attrition rate for I (D) outcome = 0.00 (0.13) 
 
Operating characteristics 
---------------------------------------------------------------------- 
           Alpha(1S)     Power  theta|H0  theta|H1   Length*     Time* 
---------------------------------------------------------------------- 
Stage 1       0.1000     0.950     0.000     0.250     0.945     0.945 
Stage 2       0.0250     0.900    -0.120     0.000     2.375     3.320 
Pairwise      0.0250     0.860                                   3.320 
---------------------------------------------------------------------- 
 *  Length (duration of each stage) is expressed in year periods 
 
Cumulative sample sizes per arm per stage 
                       ---------Stage 1---------  ---------Stage 2--------- 
                       Overall  Control   Exper.  Overall  Control   Exper. 
--------------------------------------------------------------------------- 
Number of active arms        2        1        1        2        1        1 
Accrual rate*            200.0    100.0    100.0    200.0    100.0    100.0 
Patients for analysis      120       60       60      392      196      196 
Patients recruited**       190       95       95      450      225      225 
--------------------------------------------------------------------------- 
 *  Accrual rates are specified in number of patients per year 
 ** Accounts for loss-to-follow-up rate and includes those recruited during follow-up periods 
 
 
.  
end of do-file 
 
 
 
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Note to file 1 for SimpliciTB SAP v3.0 May 2021 
NtF1 “Positive with contamination” culture results 
This is to clarify that MGIT cultures with the final result “positive with 
contamination” were considered to be positive when determining culture conversion 
status.  
The SAP section 3.1.1 should read “The MGIT culture results that are contaminated 
or with no result will be treated as missing” instead of “The MGIT culture results that 
are positive with contamination, contaminated, or with no result will be treated as 
missing.” 
The extra words were inserted in error between SAP version 2.0 (“False positive or 
contaminated sputum cultures, without speciation data confirming presence of 
M.tb, will be treated as missing.”) and version 3.0 (“The MGIT culture results that are
positive with contamination, contaminated, or with no result will be treated as
missing.”).
Signed 
Date: 11th November 2021 
Lindsay Thompson 
Statistician for the SimpliciTB Trial 
Institute of Clinical Trials and Methodology 
MRC Clinical Trials Unit at UCL 
90 High Holborn 2nd Floor  
London WC1V 6LJ 
40 of 42


Note to file 2 for SimpliciTB SAP v3.0 May 2021 
NtF2 Reporting of TEAEs under SMQs 
This note to file clarifies the reporting of TEAEs under the SMQs.  
The SimpliciTB SAP v3.0 (dated May 2021) section 8.2.9 states: 
 “The number and percentage of participants with the following specific TEAEs will be presented 
separately: grade 2, 3 or 4 myalgia, grade 3 or 4 cardiac rhythm disturbances, grade 3 or 4 lipase, 
pancreatitis, peripheral neuropathy and myelosuppression.” 
Section 8.2.9 should have said: 
“The number and percentage of participants with the following specific TEAEs will be presented 
separately: grade 2, 3 or 4 myalgia, grade 3 or 4 cardiac rhythm disturbances, pancreatitis, 
peripheral neuropathy and myelosuppression.” 
In addition, the following should have been included in the SAP: 
“Following an SMQ analysis of the adverse events using the online MedDRA SMQ Analysis tool, the 
number and percentage of participants with TEAEs falling under the following SMQs will be 
presented”: 
SMQ Category 
SMQ Analysis Rule 
Hepatic Event 
All PTs under SMQ (hepatic disorder) 
Seizure (neurological) 
All PTs under SMQ (Convulsions) 
Peripheral Neuropathy  
All PTs under SMQ (peripheral neuropathy) 
Lactic Acidosis 
All PTs under SMQ (lactic acidosis) 
Pancreatitis, Amylase elevation, Lipase elevation 
All Narrow PTs and broad B terms  under acute 
pancreatitis SMQ 
Optic neuropathy 
All PTs under SMQ (optic nerve disorder) 
Myelosuppression 
All PTs under SMQ (Haematopoetic cytopenias) 
Cardiac Rhythm Disturbances 
All PTs under SMQ (Cardiac arrhythmias) 
Musculoskeletal System 
(Myalgia) 
All PTs under SMQ (Rhabdomyolysis/myopathy), excluding 
the following PTs: 
Creatinine renal clearance decreased 
Hypocalcaemia 
Signed 
Date: 11th November 2021 
Lindsay Thompson 
Statistician for the SimpliciTB trial 
Institute of Clinical Trials and Methodology 
MRC Clinical Trials Unit at UCL 
90 High Holborn 2nd Floor  
London WC1V 6LJ 
41 of 42


Note to file 3 for SimpliciTB SAP v3.0 May 2021 
NtF3 Liver Enzyme Plots 
This note clarifies the drawing of the liver enzyme plots.  
The SimpliciTB SAP v3.0 (dated May 2021), section 8.2.8.2 states: 
 “Liver enzyme profile plots will be provided for participants with treatment 
emergent serious adverse events that have toxicity grade 3 or higher for either AST, 
ALT, ALP or total bilirubin.” 
This was intended to be in section 8.2.8.2 and read: 
“Liver enzyme profile plots will be provided for participants with laboratory tests 
with toxicity grade 3 or higher for AST or ALT. These plots will include ALT, AST, ALP, 
and total bilirubin.” 
Signed 
Date: 11th November 2021 
Lindsay Thompson 
Statistician for the SimpliciTB trial 
Institute of Clinical Trials and Methodology 
MRC Clinical Trials Unit at UCL 
90 High Holborn 2nd Floor  
London WC1V 6LJ 
42 of 42