Conditions: Tuberculosis
Keywords: Tuberculosis Multi Drug-Resistant Tuberculosis Drug-Sensitive Tuberculosis PA-824 Bedaquiline Moxifloxacin Pyrazinamide Quinolone Pretomanid NC-005
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 240
Healthy volunteers: no

Brief summary:
The purpose of this study is to determine the mycobactericidal activity of combinations of bedaquiline (J), moxifloxacin (M), PA-824 (Pa) and pyrazinamide (Z) regimens during 8 weeks of treatment.

Detailed description:
The trial design is a phase 2, multi-center, open-label, partially randomized clinical trial in four parallel treatment groups. Subjects with drug-sensitive tuberculosis (DS-TB) will be randomized to receive either J(loading dose/three times a week)PaZ; or J(200mg)PaZ; or HRZE. Subjects with multi drug-resistant tuberculosis will receive J(200mg)MPaZ. The HRZE treatment arm is included as a control for the drug-sensitive treatments and as a control for the quantitative laboratory mycobacteriology testing.

A total of approximately 240 male and female, newly diagnosed subjects with drug-sensitive or multi drug-resistant, smear positive pulmonary tuberculosis aged 18 to 75 years (inclusive) will be included in the study. A total of 180 subjects with drug-sensitive tuberculosis (60 per treatment arm) will be randomized. Up to 60 subjects with multi-drug resistant tuberculosis will be assigned.

All subjects will have up to a maximum of 9 days screening, receive 8 weeks of treatment, and have follow-up visits at 2 and 12 weeks after study treatment completion or last dose of investigational medicinal product in the case of early withdrawal. Subjects who withdraw from the study after receiving \< 14 days of investigational medicinal product, will only attend a follow-up visit at 2 weeks after last dose of investigational medicinal product.

Upon treatment completion, the subjects with drug-sensitive tuberculosis will be provided with sufficient doses of standard of care tuberculosis treatment, as appropriate, to cover the time period from attending their last visit at the study clinic until their scheduled visit at the TB clinic. All subjects with drug sensitive and multi-drug resistant tuberculosis will be referred to the local community tuberculosis clinics for standard anti-tuberculosis chemotherapy according to National Tuberculosis Guidelines.

Arms:
arm 1: Subjects with DS-TB. J(loading dose/t.i.w.)PaZ: Bedaquiline 400mg once daily Days 1-14, 200mg three times per week Days 15-56; plus PA-824 200mg once daily Days 1-56; plus pyrazinamide 1500mg once daily Days 1-56. arm 2: Subjects with DS-TB. J(200mg)PaZ: Bedaquiline 200mg once daily Days 1-56; plus PA-824 200mg once daily Days 1-56; plus pyrazinamide 1500mg once daily Days 1-56. arm 3: Subjects with MDR-TB. J(200mg)MPaZ: Bedaquiline 200mg once daily Days 1-56; plus moxifloxacin 400mg once daily Days 1-56; plus PA-824 200mg once daily Days 1-56; plus pyrazinamide 1500mg once daily Days 1-56. arm 4: Subjects with DS-TB. HRZE tablets (Isoniazid 75mg plus rifampicin 150mg plus pyrazinamide 400mg plus ethambutol 275mg combination tablets) dosed once daily Days 1-56 per the Subject's weight as follows: 30-37kg: 2 tablets; 38-54kg: 3 tablets; 55-70kg: 4 tablets; 71kg and over: 5 tablets.

Interventions: intervention 1: PA-824 intervention 2: bedaquiline intervention 3: moxifloxacin intervention 4: pyrazinamide intervention 5: isoniazid, rifampicin, pyrazinamide and ethambutol combination tablet
Intervention descriptions: intervention 1: oral intervention 2: oral intervention 3: oral intervention 4: oral intervention 5: oral

Protocol document:
Prot_000.pdf: 
 
  
TMP02‐B V1.0  
 
   
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CONFIDENTIAL 
 
 
 
PROTOCOL 
 
 
Protocol Title: A Phase 2 Open‐Label Partially Randomized Trial to Evaluate the Efficacy, Safety 
and Tolerability of combinations of bedaquiline, moxifloxacin, PA‐824 and pyrazinamide during 8 
weeks of treatment in Adult Subjects with Newly Diagnosed Drug‐Sensitive or Multi Drug‐
Resistant, Smear‐Positive Pulmonary Tuberculosis. 
 
 
Protocol Number: NC‐005‐(J‐M‐Pa‐Z) 
Working Protocol Version: 1.1 (Final) 
Working Protocol Date: 19 September 2014 
 
COMBINATION OF THE FOLLOWING APPROVED FINAL DOCUMENTS: 
 
Protocol V1.0 dated 31 January 2014 
Protocol Amendment 01 dated 19 September 2014 
 
 
 
 




Global Alliance for TB Drug Development 
Protocol Number: NC‐005‐(J‐M‐Pa‐Z) 
Working Protocol Version: 1.1 (Final) 
Protocol Date: 19 September 2014 
 
 
 
TMP02‐A V1.0 
 
 
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PRINCIPAL INVESTIGATOR PROTOCOL SIGNATURE PAGE 
 
 
Protocol Title: A Phase 2 Open‐Label Partially Randomized Trial to Evaluate the Efficacy, Safety and Tolerability 
of combinations of bedaquiline, moxifloxacin, PA‐824 and pyrazinamide during 8 weeks of treatment in Adult 
Subjects  with  Newly  Diagnosed  Drug‐Sensitive  or  Multi  Drug‐Resistant,  Smear‐Positive  Pulmonary 
Tuberculosis. 
Protocol Number: NC‐005‐(J‐M‐Pa‐Z) 
Working Protocol Version: 1.1 (Draft) 
Protocol Date: 19 September 2014 
 
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 
 
 
 
 
 


Global Alliance for TB Drug Development 
Protocol Number: NC‐005‐(J‐M‐Pa‐Z) 
Working Protocol Version: 1.1 (Final) 
Protocol Date: 19 September 2014 
 
 
 
TMP02‐A V1.0 
 
 
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Development Phase: 
2 
Sponsor: 
Global Alliance for TB Drug Development 
40 Wall Street, 24th Floor 
New York, NY  10005 
United States of America 
Medical Monitor: 
Name: Dr Christo van Niekerk 
Address: Global Alliance for TB Drug Development 
Boardwalk Office Park 
Ground Floor, Block 1, Suite 5 
107 Haymeadow Street, Faerie Glen, 0043 
Pretoria, South Africa 
Telephone: +27 87 700 3901 
Mobile: +27 82 550 3865 
Facsimile: +27 12 991 3045 
Email: christo.vanniekerk@tballiance.org 
Co‐ordinating Investigator: 
Name: Dr Rodney Dawson 
Address : Centre for Tuberculosis Research Innovation 
University of Cape Town Lung Institute 
George Street 
Mowbray 7800 
South Africa 
Telephone: +27 21 406 6864 
Mobile: +27 83 290 7322 
Facsimile: +27 21 406 6907 
Email: rodney.dawson@uct.ac.za 
 
 
 


Global Alliance for TB Drug Development 
Protocol Number: NC‐005‐(J‐M‐Pa‐Z) 
Working Protocol Version: 1.1 (Final) 
Protocol Date: 19 September 2014 
 
 
 
TMP02‐A V1.0 
 
 
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TABLE OF CONTENTS 
1. 
PROTOCOL SYNOPSIS ................................................................................................................................. 14 
1.1. 
Synopsis ............................................................................................................................................. 14 
1.2. 
Trial Flow Chart – Screening Period to Day 140 Follow Up Visit ....................................................... 20 
1.3 
Trial Flow Chart – 8 to 26 Month Telephonic Survival Follow Up Period .......................................... 21 
2. 
INTRODUCTION ......................................................................................................................................... 24 
2.1. 
Background ........................................................................................................................................ 24 
2.2. 
Agents to be Studied ......................................................................................................................... 25 
2.2.1. 
Bedaquiline ................................................................................................................................ 25 
2.2.1.1. 
Bedaquiline Preclinical Studies .......................................................................................... 25 
2.2.1.2. 
Bedaquiline Clinical Studies ............................................................................................... 26 
2.2.1.3. 
Bedaquiline Clinical Safety ................................................................................................. 28 
2.2.2. 
PA‐824 ....................................................................................................................................... 29 
2.2.2.1. 
PA‐824 Preclinical Studies ................................................................................................. 30 
2.2.2.2. 
PA‐824 Clinical Studies ...................................................................................................... 33 
2.2.2.3. 
Clinical Safety ..................................................................................................................... 40 
2.2.3. 
Moxifloxacin .............................................................................................................................. 43 
2.2.3.1. 
Moxifloxacin Clinical Studies ............................................................................................. 44 
2.2.3.2. 
Moxifloxacin Clinical Safety ............................................................................................... 44 
2.2.4. 
Pyrazinamide ............................................................................................................................. 45 
2.3. 
Regimens to be Studied ..................................................................................................................... 46 
2.3.1. 
Non‐clinical Studies ................................................................................................................... 46 
2.3.2. 
Clinical Study NC‐003 – Preliminary Results .............................................................................. 46 
2.4. 
Control: HRZE ..................................................................................................................................... 48 
2.5. 
Known and Potential Risks and Benefits of the Investigational Medicinal Product/s ...................... 48 
2.5.1. 
Bedaquiline ................................................................................................................................ 48 
2.5.2. 
PA‐824 ....................................................................................................................................... 49 
2.5.3. 
Pyrazinamide ............................................................................................................................. 50 
2.5.4. 
Moxifloxacin .............................................................................................................................. 50 
2.6. 
Overall Benefit/Risk Assessment ....................................................................................................... 51 
3. 
TRIAL RATIONALE AND OBJECTIVES .......................................................................................................... 51 
3.1. 
Trial Rationale .................................................................................................................................... 51 
3.2. 
Study Design Rationale ...................................................................................................................... 52 
3.3. 
Dose Rationale ................................................................................................................................... 52 


Global Alliance for TB Drug Development 
Protocol Number: NC‐005‐(J‐M‐Pa‐Z) 
Working Protocol Version: 1.1 (Final) 
Protocol Date: 19 September 2014 
 
 
 
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3.3.1. 
Bedaquiline ................................................................................................................................ 52 
3.3.2. 
PA‐824 ....................................................................................................................................... 52 
3.3.3. 
Moxifloxacin .............................................................................................................................. 53 
3.3.4. 
Pyrazinamide ............................................................................................................................. 53 
3.3.5. 
HRZE Combination Tablets ........................................................................................................ 53 
3.4. 
Trial Objectives .................................................................................................................................. 53 
4. 
TRIAL DESIGN ............................................................................................................................................. 54 
4.1. 
Summary ............................................................................................................................................ 54 
4.2. 
Trial Endpoints ................................................................................................................................... 55 
4.2.1. 
Primary Endpoint ....................................................................................................................... 55 
4.2.2. 
Secondary Endpoints ................................................................................................................. 55 
4.2.2.1. 
Efficacy: .............................................................................................................................. 55 
4.2.2.2. 
Safety and Tolerability: ...................................................................................................... 56 
4.2.2.3. 
Pharmacokinetics / Pharmacokinetics‐Pharmacodynamics (PK‐PD): ............................... 56 
4.2.2.4. 
Exploratory Endpoints: ...................................................................................................... 58 
4.2.2.5. 
General Mycobacteriology: ............................................................................................... 58 
4.3. 
Trial Population ................................................................................................................................. 59 
4.3.1. 
Inclusion Criteria ........................................................................................................................ 59 
4.3.2. 
Exclusion Criteria ....................................................................................................................... 60 
4.4. 
Treatment Plan:  Schedule of Assessments ....................................................................................... 62 
4.4.1. 
Screening Period (Days ‐9 to Day ‐1) ......................................................................................... 63 
4.4.1.1. 
Day ‐9 to ‐3 ........................................................................................................................ 63 
4.4.1.2. 
Day ‐2 ................................................................................................................................. 64 
4.4.1.3. 
Day ‐1 ................................................................................................................................. 64 
4.4.2. 
Treatment Period (Day 1 to Day 57) .......................................................................................... 64 
4.4.2.1. 
Day 1 .................................................................................................................................. 66 
4.4.2.2. 
Day 4 .................................................................................................................................. 66 
4.4.2.3. 
Day 8; 22; 36 and 50 (+/‐ 2 days window for Visits on Days 22, 36 and 50) ..................... 67 
4.4.2.4. 
Day 14 ................................................................................................................................ 67 
4.4.2.5. 
Day 15 and 43 (+/‐ 2 days window for Visit on Day 43) .................................................... 67 
4.4.2.6. 
Day 29 (+/‐ 2 days window) ............................................................................................... 68 
4.4.2.7. 
Day 56 ................................................................................................................................ 68 
4.4.2.8. 
Day 57 ................................................................................................................................ 68 


Global Alliance for TB Drug Development 
Protocol Number: NC‐005‐(J‐M‐Pa‐Z) 
Working Protocol Version: 1.1 (Final) 
Protocol Date: 19 September 2014 
 
 
 
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4.4.2.9. 
Early Withdrawal ............................................................................................................... 69 
4.4.3. 
Follow‐Up Period (Day 70 to Day 140) ...................................................................................... 69 
4.4.3.1. 
Day 70 or 2 Weeks after Last Dose of IMP (+/‐ 3 days window) ....................................... 69 
4.4.3.2. 
Day 140 or 12 Weeks after Last Dose of IMP (+/‐ 14 days window) ................................. 69 
4.4.4. 
Telephonic Survival Follow Up Contact for Survival Data at 6, 12, 18 and 24 months after  Last 
Dose of IMP (+/‐ 14 day window) i.e. Month 8, Month 14, Month 20 and Month 26 .............................. 70 
4.5. 
Treatment Discontinuation and Subject Withdrawal ........................................................................ 70 
4.6. 
Stopping Rules ................................................................................................................................... 70 
4.7. 
Subject Progress Definitions .............................................................................................................. 71 
4.7.1. 
Enrollment ................................................................................................................................. 71 
 
Screening Failure ............................................................................................................................... 71 
 
Enrolled .............................................................................................................................................. 71 
4.7.2. 
Completed Treatment ............................................................................................................... 71 
4.7.3. 
Early Withdrawal ....................................................................................................................... 71 
4.7.4. 
Completed Trial ......................................................................................................................... 71 
4.8. 
Restrictions ........................................................................................................................................ 71 
4.8.1. 
Prior and Concomitant Medications and Other Treatments ..................................................... 71 
4.8.1.1. 
Recommendations for Concomitant Use of Anti‐Malarials............................................... 72 
4.8.1.2. 
Concomitant Use of Antiretroviral Therapy ...................................................................... 72 
5. 
INVESTIGATIONAL MEDICINAL PRODUCT ................................................................................................. 73 
5.1. 
Trial Treatments ................................................................................................................................ 73 
5.2. 
Method of Assigning Subjects to Treatment Groups ........................................................................ 73 
5.3. 
IMP Administration ............................................................................................................................ 74 
5.4. 
Subject Compliance ........................................................................................................................... 74 
5.5. 
Blinding and Procedures for Breaking the Blind ................................................................................ 74 
5.6. 
IMP Packaging and Labeling .............................................................................................................. 74 
5.6.1. 
Packaging ................................................................................................................................... 74 
5.6.2. 
Labeling ...................................................................................................................................... 75 
5.7. 
Storage ............................................................................................................................................... 76 
5.8. 
Dispensing and Accountability .......................................................................................................... 76 
5.9. 
Returns and Destruction .................................................................................................................... 76 
6. 
TRIAL VARIABLES AND PROCEDURES ........................................................................................................ 77 
6.1. 
Demographic and Baseline Variables and Procedures ...................................................................... 77 
6.2. 
Efficacy Variables and Procedures ..................................................................................................... 78 


Global Alliance for TB Drug Development 
Protocol Number: NC‐005‐(J‐M‐Pa‐Z) 
Working Protocol Version: 1.1 (Final) 
Protocol Date: 19 September 2014 
 
 
 
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6.3. 
Safety and Tolerability Variables and Procedures ............................................................................. 78 
6.4. 
Pharmacokinetic Variables and Procedures ...................................................................................... 79 
6.5. 
Mycobacteriology Characterization Variables and Procedures ........................................................ 80 
7. 
ADVERSE EVENTS ....................................................................................................................................... 82 
7.1. 
Definitions ......................................................................................................................................... 82 
7.1.1. 
Adverse Event (AE) .................................................................................................................... 82 
7.1.2. 
Serious Adverse Event (SAE) ...................................................................................................... 82 
7.1.3. 
Unlisted (Unexpected) Adverse Event ....................................................................................... 83 
7.1.4. 
Life threatening ......................................................................................................................... 83 
7.1.5. 
Associated with the Use of the Drug ......................................................................................... 83 
7.1.6. 
Attribution/Causality ................................................................................................................. 83 
7.1.7. 
Severity ...................................................................................................................................... 83 
7.1.8. 
Other AE Definitions .................................................................................................................. 84 
7.2. 
Reporting ........................................................................................................................................... 84 
7.2.1. 
Adverse Event (AE) .................................................................................................................... 84 
7.2.2. 
Serious Adverse Event (SAE) ...................................................................................................... 85 
7.2.3. 
Follow up of Adverse Events ..................................................................................................... 85 
7.2.4. 
Post‐Trial Adverse Events .......................................................................................................... 86 
7.2.5. 
Clinical Laboratory Adverse Events ........................................................................................... 86 
7.2.6. 
Disease under Study .................................................................................................................. 86 
7.2.7. 
Overdose .................................................................................................................................... 86 
7.2.8. 
Drug Interaction......................................................................................................................... 86 
7.2.9. 
Pregnancy .................................................................................................................................. 86 
7.3. 
Monitoring and Safety for Specific Toxicities .................................................................................... 87 
7.3.1. 
ALT and AST ............................................................................................................................... 87 
7.3.2. 
Amylase elevation ..................................................................................................................... 87 
7.3.3. 
Lipase elevation ......................................................................................................................... 88 
7.3.4. 
Musculo‐skeletal System and Cardiac Muscle ........................................................................... 88 
7.3.5. 
LDH ............................................................................................................................................ 88 
7.3.6. 
Cardiac Rhythm Disturbances.................................................................................................... 88 
7.3.7. 
Other toxicities .......................................................................................................................... 89 
7.4. 
Safety Monitoring by the Data Safety Monitoring Committee ......................................................... 89 
8. 
STATISTICAL ANALYSIS ............................................................................................................................... 89 
8.1. 
Analysis Population ........................................................................................................................... 89 
8.2. 
Sample Size ........................................................................................................................................ 89 


Global Alliance for TB Drug Development 
Protocol Number: NC‐005‐(J‐M‐Pa‐Z) 
Working Protocol Version: 1.1 (Final) 
Protocol Date: 19 September 2014 
 
 
 
TMP02‐A V1.0 
 
 
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8.3. 
Interim Analyses ................................................................................................................................ 90 
8.4. 
Primary Endpoint Analysis ................................................................................................................. 90 
8.5. 
Secondary Endpoint Analysis ............................................................................................................. 90 
8.5.1. 
Efficacy ....................................................................................................................................... 90 
8.5.2. 
Safety and Tolerability Analysis ................................................................................................. 91 
8.5.3. 
Pharmacokinetics: ..................................................................................................................... 92 
8.5.4. 
Pharmacokinetics‐Pharmacodynamics (PK‐PD): ....................................................................... 92 
8.6. 
Exploratory Endpoint Analysis ........................................................................................................... 92 
8.6.1. 
Efficacy ....................................................................................................................................... 92 
8.7. 
General Mycobacteriology ................................................................................................................ 92 
9. 
RECORDS MANAGEMENT .......................................................................................................................... 92 
9.1. 
Data Collection .................................................................................................................................. 92 
9.2. 
Source Documents ............................................................................................................................. 92 
9.3. 
File Management at the Trial Centre................................................................................................. 92 
9.4. 
Records Retention at the Trial Centre ............................................................................................... 92 
10. 
QUALITY CONTROL AND ASSURANCE ................................................................................................... 93 
10.1. 
Site Procedures .............................................................................................................................. 93 
10.2. 
Monitoring ..................................................................................................................................... 93 
10.3. 
Auditing ......................................................................................................................................... 93 
11. 
ETHICS AND REGULATORY ..................................................................................................................... 94 
11.1. 
Basic Principles .............................................................................................................................. 94 
11.2. 
Independent Ethics Committee/Institutional Review Board (IEC/IRB) Review ............................. 94 
11.3. 
Regulatory Authorities ................................................................................................................... 94 
11.4. 
Informed Consent .......................................................................................................................... 94 
11.5. 
Confidentiality ............................................................................................................................... 95 
12. 
PUBLICATION POLICY ............................................................................................................................. 95 
13. 
PROTOCOL AMENDMENT POLICY ......................................................................................................... 95 
14. 
FINANCIAL ASPECTS, INSURANCE AND INDEMNITY .............................................................................. 95 
15. 
REFERENCES ........................................................................................................................................... 97 
APPENDIX 1 THE IUATLD SCALE ...................................................................................................................... 100 
APPENDIX 2 DIVISION OF MICROBIOLOGY AND INFECTIOUS DISEASES (DMID) ADULT TOXICITY TABLE ...... 101 
APPENDIX 3 CARDIOVASCULAR SAFETY .......................................................................................................... 110 
APPENDIX 4 KARNOFSKY PERFORMANCE STATUS SCALE DEFINITIONS RATING (%) CRITERIA ...................... 111 
APPENDIX 5 TUBERCULOSIS SYMPTOM PROFILE (Version 3) ......................................................................... 112 
 


Global Alliance for TB Drug Development 
Protocol Number: NC‐005‐(J‐M‐Pa‐Z) 
Working Protocol Version: 1.1 (Final) 
Protocol Date: 19 September 2014 
 
 
 
TMP02‐A V1.0 
 
 
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TABLES 
Table 1: PA‐824 Animal Safety and Toxicology Findings ................................................................................... 32 
Table 2: PA‐824 Phase 1 Clinical Studies ........................................................................................................... 34 
Table 3: PA‐824 Phase 2 Studies ....................................................................................................................... 38 
Table 4: NC‐002 Elevations in Alanine Aminotransferase ................................................................................. 42 
Table 5: Summary of Phase 2b studies in which moxifloxacin were administered as part of a four‐drug regimen 
during the intensive phase of treatment (total treatment duration: 2 months) .............................................. 44 
Table 6: NC‐003 Efficacy Results: Daily BAlogCFU(0‐14) ................................................................................... 47 
Table 7: NC‐003 Safety Data .............................................................................................................................. 47 
Table 8 : PK Analyte/s Per Treatment Arm ........................................................................................................ 56 
Table 9 : PK Analyte/s Per Treatment Arm ........................................................................................................ 57 
Table 10 : General Mycobacteriology ................................................................................................................ 58 
Table 11 : Treatment Groups ............................................................................................................................. 73 
Table 12: Investigational Medicinal Product Details ......................................................................................... 75 
Table 13 : PK Analyte/s per Treatment Arm ...................................................................................................... 80 
Table 14 : PK Analyte/s per Treatment Arm ...................................................................................................... 80 
Table 15 : General Mycobacteriology ................................................................................................................ 81 
Table 16: Adverse Events Attribution/Causality Ratings ................................................................................... 83 
Table 17: Adverse Event Severity Ratings ......................................................................................................... 83 
 
FIGURES 
Figure 1: Trial Schematic ................................................................................................................................... 55 


Global Alliance for TB Drug Development 
Protocol Number: NC‐005‐(J‐M‐Pa‐Z) 
Working Protocol Version: 1.1 (Final) 
Protocol Date: 19 September 2014 
 
 
 
TMP02‐A V1.0 
 
 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
ADME 
Absorption, Distribution, Metabolism, and Excretion 
AE 
Adverse Event 
AIDS 
Acquired Immune Deficiency Syndrome 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
AREDS2 
Age Related Eye Disease Study 2 
ART 
Antiretroviral Therapy 
AST  
Aspartate Aminotransferase 
AUC  
Area under the plasma concentration time curve 
AUC(0‐24) 
Area under the plasma concentration time curve from zero to end of dosing interval  
AUC(0‐t) 
Area under the PK plasma concentration time (t) curve from zero to the last quantifiable 
PK plasma concentration prior to the subsequent dose, using the linear trapezoidal rule  
BA 
Bactericidal Activity 
BMI 
Body Mass Index 
bpm 
Beats per minute  
BUN 
Blood urea nitrogen 
C 
Clofazimine 
°C 
Degrees Celsius 
CFU 
Colony Forming Units 
CK 
Creatine Phosphokinase 
CK‐MB 
Creatine Phosphokinase of Muscle Brain 
Cmax  
Maximum observed plasma concentration 
Cmin 
Minimum observed plasma concentration at the end of the dosing interval 
CNS 
Central Nervous System  
CYP3A4 
Cytochrome P450 3A4 
DBP 
Diastolic Blood Pressure 
DDI 
Drug‐Drug Interactions 
DMID 
Division of Microbiology and Infectious Diseases  
DNA 
Deoxyribonucleic acid 
DOTS  
Directly Observed Treatment, Short Course, Internationally agreed strategy for TB control 
DS 
Drug‐Sensitive 
DSMC 
Data Safety Monitoring Committee 
DST 
Drug Sensitivity Testing 
eCRF 
Electronic Case Report Form 
EBA 
Early Bactericidal Activity 
ECG  
Electrocardiogram 
ELISA 
Enzyme‐Linked Immunosorbent Assay 
EMA 
European Medicines Agency 
ERPF 
Effective Renal Plasma Flow 
FDA 
United States Food and Drug Administration 
FF 
Filtration Fraction 
FSH 
Follicle‐Stimulating Hormone 


Global Alliance for TB Drug Development 
Protocol Number: NC‐005‐(J‐M‐Pa‐Z) 
Working Protocol Version: 1.1 (Final) 
Protocol Date: 19 September 2014 
 
 
 
TMP02‐A V1.0 
 
 
Page 12 of 112  Confidential 
 
GCP  
Good Clinical Practice 
GFR 
Glomerular Filtration Rate 
GGT 
Gamma‐glutamyltransferase 
hERG 
Human ether‐à‐go‐go‐related gene 
HIV  
Human Immunodeficiency Virus 
hr 
Hour 
HRZE 
isoniazid plus rifampicin plus pyrazinamide plus ethambutol 
HRZM 
Isoniazid plus rifampicin plus pyrazinamide plus moxifloxacin 
IB 
Investigator Brochure 
IC50 
50% inhibitory concentration 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IMP 
Investigational Medicinal Product 
IUATLD 
International Union Against Tuberculosis and Lung Disease 
i.v 
Intravenous 
J 
Bedaquiline (TMC207) 
Kg 
Kilogram  
LDH 
Lactate Dehydrogenase 
LFT 
Liver Function Test 
lKr 
Delayed rectifier potassium current 
LH 
Luteinizing Hormone 
LSLV 
Last Subject Last Visit 
m  
Meters 
M 
Moxifloxacin 
MBD 
Minimum Bactericidal Dose 
M2 
Bedaquiline metabolite M2 
MDR 
Multi Drug‐Resistant 
MED 
Minimum Effective Dose 
mg 
Milligrams 
mg/dl 
milligram per deciliter 
MGIT 
Mycobacterial Growth Indicator Tube 
MIC  
Minimum inhibitory concentration 
ml 
Milliliter 
mmHg 
Millimeter of mercury 
M. Tb 
Mycobacterium Tuberculosis 
ms 
Millisecond 
NIH 
National Institute of Health 
NLME 
Non‐linear Mixed Effect 
NOAEL 
No Observed Adverse Effect Level 
NRTI 
Nucleoside Reverse Transcriptase Inhibitor 
Pa 
PA‐824 
PD 
Pharmacodynamic  
PE 
Physical Examination 


Global Alliance for TB Drug Development 
Protocol Number: NC‐005‐(J‐M‐Pa‐Z) 
Working Protocol Version: 1.1 (Final) 
Protocol Date: 19 September 2014 
 
 
 
TMP02‐A V1.0 
 
 
Page 13 of 112  Confidential 
 
PK  
Pharmacokinetic 
PR 
Electrocardiographic PR interval 
q.d. 
Once daily dosage 
QRS 
Electrocardiographic QRS interval 
QT 
Electrocardiographic QT interval 
QTc 
Corrected QT interval 
QTcB 
QT interval corrected by Bazett’s method 
QTcF 
QT interval corrected by Fridericia’s method 
RR 
Electrocardiographic RR interval 
RR 
Respiratory Rate 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic Blood Pressure 
sc 
Subcutaneous 
SIRE 
Streptomycin, isoniazid, rifampicin and ethambutol 
SSCC 
Serial Sputum Colony Counts 
T 
Time 
t½ 
Apparent terminal elimination phase half‐life 
TB 
Tuberculosis 
TEAEs 
Treatment‐Emergent Adverse Events 
t.i.w 
Three times a week 
Tmax 
Time at which Cmax is observed 
TMIC 
Time over Minimum Inhibitory Concentrations 
TTP  
Time to Sputum Culture Positivity 
UA 
Uric Acid 
ULN 
Upper Limit of Normal 
ug/ml 
microgram per milliliter 
WBC 
White Blood Cell 
WHO  
World Health Organization 
XDR 
Extensively drug‐resistant 
Z 
Pyrazinamide 
Definitions: 
BA 
(Bactericidal Activity) 
An agent’s ability to kill mycobacteria originating within pulmonary cavities. 
BA TTP 
 
Determination of BA by measurement in an automated liquid culture system of 
time to positivity (TTP) of M. Tuberculosis from an Overnight Sputum Sample.  
BA CFU 
 
Determination of BA by quantification of solid medium of viable Colony Forming 
Units (CFU) of M. Tuberculosis from an Overnight Sputum Sample.  
pncA 
pncA is a gene encoding pyrazinamidase in Mycobacterium species. 
 
 
 


Global Alliance for TB Drug Development 
Protocol Number: NC‐005‐(J‐M‐Pa‐Z) 
Working Protocol Version: 1.1 (Final) 
Protocol Date: 19 September 2014 
 
 
 
TMP02‐A V1.0 
 
 
Page 14 of 112  Confidential 
 
1. PROTOCOL SYNOPSIS 
1.1. 
Synopsis 
Name of Sponsor/Company:
Global Alliance for TB Drug Development
For National Authority Use Only
Name of Finished Products:
Bedaquiline tablets (J), Moxifloxacin 
tablets (M), PA‐824 tablets (Pa), 
Pyrazinamide tablets (Z) and HRZE 
tablets. 
Protocol Title: 
A Phase 2 Open‐Label Partially Randomized Trial to Evaluate the Efficacy, Safety and 
Tolerability of combinations of bedaquiline, moxifloxacin, PA‐824 and pyrazinamide 
during 8 weeks of treatment in Adult Subjects with Newly Diagnosed Drug‐Sensitive 
or Multi Drug‐Resistant, Smear‐Positive Pulmonary Tuberculosis. 
Treatment Indication: 
Pulmonary Tuberculosis (TB)
Trial Objective: 
Assess the mycobactericidal activity of combinations of bedaquiline, moxifloxacin, 
PA‐824 and pyrazinamide regimens during 8 weeks of treatment. 
Trial Design: 
Phase 2, multi‐center, open‐label, partially randomized clinical trial in four parallel 
treatment  groups.    Subjects  with  Drug‐Sensitive  (DS)  TB  will  be  randomized  to 
receive either J(loading dose/t.i.w.)PaZ; or J(200mg)PaZ; or HRZE.  Subjects with Multi Drug‐
Resistant (MDR) TB will receive J(200mg)MPaZ.  
 
The HRZE treatment arm is included as a control for the drug‐sensitive treatments 
and as a control for the quantitative laboratory mycobacteriology testing.  
 
All  Subjects  will  have  up  to  a  maximum  of  9  days  screening,  receive  8  weeks  of 
treatment,  and  have  follow‐up  visits  at  2  and  12  weeks  after  study  treatment 
completion or last dose of IMP in the case of early withdrawal. Telephonic contact to 
collect survival data will be conducted at 6, 12, 18 and 24 months after completion 
of study treatment. Subjects who withdraw from the study after receiving < 14 days 
of IMP, will only attend a follow‐up visit at 2 weeks after the last dose of IMP and the 
telephonic  contact  will  not  be  conducted  for  these  Subjects,  while  Subjects 
completing > 14 days of treatment are required to complete all scheduled Follow Up. 
 
Upon  treatment  completion,  the  DS‐TB  Subjects  will  be  provided  with  sufficient 
doses of standard of care TB treatment, as appropriate, to cover the time period from 
attending their last visit at the study clinic until their scheduled visit at the TB clinic. 
All DS‐TB and MDR‐TB Subjects will be referred to the local community TB clinics for 
standard anti‐tuberculosis chemotherapy according to National TB Guidelines.  
Patient Population: 
A total of approximately 240 male and female, newly diagnosed Subjects with drug‐
sensitive or multi drug‐resistant, smear positive pulmonary tuberculosis aged 18 to 
75 years (inclusive). A total of 180 DS‐TB Subjects (60 per treatment arm) will be 
randomized. Up to 60 MDR‐TB Subjects will be assigned. 
Test Product, Dose and Mode of 
Administration: 
The Test Product will be supplied as:
 
Bedaquiline 100mg Tablets; 
 
Moxifloxacin 400mg Tablets; 
 
PA‐824 200mg Tablets; 
 
Pyrazinamide 500mg Tablets  
Treatment  will  be  administered  orally  for  8  consecutive  weeks  (56  days),  in  the 
following dosing schemes:  
Subjects with DS‐TB: 
 
J(loading dose/t.i.w.)PaZ: Bedaquiline 400mg once daily Days 1‐14, 200mg three times 
per  week  Days  15‐56;  plus  PA‐824  200mg  once  daily  Days  1‐56;  plus 
pyrazinamide 1500mg once daily Days 1‐56; 
 
J(200mg)PaZ: Bedaquiline 200mg once daily Days 1‐56; plus PA‐824 200mg once 
daily Days 1‐56; plus pyrazinamide 1500mg once daily Days 1‐56; 


Global Alliance for TB Drug Development 
Protocol Number: NC‐005‐(J‐M‐Pa‐Z) 
Working Protocol Version: 1.1 (Final) 
Protocol Date: 19 September 2014 
 
 
 
TMP02‐A V1.0 
 
 
Page 15 of 112  Confidential 
 
Subjects with MDR‐TB:
 
J(200mg)MPaZ: Bedaquiline 200mg once daily Days 1‐56; plus moxifloxacin 400mg 
once  daily  Days  1‐56;  plus  PA‐824  200mg  once  daily  Days  1‐56;  plus 
pyrazinamide 1500mg once daily Days 1‐56. 
Instructions for Dosing of above IMP: 
 
 
Preferably  to  be  taken  around  breakfast  time,  with  a  glass  of  water 
(approximately 240ml); 
 
Subjects should take the above IMP with a meal (generally allow the Subjects a 
window of 30 minutes before to 30 minutes after a meal); 
 
For the J(loading dose/t.i.w.) DS‐TB treatment arm: The bedaquiline dosing schedule 
is 400mg daily on days 1‐14, and then 200mg 3x per week for Days 15‐56. The 3x 
per week doses must be given on the following specific days to accommodate 
the PK sampling: Days 15, 17, 20, 22, 24, 27, 29, 31, 34, 36, 38, 41, 43, 45, 48, 50, 
53 and 56. 
Positive Control Product, Dose, 
and Mode of Administration: 
The Control Product will be supplied as:
 
HRZE tablets (Isoniazid 75mg plus rifampicin 150mg plus pyrazinamide 
400mg plus ethambutol 275mg combination tablets). Vitamin B6 25mg will 
be provided, prescribed and dispensed as a daily supplement to all 
Subjects participating in the HRZE treatment arm.  
 
Treatment will be administered orally once daily for 8 consecutive weeks (56 days) 
to DS‐TB Subjects only, as follows:   
 
HRZE tablets Days 1‐56 with the daily dose per the Subject’s weight as follows: 
30‐37kg:  2  tablets;  38‐54kg:  3  tablets;  55‐70kg:  4  tablets;  71kg  and  over:  5 
tablets.  
 
Vitamin B6: one 25mg tablet daily Days 1‐56.  
 
Instructions for Dosing of above IMP: 
 
Preferably  to  be  taken  around  breakfast  time,  with  a  glass  of  water 
(approximately 240ml); 
 
HRZE should not be taken with a meal (generally, no closer to meals than 1 hour 
before or 2 hours after a meal); 
 
Vitamin B6 25mg supplement to be taken with the HRZE dose. 
Criteria for evaluation: 
 
The Overnight Sputum Samples will be used to determine the primary outcome of the study. 
Primary Endpoint: The Bactericidal Activity (BATTP(0‐56)) as determined by the rate of change in time to sputum culture 
positivity (TTP) over 8 weeks of treatment in the Mycobacterial Growth Indicator Tube system, represented by the model‐
fitted log(TTP) results as calculated by the regression of the observed log(TTP) results over time. 
Secondary Endpoints:  
Efficacy: 
 
The BATTP(0‐2) and BATTP(14‐56) as determined by the rate of change in time to sputum culture positivity (TTP) over 
Days 0 to 2, and Days 14 to 56 treatment, represented by the model‐fitted log(TTP) as calculated by the regression of 
the observed log(TTP) counts over time. 
 
The BACFU(0‐56), BACFU(0‐2) and BACFU(14‐56) as determined by the  rate of change in colony forming units (CFU) over 
8 weeks of treatment, represented by the model‐fitted log(CFU) results as calculated by the regression of the observed 
log(CFU) results over time. 
 
Time to sputum culture conversion using data from weekly cultures through 8 weeks of treatment (separately, on 
solid and liquid media). 
 
Proportion of Subjects with sputum culture conversion at 4, 6 and 8 weeks (separately, on solid and liquid media). 
 
The BACFU(0‐56, 0‐2 and 14‐56) and BATTP(0‐56, 0‐2 and 14‐56)  of J(loading dose/t.i.w.)PaZ compared to J(200mg)PaZ from DS‐
TB treatment arms. 


Global Alliance for TB Drug Development 
Protocol Number: NC‐005‐(J‐M‐Pa‐Z) 
Working Protocol Version: 1.1 (Final) 
Protocol Date: 19 September 2014 
 
 
 
TMP02‐A V1.0 
 
 
Page 16 of 112  Confidential 
 
 
Investigation of the methodology of sputum sampling by comparing CFU counts and TTP results, each quantified in 
both Coached Spot Sputum and Overnight Sputum samples; however Overnight Sputum Samples are considered the 
reference samples.  
 
Safety and Tolerability:  
 
Incidence  of  Treatment  Emergent  Adverse  Events  (TEAEs)  will  be  presented  by  severity  (DMID  Grade),  drug 
relatedness and seriousness, leading to early withdrawal and leading to death, by group.   
 
Quantitative and qualitative clinical laboratory result measurements, including observed and change from baseline 
will be presented and summarized by group. 
 
Quantitative and qualitative measurement of ECG results (heart rate, RR interval, PR interval, QRS interval, QT interval 
and QTc interval), including observed and change from baseline will be presented. QT/QTc intervals, including post 
baseline and change from baseline will also be categorized and presented, by group.  
 
Descriptive statistics will be presented for ophthalmology slit lamp examination data (age related eye disease study 2 
[AREDS2]  lens  opacity  classification  and  grading)  and  listed  by  Subject.  Categorical  data  for  lens  opacity  will  be 
summarized  in  a  frequency  table  for  the  left  and  right  eye,  respectively,  including  change  from  baseline,  and 
summarized by group. 
 
Descriptive statistics will be presented for serum FSH measurements (mean and median at baseline, 4, 8, and 10 weeks 
and mean change from baseline at 4, 8, and 10 weeks) by group.  
 
Other safety variables will be presented by group and listed by Subject. 
These data will be presented as descriptive analyses, and no inferential tests will be carried out.  
Pharmacokinetics: 
Pharmacokinetics will consist of two separate schedules:  
 
All Subjects: 
 
Pre‐dose sampling at Days 1, 4, 8, 15, 22, 29, 36, 43, 50 and during the site visit on Days 57 and 70 to measure 
Ctrough levels of J, J metabolite M2, M, Pa and Z as per the table below. 
 
PK Sub‐study Subjects:  
 
In addition to the general PK samples, there will be intense PK sampling on Days 14 and 56 at pre‐dose, 1, 2, 4, 8 
and 24 hours after dosing in a sub‐group of 15 Subjects in each treatment arm across selected sites.  
Pharmacokinetic Analysis: 
All measured PK concentrations will be listed. 
For the Ctrough samples, only descriptive statistics will be prepared (average Ctrough) derived for each analyte on Days 4, 8, 
15, 22, 29, 36, 43, 50, 57 and 70 as follows: 
Treatment Arm 
Analyte/s 
Subject Population
J(loading dose/t.i.w.)PaZ  
J, J metabolite M2, Pa, Z 
DS‐TB 
J(200mg)PaZ 
J, J metabolite M2, Pa, Z 
DS‐TB 
J(200mg)MPaZ 
J, J metabolite M2, M, Pa, Z 
MDR‐TB 
HRZE 
Z 
DS‐TB 
 
For the PK sub‐study samples, the following PK parameters will be estimated from the individual (per Subject) PK plasma 
concentrations: minimum observed PK plasma concentration (Cmin), maximum observed PK plasma concentration(Cmax), 
time to reach Cmax obtained without interpolation (Tmax), area under the PK plasma concentration time (t) curve from zero 
to the last quantifiable PK plasma concentration prior to the subsequent dose, using the linear trapezoidal rule (AUC(0‐t)), 
area under the PK plasma concentration time (t) curve from zero to 24 hours (AUC(0‐24)). These will be derived for each 
analyte, on Days 14 and 56, as follows: 
 
 
 


Global Alliance for TB Drug Development 
Protocol Number: NC‐005‐(J‐M‐Pa‐Z) 
Working Protocol Version: 1.1 (Final) 
Protocol Date: 19 September 2014 
 
 
 
TMP02‐A V1.0 
 
 
Page 17 of 112  Confidential 
 
Treatment Arm 
Analyte/s 
Subject Population
J(loading dose/t.i.w.)PaZ  
J, J metabolite M2, Pa, Z 
DS‐TB 
J(200mg)PaZ 
J, J metabolite M2, Pa, Z 
DS‐TB 
J(200mg)MPaZ 
J, J metabolite M2, M, Pa, Z 
MDR‐TB 
HRZE 
Z 
DS‐TB 
 
J(200mg)PaZ compared to J(loading dose/t.i.w.)PaZ and J(200mg)MPaZ:  
 
In order to compare the effects of the two J dosing schemes on bedaquiline exposure, the Cmax, Cmin and AUC of J and M2 
will be compared using PK sub‐study data from days 14 and 56 from the J(loading dose/t.i.w)PaZ and J(200mg)PaZ DS‐TB arms. A 
secondary comparison of the PK parameters from the sub‐study parameters of J and M2 between the J(200mg)PaZ  DS‐TB 
and J(200mg)MPaZ  MDR‐TB treatment arms will also be performed. 
 
Another comparison of J and M2 exposure will be performed using the Ctrough data from the J(loading dose/t.i.w)PaZ and J(200mg)PaZ 
DS‐TB arms, with a secondary comparison between the J(200mg)PaZ DS‐TB and J(200mg)MPaZ MDR‐TB treatment arms. 
 
Pharmacokinetics‐Pharmacodynamics (PK‐PD):   
Pearson correlation coefficients will be reported for the correlation analysis of all relevant PK‐PD and exploratory PK‐PD 
endpoints. 
Descriptive summary statistics for TMIC will be presented. 
Exploratory PK‐PD Endpoints: 
 
Correlations between Ctrough plasma drug concentrations, efficacy and safety findings will be performed in an 
exploratory fashion. 
 
Comparison of TMIC (based on data from the PK sub‐study parameters) for J between J(loading dose/t.i.w.), PaZ and 
J(200mg)PaZ in DS‐TB arms. 
 
Correlations between plasma drug concentrations and efficacy and safety findings will be performed in an 
exploratory fashion, as follows: 
BATTP(0‐56) and BATTP(14‐56) versus the following PK variables (at Day 14 and Day 56) will be presented for J, Pa and 
M: 
o 
Cmax 
o 
AUC(0‐24) 
o 
Time over Minimum inhibitory concentration (TMIC) of J, Pa and M, both with and without taking 
protein binding shift into account. 
Exploratory Endpoints: 
 
Sub‐analysis of the primary and secondary efficacy endpoints of the MDR‐TB pyrazinamide resistant Subjects 
compared to the MDR‐TB sensitive Subjects. 
 
Sub‐analysis of the primary and secondary efficacy endpoints of the H or R mono‐resistant Subjects will be evaluated 
as separate sub‐groups. 
General Mycobacteriology: 
Overnight Sputum and Coached Spot Sputum Samples will be obtained at all scheduled visits, except the Screening Visit 
when only a Coached Spot Sputum Sample will be collected. Sputum samples will not be collected at Early Withdrawal 
Visits. Cultures will be grown from all Overnight Sputum and Coached Spot Sputum Samples collected from Day ‐2 onwards. 
The Overnight Sputum Samples will be considered the reference samples. 
The following mycobacteriology assays will be carried out: 


Global Alliance for TB Drug Development 
Protocol Number: NC‐005‐(J‐M‐Pa‐Z) 
Working Protocol Version: 1.1 (Final) 
Protocol Date: 19 September 2014 
 
 
 
TMP02‐A V1.0 
 
 
Page 18 of 112  Confidential 
 
Sample 
Type 
Assessments
Comments
Screening 
Coached 
Spot 
Sputum 
Sample 
 
Direct microscopy for acid‐fast bacilli 
 
Molecular assay for identification of M. Tb and drug 
susceptibility (such as GeneXpert or MTBDRplus) to 
confirm the diagnosis of TB and distinguish between 
DS‐TB and MDR‐TB 
 
Molecular test for fluoroquinolone resistance (such 
as MTBDRsl) for MDR‐TB Subjects to establish 
susceptibility to moxifloxacin 
All to be performed at 
the Trial 
Appointed Laboratory. 
Baseline  
Overnight 
Sputum 
Samples 
named Day ‐2 
and ‐1 
Overnight 
Sputum 
Sample 
 
Direct microscopy for acid‐fast bacilli 
 
Molecular / antigen test to confirm M. Tb 
 
Culture: MGIT and Solid Media (quantitative for CFU) 
 
DST : SIRE, Z 
 
MIC : J, Pa, M 
 
DNA for pncA Sequencing 
Z DST resistance must 
be repeated to 
confirm. 
Baseline  
Coached Spot 
Sputum 
Samples 
named Day ‐2 
and ‐1 
Coached 
Spot 
Sputum 
Sample 
 
Culture: MGIT and Solid Media (quantitative for CFU) 
 
For determination of 
logCFU and logTTP 
rates of change for 
comparison to cultures 
from Overnight 
Sputum Sample. 
Overnight 
Sputum 
Sample 
named Days 1, 
3, 7, 14, 21, 
28, 35, 42, 49 
and 56 
Overnight 
Sputum 
Sample 
 
Culture: MGIT and Solid Media (quantitative for CFU) 
 
The last positive sample from withdrawn Subjects 
who have not converted to culture negative status 
OR Subjects who are still culture positive at 8 weeks 
OR the first positive sample after conversion to 
culture negative status for subjects who have 
‘relapsed’*  
o 
DST : SIRE, Z 
o 
MIC: J, Pa, M 
 
Coached Spot 
Sputum 
Sample 
named Days 1, 
3, 7, 14, 21, 
28, 35, 42, 49 
and 56 
Coached 
Spot 
Sputum 
Sample 
 
Culture: MGIT and Solid Media (quantitative for CFU) 
 
For determination of 
logCFU and logTTP 
rates of change for 
comparison to cultures 
from Overnight 
Sputum Sample. 
 
The above assays will be carried out according to procedures described in the Laboratory Manual.  
 
The Coached Spot Sputum Sample can be used for all assays, except CFU and TTP, if results cannot be obtained from 
the Overnight Sputum Sample. 
 
pncA sequencing and MIC isolates can be batched at the end of the study.  
 
*If the Subject was treated with study medication for less than 9 days, the mycobacteriology testing will be 
performed on the Day ‐2 sample isolate only.  
 
*Culture negativity is defined as the first of two consecutive negative cultures, except for the week 8 time point, 
where a singular negative is acceptable. 
Statistical Methods:  
 
The primary efficacy analysis of the primary efficacy endpoint, i.e. BATTP(0‐56), as determined by the rate of change in the 
log TTP in sputum over 8 weeks of treatment, will be analyzed using non‐linear mixed effects (NLME) regression 
modeling. Sensitivity analyses may be performed using different model assumptions for the NLME regression model. 
Subgroup analyses, such as by site and human immunodeficiency virus (HIV) status, may be performed as exploratory 
analyses. The Statistical Analysis Plan (SAP) will be developed before the database is locked. 
 


Global Alliance for TB Drug Development 
Protocol Number: NC‐005‐(J‐M‐Pa‐Z) 
Working Protocol Version: 1.1 (Final) 
Protocol Date: 19 September 2014 
 
 
 
TMP02‐A V1.0 
 
 
Page 19 of 112  Confidential 
 
Trial Duration: 
 
Estimated date of first Subject enrolled: 
 
Quarter 3, 2014 
Estimated date of last Subject enrolled: 
 
Quarter 3, 2015 
Estimated date of last Subject completed: 
                Quarter 2, 2018 
Duration of study: ~38 months (12 months enrolment period plus up to 9 days screening plus 8 week treatment period 
plus 24 month post‐treatment follow‐up). In the event of the DS‐TB treatment arms being fully recruited (i.e. 60 Subjects 
in each of the three treatment arms) before the MDR‐TB treatment arm has enrolled 60 Subjects, the Sponsor may elect 
to close the study for all treatment arms or close the DS‐TB treatment arms and continue the study with MDR‐TB 
recruitment while analysing the DS‐TB data. 


Global Alliance for TB Drug Development 
Protocol Number: NC‐005‐(J‐M‐Pa‐Z) 
Working Protocol Version: 1.1 (Final) 
Protocol Date: 19 September 2014 
 
  
TMP02‐B V1.0  
 
   
Page 20 of 112  Confidential          
1.2. 
Trial Flow Chart – Screening Period to Day 140 Follow Up Visit 
Period 
Screening 
Treatment 
Follow Up 
Visit Day a 
(‐9 to ‐3)b 
‐2b 
‐1 
1 
4 
8 
14h 
15 
22 
29 
36 
43 
50 
56h 
57 
Early 
Withdrawalr
70 
140 
Week 
 
‐1 
1 
 
2 
3 
4 
5 
6 
7 
 
8 
10 
20 
Written Informed 
Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical & Treatment 
History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12‐Lead ECGc 
X  
 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
X 
X 
X 
   
Laboratory Safety 
Testsd 
X 
 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
Urine Pregnancy Teste 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
X 
X 
X 
HIV and CD4 Countf 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Drug Screeng  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Karnofsky Score 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TB Symptom Profile 
(TSP) QuestionnaireS 
X 
 
 
 
 
 
 
X 
 
X 
 
 
 
 
X 
X 
 
 
Pharmacokinetic 
Samplingh 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Chest X‐rayi 
Xi 
( Xi) 
( Xi) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signsj 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
Physical Examination ‐ 
fullk 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
Physical Examination –  
limitedk 
 
 
 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
X 
 
Ophthalmologyl 
Examination 
Xl 
( Xl) 
( Xl) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xl 
Randomization/Treat
ment Assignmentm 
 
 
Xm 
Xm 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IMP 
Administrationn 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Overnight  Sputum  
Sampleo 
Name of Sample (Day) 
 
X 
 
‐2 
X 
 
‐1 
X 
 
1 
X 
 
3 
X 
 
7 
 
X 
 
14 
X 
 
21 
X 
 
28 
X 
 
35 
X 
 
42 
X 
 
49 
 
X 
 
56 
 
 
 
Coached Spot Sputum 
Samplesp 
Name of Sample (Day) 
X 
 
Screen 
X 
 
‐2 
X 
 
‐1 
X 
 
1 
X 
 
3 
X 
 
7 
 
X 
 
14 
X 
 
21 
X 
 
28 
X 
 
35 
X 
 
42 
X 
 
49 
 
X 
 
56 
 
 
 
Concomitant Meds/ 
Other Treatments 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Adverse Eventsq 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Referral to National TB 
Treatment Program 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 


Global Alliance for TB Drug Development 
Protocol Number: NC‐005‐(J‐M‐Pa‐Z) 
Working Protocol Version: 1.1 (Final) 
Protocol Date: 19 September 2014 
 
  
TMP02‐B V1.0  
 
   
Page 21 of 112  Confidential          
1.3 Trial Flow Chart – 8 to 26 Month Telephonic Survival Follow Up Period 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
a: 
Visit Window periods: 
 
Up to and including Day 15 ‐ No visit window (in order to accommodate PK sampling); 
 
Day 14 must occur on Day 14, relative to Day 1 (in order to accommodate PK sampling for PK sub‐study 
Subjects only); 
 
Days 22 to 50 +/‐ 2 days; 
 
Days 56 and 57 must occur on Days 56 and 57, relative to Day 1 (in order to accommodate PK sampling. The 
Day 56 visit is for PK sub‐study Subjects only); 
 
Day 70 (or 2 weeks after last dose of IMP in the case of early withdrawal) +/‐ 3 days; 
 
Day 140 (or 12 weeks after last dose of IMP in the case of early withdrawal) +/‐ 14 days; 
 
The 8, 14, 20 and 26 Month Telephonic Survival Follow Up Contacts will be 6, 12, 18 and 24 months, 
respectively, after study treatment completion +/‐ 14 days; 
Please Note  : IMP dosing should not exceed 56 days even if visit windows are utilized;  
 
 
 
: If a visit window is utilized, the next visit must be scheduled relative to Day 1.  
b:  
Screening Days ‐9 to ‐3:  
 
May occur over a number of days i.e. all screening procedures do not have to be performed on the same 
day.  
c: 
12‐lead ECGs:  
 
Single ECG to be performed at Screening Visit, all other ECGs to be done in triplicate. 
 
All ECGs to be performed before any other assessments and before IMP administration. 
 
Results from central reading of Day ‐9 to ‐3 ECG should be used to determine eligibility.  
 
At Day 29 a triplicate ECG is performed both pre‐dose and then again 2 hours (+/‐ 15 minutes) post IMP 
administration. 
d:  
Laboratory Assessments (refer to Section 6.3 for details of Laboratory Safety Assessments):  
 
During the treatment period, safety laboratory samples to be collected prior to dosing. The Day‐1 collection 
and testing is for Serum FSH only.  
 
Serum FSH performed at Baseline (Day ‐9 to ‐3 and Day‐1), Days 29, 57 and 70 or at the Early Withdrawal 
Visit on male Subjects only.  
e: 
Urine Pregnancy Test: Women of child bearing potential only, whether they are sexually active or not.  
f: 
HIV and CD4 Count:  
 
If  an  HIV  test  was  performed  within  1  month  prior  to  trial  start,  it  need  not  be  repeated  as  long  as 
documentation can be provided (ELISA and/or Western Blot). 
 
For specific ART treatment allowed while the Subject is on IMP please refer to section 4.8.1.2 
 
Subjects may be on current ART or commence ART during the study if required, provided there is at least a 
2 week interval between commencing IMP and the start of ART.  
g: 
Urine Drug Screen: Cannabinoids, cocaine, amphetamines, opiates, benzodiazepines, barbiturates.   
 
 
Period  
8 – 26 Month Telephonic Survival Follow Up Period 
Month 
Month 8 
(6 months after 
study treatment 
completion) 
Month 14  
(12 months after 
study treatment 
completion) 
Month 20  
(18 months after 
study treatment 
completion) 
Month 26  
(24 months after 
study treatment 
completion) 
Obtain Subject 
survival data 
x 
x 
x 
x 


Global Alliance for TB Drug Development 
Protocol Number: NC‐005‐(J‐M‐Pa‐Z) 
Working Protocol Version: 1.1 (Final) 
Protocol Date: 19 September 2014 
 
 
 
TMP02‐A V1.0 
 
 
Page 22 of 112  Confidential 
 
h: 
Pharmacokinetic Sampling:  
Pharmacokinetic Sampling will consist of two separate schedules:  
 
All Subjects:   
Pre‐dose sampling at Days 1, 4, 8, 15, 22, 29, 36, 43, 50 and during the site visit on Days 57 and 70, to 
measure Ctrough levels of J, J metabolite M2, M, Pa, Z. 
 
PK Sub‐study Subjects:  
 
In Addition to the general PK samples, there will be intense PK sampling on Days 14 and 56 at pre‐dose, 1, 
2, 4, 8 and 24 hours after dosing in a sub‐group of 15 Subjects in each of the treatment arms across selected 
sites. 
 
PK Sub‐group Subjects do not need to be hospitalized for the PK sampling, but may remain as outpatients 
at the clinic for the applicable day, and return the following morning for their 24 hour post‐dosing sample 
collection. 
 
PK samples are to be collected at the specified time points within the allowed applicable window periods as 
follows: Pre‐dose: 0‐5 minutes before dose; 1‐8 hours post‐dose: +/‐ 5 minutes of dosing time; 24 hours 
post‐dose: +/‐ 15 minutes of dosing time and prior to next dose. 
 
The site staff should attempt to take the PK samples at the same time of day for each time point.    
i: 
Chest X‐Ray:  
 
May be performed at Day ‐2 or Day ‐1 if not already performed at Day ‐9 to ‐3; or if performed within 7 days 
prior to signing consent, the X‐ray does not need to be repeated if the report and X‐ray are available for 
review and interpretation.   
j: 
Vital Signs:  
 
Systolic blood pressure (SBP) and diastolic blood pressure (DBP) (mmHg), heart rate (beats per minute 
[bpm]), respiratory rate (RR ‐ breaths per minute), body temperature (0C) and weight (kg).  
 
During the treatment period, to be performed before IMP administration.  
 
The same method for measurement of body temperature should be used throughout the study. 
k: 
Physical Examinations:  
 
Height (m) will only be measured at Day ‐9 to ‐3.  
 
Limited Physical Examinations include: pulmonary, cardiovascular and abdominal examinations.  
 
During the treatment period, to be performed before IMP administration. 
l: 
Ophthalmology Examination:  
 
Ophthalmologic  medical  history,  visual  acuity  and  slit  lamp  examination  will  be  performed  by  an 
ophthalmologist with AREDS2 training during the screening period (Days ‐9 to ‐1), and at Day 140 or at least 
90 days post the last dose of study medication. The study Ophthalmologist could delegate the Visual Acuity 
Test examination to a trained optometrist or other qualified personnel. The Ophthalmologists would still be 
responsible to review, approve and sign‐off the Ophthalmology Report Forms, including sections completed 
by other designated personnel. 
 
May be performed at Day ‐2 or Day ‐1 if not already performed at Day ‐9 to ‐3. 
m: 
Randomization/Treatment Assignment:  
 
Initial randomization may occur once all of the screening results are available and the Investigator has 
determined that the Subject is eligible for the trial.  
 
May occur at Day 1 if not already performed at Day ‐1. 
n: 
Investigational Medicinal Product (IMP) Administration:  
 
To be taken orally once daily for 8 weeks (56 days), preferably around breakfast time, with a glass of water 
(approximately 240ml);  
 
Subjects on the HRZE treatment arm should not take IMP with a meal (generally, no closer to meals than 1 
hour before or 2 hours after a meal) and should take the Vitamin B6 25mg supplement with the HRZE dose; 
 
Subjects on the bedaquiline containing arms should take IMP with a meal (generally allow the Subjects a 
window of 30 minutes before to 30 minutes after a meal); 
 
When Subjects return for clinic visits or are hospitalized, they will be dosed on site;   
 
For the J(loading dose/t.i.w.) DS‐TB treatment arm: The bedaquiline dosing schedule is 400mg daily on Days 1‐14, 
and then 200mg 3x per week for Days 15‐56. The 3x per week doses must be given on the following specific 
days to accommodate the PK sampling: Days 15, 17, 20, 22, 24, 27, 29, 31, 34, 36, 38, 41, 43, 45, 48, 50, 53 
and 56. 
o:  
Overnight Sputum Sample (refer to Section 6.1 and 6.2 for details of procedures):  


Global Alliance for TB Drug Development 
Protocol Number: NC‐005‐(J‐M‐Pa‐Z) 
Working Protocol Version: 1.1 (Final) 
Protocol Date: 19 September 2014 
 
 
 
TMP02‐A V1.0 
 
 
Page 23 of 112  Confidential 
 
 
Overnight Sputum Sample may be collected for a number of screening days if the screening Spot Sputum 
Sample  results  are  delayed,  or  the  mycobacterial  testing  on  the  first  Spot  Sputum  Sample  shows  an 
indeterminate result, in which case the test may be repeated on freshly collected Coached Spot Sputum or 
an Overnight Sputum Sample, and that result will be used.   
 
Of the screening period samples collected, only the Day ‐2 and Day ‐1 Overnight and Coached Spot Sputum 
samples will be used for the Efficacy Endpoint tests. 
 
Naming of Overnight Sputum Samples for the Trial Period Days ‐3 to Day 1: The day Overnight Sputum 
Sample collection ends reflects the day to which that sample applies e.g. a sample where collection starts 
on Day ‐3 and ends on Day ‐2, is designated as the Day ‐2 Overnight Sputum Sample and results are also 
referred to as Day ‐2 results.  
 
Naming of Overnight Sputum Samples for the Trial Period Days 3 to 57: The day Overnight Sputum Sample 
starts reflects the day to which that sample applies e.g. a sample where collection starts on Day 3 and ends 
on Day 4, is designated as the Day 3 Overnight Sputum Sample and results are also referred to as Day 3 
results.  
 
The Subject should be instructed to collect the sample from approximately 4pm the afternoon prior to the 
visit and for approximately 16 hours overnight for each of the sampling days. Collection must be completed 
prior to the administration of the next day’s IMP, which will be administered at the study site.   
 
If a Subject arrives at a clinic visit without an Overnight Sputum Sample or if no results could be obtained 
from the Overnight Sputum Sample, the Coached Spot Sputum Sample will be used for all assays.  
 
All isolates from positive cultures should be stored until study completion.  
p: 
Coached Spot Sputum Sample (refer to Section 6.1 and 6.2 for details of procedures): 
 
If the Screening Spot Sputum smear or molecular testing shows a negative/scanty/indeterminate result, 
the test may be repeated on freshly collected Coached Spot Sputum Sample or Overnight Sputum Sample 
during the allocated screening period. 
 
In addition to using the Coached Spot Sputum Sample as comparator against the Overnight Sputum Sample 
for the rate of change in logCFU and logTTP, the Coached Spot Sputum Sample can also be used for all 
assays, except CFU and TTP, if results cannot be obtained from the Overnight Sputum Sample.  
 
Naming of Coached Spot Sputum Samples for the Trial Period Days ‐9 to Day 1: The Day ‐9 to ‐3 Coached 
Spot Sputum Sample/s will be named ‘screen’ (note, there is no matching Overnight Sputum Sample). The 
naming of Coached Spot Sputum Samples for Days ‐2, ‐1 and 1 will be designated as Day ‐2, ‐1 and 1 
respectively and results are also referred to as Day ‐2, ‐1 and 1 results.  
 
Naming of Coached Spot Sputum Samples for the Trial Period Days 3 to 57: The naming of Coached Spot 
Sputum Samples will match the naming of Overnight Sputum Samples for that period, i.e. the Coached Spot 
Sputum Sample collected on Visit Day 4 will be named Day 3 etc. and results are referred to as Day 3 results.  
 
All isolates from positive cultures should be stored until study completion.  
q: 
Adverse events: Will be collected by the Investigator from the time a Subject signs the Informed Consent Form 
until the Subject has completed their last follow‐up visit as follows: 
 
All AEs and SAEs – through to the end of the Day 70 Visit;   
 
Only ophthalmologic related AEs and all SAEs ‐ from Day 70 through to Day 140 Visit; 
 
Deaths reported during the Survival Follow Up period wil be reported as SAES. 
r:  
Early Withdrawal: 
 
Subjects who withdraw after 14 days or less of IMP administration are to return for the first follow‐up visit 
(i.e. 2 weeks after the last dose of IMP) only. 
 
Subjects who withdraw after > 15 days of IMP administration are to return for the first and second follow‐
up visits (2 and 12 weeks after last dose of IMP). The 8, 14, 20 and 26 Month Telephonic Survival Follow Up 
Contact will also be carried out for these Subjects. 
s:  
Tuberculosis Symptom Profile (TSP) Questionnaire: 
 
To be completed once during Visit Days ‐9 to ‐3, Day 15, Day 29, Day 57 and the Early Withdrawal Visit.  


Global Alliance for TB Drug Development 
Protocol Number: NC‐005‐(J‐M‐Pa‐Z) 
Working Protocol Version: 1.1 (Final) 
Protocol Date: 19 September 2014 
 
  
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2. INTRODUCTION  
2.1. 
Background 
Although some progress has been made in recent years in controlling 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 
fatal 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 20 years and 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 Subjects, treatment takes 6 months to complete.  This, plus side effects, result in poor compliance 
which is particularly likely to occur after the second month of treatment. The full application of the DOTS 
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  compliance,  drug  resistance  is  becoming  more 
common and fears of an epidemic with virtually untreatable strains of TB – extensively drug resistant TB (XDR‐
TB)  ‐  are  growing.    Since  the  discovery  of  the  rifamycins  (1),  and  their  introduction  into  standard  anti‐
tuberculosis regimens, very few new classes of drugs have been evaluated with a view to their registration as 
anti‐tuberculosis agents.  
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. On December 28, 2012 the U.S. Food and Drug Administration 
approved bedaquiline (SirturoTM) as part of combination therapy to treat adults with multi drug‐resistant 
pulmonary tuberculosis (MDR‐TB) when other alternatives are not available. In November of 2013, the CHMP 
recommended that delaminid be approved by the EMA for treatment of pulmonary MDR‐TB in combination 
with the WHO optimized background regimen. Although both of these regulatory actions are positive steps, 
more work needs to be done to develop new regimens for both drug‐sensitive (DS‐TB) and MDR‐TB.  New 
combination regimens are desperately needed for two reasons; to shorten treatment to a duration more easily 
manageable by patients and public health services for DS‐TB and to provide more efficacious, safer, better 
tolerated and affordable treatment for the growing number of patients suffering from MDR‐TB and XDR‐TB. 
The bactericidal action of anti‐tuberculosis agents alone or in combination can be quantified by studying the 
fall in the number of colony forming units (CFU) of M. tuberculosis (M. Tb) present in the sputum of clinical 
study Subjects with microscopy smear‐positive pulmonary TB.  In the first comprehensive evaluation of this 
technique all of the then available anti‐tuberculosis agents were studied both alone and in combination during 
the first 14 days of treatment in small groups of approximately 4 Subjects (2).  This study showed significant 
differences between the different drugs, but these differences were most obvious during the first 2 days of 
treatment and this period of activity was consequently labeled EBA (for early bactericidal activity) or “standard 
EBA”.  More recently, EBA studies have been conducted over 5, 7 and 14 days and it has become apparent 
that valuable additional information may be found by conducting EBA studies for longer than 2 days, including 
providing an indication of sterilizing as well as bactericidal activity, and dose‐ranging information, in addition 
to safety, tolerability and PK data (3‐6). A review of EBA studies conducted on the key anti‐tuberculosis drugs 
has  shown  the  value  these  studies  offer  to  demonstrate  the  early  anti‐tuberculosis  effect  that  a  new 
therapeutic agent may have and to explore the relationships between dose, pharmacokinetics and bactericidal 
activity in Subjects (7). 
In the past five years, EBA methodology of quantitative colony counting on solid medium has been adapted to 
Phase 2b, 8‐week TB treatment trials based on serial sputum colony counting to provide a more sensitive 
efficacy endpoint than the previously used binary endpoint of rate of sputum conversion measured after 8 
weeks of treatment (8‐10). This type of trial, sometimes referred to in the literature as a serial sputum colony 
counting  (SSCC) trial relies on performed throughout the treatment period, and a nonlinear mixed‐effects 
approach to data analysis, to provide a more sensitive, continuous, surrogate measure indicative of a TB 
treatment’s efficacy over a two‐month period. Such studies are conducted to provide data on which to base 
the selection of treatment‐shortening regimens to be advanced into pivotal registration Phase 3 evaluation 
studies.  The TB Alliance has recently completed one such study, NC‐002, which investigated the efficacy and 


Global Alliance for TB Drug Development 
Protocol Number: NC‐005‐(J‐M‐Pa‐Z) 
Working Protocol Version: 1.1 (Final) 
Protocol Date: 19 September 2014 
 
 
 
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Page 25 of 112  Confidential 
 
safety of 2 months of treatment with PA‐824 in combination with moxifloxacin and pyrazinamide in both DS‐
TB and MDR‐TB. The study is still undergoing analysis, but preliminary results indicate that this combination 
demonstrates a greater rate of bacterial load reduction during the 8 weeks of treatment compared to the 
current isoniazid, rifampicin, pyrazinamide and ethambutol (HRZE) standard of care. 
The current study (NC‐005) is an “SSCC” 8 week trial designed to further the investigation and development 
of the combination of bedaquiline, PA‐824 and pyrazinamide (J‐Pa‐Z) in DS‐TB and bedaquiline, moxifloxacin, 
PA‐824 and pyrazinamide in MDR‐TB, following the successful demonstration that  bedaquiline, PA‐824 and 
pyrazinamide has good 14 day EBA activity in the recently‐completed 14 day EBA Study NC‐003. 
2.2. 
Agents to be Studied 
2.2.1. Bedaquiline 
Bedaquiline (TMC207; SirturoTM package insert 11) is a new agent being developed for TB treatment. As detailed 
in the Investigator’s Brochure  (12,13) bedaquiline is a diarylquinoline that offers a novel mechanism of anti‐
tuberculosis action by specifically inhibiting mycobacterial adenosine triphosphate (ATP) synthase. (14) In vitro, 
bedaquiline  potently  inhibits  both  drug‐sensitive  and  drug‐resistant  M.  Tb  isolates  (15,  16),  and  is  also 
bactericidal against non‐replicating M. Tb (17). 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  (18).  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  (18)  and  in  a 
subsequent study it was more active in the mouse model than HRZ (19). 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.  
To date, bedaquiline has been studied as monotherapy in two dose‐ranging EBA trials (C202 and TMC207‐
CL001) (20,21), in two combination EBA trials (NC‐001 (22) and NC‐003) and in 2 Phase 2b studies (C208 and C209).  
In the monotherapy studies, bedaquiline was dosed over a range of 100‐400 mg/day. Subjects with TB had 
approximately a 1 log decrease in logCFU over 14 days at all doses studied.  The first 14 day EBA combination 
study (NC‐001) demonstrated that bedaquiline in combination with pyrazinamide (J‐Z) and bedaquiline in 
combination with PA‐824 (J‐Pa) had positive EBA activity. The second 14 day EBA combination study (NC‐003), 
currently undergoing analysis, included a number of bedaquiline‐containing arms: bedaquiline, pyrazinamide 
and clofazimine (J‐Z‐C), bedaquiline, PA‐824 and clofazimine (J‐Pa‐C); bedaquiline, PA‐824 and pyrazinamide 
(J‐Pa‐Z) and bedaquiline, PA‐824, pyrazinamide and clofazimine (J‐Pa‐Z‐C). Among these, J‐Pa‐Z had the best 
activity which was at least as good as the HRZE control. Finally, the 2 completed Phase 2b studies form the 
pivotal  studies  reviewed  by  the  FDA  for  accelerated  approval  of  bedaquiline  (SirturoTM).  Together,  these 
clinical studies provide justification for proceeding to the current study and are described briefly below and in 
greater detail in the IB. 
2.2.1.1. 
Bedaquiline Preclinical Studies 
Full details of the preclinical studies are provided in the current bedaquiline Investigator’s Brochure (12,13) and 
Sirturo TM label (11). 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. 


Global Alliance for TB Drug Development 
Protocol Number: NC‐005‐(J‐M‐Pa‐Z) 
Working Protocol Version: 1.1 (Final) 
Protocol Date: 19 September 2014 
 
 
 
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Bedaquiline demonstrated similar in vitro efficacy against M. Tb clinical isolates resistant to the known anti‐
TB drugs (isoniazid, rifampin, 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 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 (12,13). 
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 was 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  i.v.  administration,  but  not  in  the  conscious  dog.  In  conscious,  telemetered  dogs,  oral 
bedaquiline had no relevant effects on cardio‐hemodynamic and electrocardiogram (ECG) parameters.  
Prior to the use of PA‐824 in combination with bedaquiline in clinical study NC‐001, a preclinical cardiovascular 
safety  pharmacology  study  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 PA‐824 on Day 7. The effect of PA‐824 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.  
2.2.1.2. 
Bedaquiline Clinical Studies 
In  the  clinical  studies  conducted  to  date,  a  total  of  approximately  645  Subjects  (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 subjects received bedaquiline, either as 
monotherapy (J) or in combination with other agents (J‐Pa or J‐Z) in study NC‐001, and 45 more in study NC‐
003  (J‐Pa‐Z,  J‐Pa‐C,  J‐Pa‐Z‐C).  Four  short‐term  Phase  2a  trials  enrolled  treatment‐naïve  subjects  (C202, 
TMC207‐CL001,  NC‐001  and  NC‐003).  One  long‐term,  open‐label,  Phase  2  trial,  in  MDR‐TB  Subjects 
(bedaquiline‐TiDP13‐C209)  and  one  long‐term,  Phase  2b  trial,  consisting  of  2  different  stages  in  Subjects 
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 (12,13) and Sirturo TM label (11).  
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 Subjects. Bedaquiline was well 
absorbed with time to reach the maximum plasma concentration at approximately 5 hours post‐dose. The 


Global Alliance for TB Drug Development 
Protocol Number: NC‐005‐(J‐M‐Pa‐Z) 
Working Protocol Version: 1.1 (Final) 
Protocol Date: 19 September 2014 
 
 
 
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maximum plasma concentration and AUC increased proportionally up to the highest doses studied (up to 
700mg  in  a  single  dose‐ranging  study,  800mg  single  dose  in  study  bedaquiline‐TBC1003  and  400mg  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  Subjects  and  Subjects  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 Subjects 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 study (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 study (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. Study C202 was a 7 day study of three daily doses of bedaquiline (25, 100 and 400mg) in treatment‐
naïve  Subjects  with  MDR‐TB.  In  this  study,  the  400mg  dose  group  demonstrated  positive  EBA  and  was 
numerically superior to the 25 and 100mg doses. In study TMC207‐CL001, doses of 100, 200, 300 and 400mg 
daily (following a 2‐day loading dose) were studied in Subjects 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 Subjects with TB and that higher doses appear to have greater efficacy. 
A 14 day EBA regimen study (TB Alliance Study NC‐001‐(J‐M‐Pa‐Z)) evaluated bedaquiline administered as 
monotherapy at 400 mg/d or in combination at that dose with either PA‐824 administered at 200 mg/d or 
weight‐adjusted pyrazinamide, to Subjects 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  Subjects  given 
bedaquiline 400 mg/d after a 2 day loading dose. In the cohort of 15 Subjects 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 
Subjects given bedaquiline 400 mg/d after a loading dose plus 200 mg/d PA‐824, the mean logCFU decreased 
by 1.9. While it appeared that the addition of PA‐824 potentiated the anti‐tuberculosis activity of bedaquiline, 
the mean logCFU decrease of the combination was similar to that of PA‐824, administered alone at the 200 
mg/d dose in the two prior EBA studies of PA‐824 monotherapy. 
The second 14 day EBA combination study (NC‐003), currently undergoing analysis, included a number of 
bedaquiline‐containing  arms:  bedaquiline,  pyrazinamide  and  clofazimine  (J‐Z‐C),  bedaquiline,  PA‐824  and 
clofazimine (J‐Pa‐C), bedaquiline, PA‐824, and pyrazinamide (J‐Pa‐Z) and bedaquiline, PA‐824, pyrazinamide 
and clofazimine (J‐Pa‐Z‐C). Among these, J‐Pa‐Z had the best activity which was at least as good as the HRZE 
control. As J‐PA‐Z is the regimen under study in the current trial (NC‐005), this study is discussed in detail in 
section 2.3. 
The long‐term efficacy of bedaquiline in Subjects 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 Subjects in the bedaquiline group became MGIT culture negative compared to 8.7% of 
Subjects in the placebo group. At Week 24 in Stage 1, after 8 weeks of investigational treatment and 24 weeks 


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of background treatment, 81.0% of Subjects in the bedaquiline group and 65.2% of Subjects in the placebo 
group showed treatment success, i.e., completed week 24 and were MGIT 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 favor of bedaquiline 
was shown. In both analyses, an identical number of Subjects 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 Subjects. Culture conversion rates after 24 weeks of treatment with bedaquiline as part of 
an individualized anti‐tuberculosis regimen were higher in Subjects with lower extent of resistance of the M. 
Tb strain and in Subjects with no lung cavitation compared to Subjects with cavitations (in one or both lungs). 
2.2.1.3. 
Bedaquiline Clinical Safety  
In the pooled safety data from the 8 Phase 1 trials, bedaquiline was generally safe and well tolerated. In the 
bedaquiline pooled treatment group, adverse events (AEs) were most frequently related to nervous system 
disorders and gastrointestinal disorders. The most frequent AE was headache. The most frequent AEs of at 
least grade 2 were headache, influenza, lipase increased, laceration and hyperuricemia and lipase increased 
for grade 3, respectively. Three Subjects withdrew due to the following events: a moderate urinary tract 
infection, pharyngolaryngeal pain and pyrexia, and a grade 3 lipase increase. In a phase I study looking at drug‐
drug interactions between bedaquiline and either rifampin or rifabutin, 7 Subjects experienced SAEs.  Of those 
Subjects, 5 experienced SAEs of lymphocytopenia (all received Rifabutin), one experienced an SAE of elevated 
Creatine  Kinase  (Rifampin  arm)  and  one  experienced  a  grade  4  Total  Bilirubin  SAE  (Rifampin  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 TMC207 or rifabutin. 
No deaths occurred in Phase 1 trials. In the Phase 1 trails, one HIV‐1 infected Subject experienced 2 serious 
adverse events (SAEs): (grade 3 diarrhea and dehydration; both SAEs were considered not to be related to 
bedaquiline, NVP, or N(t)RTIs therapy but to be related to HIV).  
In the Phase 2a trial, C202, apart from a suggestion of more QTcF prolongation in the bedaquiline 400mg 
group, bedaquiline was generally safe and well tolerated. The most commonly reported AE was hemoptysis. 
Two Subjects in the bedaquiline 400mg group died during the follow‐up period. These were a 25‐year old 
female who died due to 2 grade 4 SAEs, i.e., retroviral infection and pulmonary TB, and a 41‐year old male, 
who was prematurely withdrawn from trial due to a positive urinalysis test for cannabinoids and who died due 
to an episode of massive hemoptysis. There were no other SAEs reported in the bedaquiline group. In the 
pooled safety data from the placebo‐controlled Phase 2b trial, C208, the most frequently reported AEs in the 
bedaquiline group were nausea, arthralgia, headache, hyperuricemia, and vomiting.  
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 Subjects in the Any bedaquiline group and 5 Subjects 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  Subjects  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 
Subjects (12.7%) compared to 3 placebo Subjects (3.7%). Based on the pooled results (Stage 1 and 2) while 
being followed in the placebo‐controlled trial, 7 Subjects in the Any bedaquiline group and 1 Subject 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 


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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 Subjects 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 Subject in the bedaquiline group (pulmonary TB) and 2 
Subjects in the Placebo group (TB‐related illness and pulmonary TB) in Stage 1 died, and 4 Subjects in the 
bedaquiline group (3 Subjects with TB‐related illness, 1 Subject motor vehicle accident) and 2 Subjects in the 
Placebo group (both TB‐related illness) died after they discontinued Stage 2 of the trial. None of these Subjects 
had a treatment‐emergent QTcF ≥ 500 ms. 
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 Subjects 
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 in Subjects 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 Subjects (6.9%) have died (12 Subjects during the 
trial and 4 Subjects 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 Subjects has a treatment‐
emergent adverse event. 
In study NC‐001‐(J‐M‐Pa‐Z), three Subjects in a bedaquiline‐containing treatment arm, were withdrawn. One 
on a bedaquiline (400mg) only arm for a Grade 3 ALT and GGT elevation although the elevation occurred prior 
to the first dose of study medication: one on a bedaquiline (400mg) plus pyrazinamide (weight banded) arm 
for a Grade 3 ALT and AST elevation, and one on a PA‐824 (200mg) and bedaquiline (400mg) arm for to a Grade 
3 ALT elevation. 
Bedaquiline has been recently studied in combination with other agents, including the combination to be 
studied in the current study (J‐Pa‐Z), in a 14 day EBA study (NC‐003). Because NC‐003 forms the basis of moving 
J‐Pa‐Z into Phase 2b, findings from this study are presented in section 2.3 Regimens to be Studied. 
2.2.2. PA‐824 
As detailed in the Investigator’s Brochure  (23), 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 (24). PA‐824 demonstrated in vitro activity against both DS‐ and MDR‐TB (25), and in vivo 
activity in a mouse model of tuberculosis (24,25).  
PA‐824 has been studied in four 14‐day EBA trials to date, including two monotherapy dose‐ranging studies 
and  two  combination  EBA  studies.    PA‐824  monotherapy  has  demonstrated  substantial  mycobactericidal 
activity. The efficacy data from study PA‐824‐CL‐007 indicated that all doses of PA‐824 (200, 600, 1000 and 
1200mg) produced an equivalent decrease in sputum CFU counts over the 14‐day treatment period.  In study 
PA‐824‐CL‐010, an EBA study with a similar design to study PA‐824‐CL‐007 except for the use of lower doses 
of PA‐824 (50, 100, 150 and 200mg/day), results indicated that PA‐824 treatment resulted in a measurable 
dose‐dependent mycobactericidal activity over the dose range studied, and supported a clinical dose of 200mg 
per day.  In study NC‐001‐(J‐M‐Pa‐Z) an EBA study with multiple treatment combinations, the three drug 
combination of PA‐824 (200mg per day), moxifloxacin and pyrazinamide (Pa‐M‐Z) demonstrated potential as 


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a treatment shortening regimen and was progressed into an 8 week “SSCC” study (NC‐002) in which the 
combination was shown to be statistically better that the HRZE control on some measures of activity.  In the 
second 14‐day combination EBA study (NC‐003), the bedaquiline, PA‐824 and pyrazinamide (J‐Pa‐Z) regimen 
showed promising activity and has been selected to move forward in development and is the focus of the 
current study (NC‐005). 
2.2.2.1. 
PA‐824 Preclinical Studies 
Microbiology 
In vitro studies have demonstrated that the minimum inhibitory concentration (MIC) of PA‐824 against a 
variety of drug‐sensitive M. Tb isolates is similar to the MIC of isoniazid (MIC of PA‐824, ≤0.015 to 0.25 µg/mL; 
MIC of isoniazid, 0.03 to 0.06 µg/mL).  PA‐824 was efficacious in vitro against drug‐resistant clinical isolates of 
M. Tb, with MIC values ranging from 0.03 to 0.53 µg/mL.  The minimum effective dose (MED) of PA‐824 was 
12.5  mg/kg/day  in  a  mouse  model  of  TB.    The  MED  is  defined  as  the  lowest  dose  able  to  prevent  the 
development of macroscopic lung lesions and splenomegaly.  The minimum bactericidal dose (MBD) was 100 
mg/kg/day in the same mouse model.  The MBD is defined as the lowest dose able to reduce the lung TB 
colony forming unit (CFU) counts by 99%.  The magnitude of CFU reduction by PA‐824 at this dose is similar to 
that seen with the highest dose of isoniazid tested in the same study (25 mg/kg/day). 
Nonclinical Safety Studies 
The  non‐clinical  safety  evaluation  of  PA‐824  includes  pharmacology,  pharmacokinetics,  toxicology  and 
metabolism studies that were conducted in accordance with current ICH guidelines. 
PA‐824 was negative in all genotoxicology studies performed.  One of its metabolites (M50) that is found in 
rat, monkey, and human plasma was positive in a screening Ames assay. M50 is not a major metabolite in 
humans and the exposure relative to parent drug is higher in the rat (24%) and monkey (18%) than in humans 
(6%).  
PA‐824‐induced effects in respiratory, CNS, and cardiovascular safety pharmacology studies were generally 
mild and reversible; effects were most prominent at 450 mg/kg/day.  PA‐824 is a weak inhibitor (IC50=20uM) 
of the hERG channel.  In a telemetry monkey study, in the dose range 50‐450 mg/kg, there was no or minor 
prolongation of the QT interval, depending on the method of correction.  The weight of evidence suggests that 
there should be no effect on QT in the dose range being explored in the clinical studies. 
Prior to the use of PA‐824 in combination with moxifloxacin in the NC‐001‐(J‐M‐Pa‐Z) study, a preclinical 
cardiovascular safety pharmacology study was conducted in unrestrained cynomolgus monkeys with both 
drugs to explore the potential for PA‐824 to alter  the QT prolongation induced by moxifloxacin.   Results 
indicate that administration of 50 mg/kg PA‐824 in combination with 100 mg/kg moxifloxacin resulted in 
increases  in  QT  and  QTc  intervals  in  1  animal  (out  of  4  animals  tested)  that  were  ~10%  higher  than 
administration of 100 mg/kg moxifloxacin alone.  Given this limited finding with the relatively high doses of 
PA‐824 and moxifloxacin employed in the preclinical study, and results of ECG monitoring in the EBA study, 
NC‐001‐(J‐M‐Pa‐Z),  Subjects will not be exposed to undue risk in the proposed clinical study, during which 
they will also undergo ECG monitoring.   
Repeat‐dose  toxicology studies with PA‐824 have been  conducted in  male  and female rats (14 days to 6 
months), and in male and female monkeys (7 days to 3 months).  In all studies, dose‐dependent reduced food 
consumption and reduced weight gain or weight loss were noted.  In addition, testicular atrophy was observed 
in rats while cataracts were observed by indirect ophthalmoscopy in both rats and monkeys. In general, toxicity 
in both rat and monkey was significantly greater when exposures exceeded approximately 300 μg•hr/mL in 
the 14‐day studies and approximately 200 μg•hr/mL in the 3‐month studies.  
Reproductive toxicology studies show that PA‐824 is not teratogenic in rats or rabbits.  In the rat fertility study, 
dose‐dependent  reduced  fertility  rates,  due  to  decreased  sperm  numbers  and  decreased  motility,  were 


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observed  at  doses  of  30  mg/kg  and  greater.    This  effect  was  partially  reversible.    As  in  the  3‐month  rat 
toxicology study, irreversible testicular lesions were not observed at 30 mg/kg, only at 100 and 300 mg/kg. 
To more fully characterize the cataract and male reproductive system findings, a 3‐month monkey study in 
sexually mature males (0, 50, 150, 300 mg/kg/day), and a 6‐month rat study (0, 30, 100, 300 mg/kg) in males 
and females were conducted.  Ocular assessments were conducted in a much more careful and systematic 
manner  than  in  the  initial  3‐month  toxicology  studies  described  above.  In  each  of  the  later  studies,  all 
ophthalmologic  examinations  were  conducted  by  a  single  ophthalmologist,  using  both  indirect 
ophthalmoscopy and slit‐lamp biomicroscopy.  Animals were screened before dosing to ensure no animal had 
cataracts at baseline, and then monthly during dosing and recovery. In this monkey study, although similar 
drug  exposures  were  attained  as  in  the  original  3  month  monkey  study,  no  cataracts  or  testes  effects 
(semenology, organ weights, histopathology, or hormones [testosterone, follicle‐stimulating hormone, Inhibin 
B]) were observed at any point during dosing or during a 20‐week recovery period.  PA‐824 does not appear 
to cause cataracts or testicular toxicity in monkeys. In the 6‐month rat study, PA‐824 caused irreversible 
cataracts at 100 mg/kg from Day 118 of the study in males and females. In contrast to the original 3‐month 
rat report, rats in this more carefully conducted study developed cataracts while on drug but not during 
recovery. The NOAEL was 30 mg/kg for cataracts and 10 mg/kg for testicular toxicity.  Rats that developed 
cataract and testicular toxicity also experienced marked decreases in body weight gain and food consumption. 
The AUC safety multiples (relative to the exposures obtained at the anticipated clinical dose of 200 mg/day) 
for cataract are ~1.5x in the rat; in the monkey at the highest dose tolerated, where there were no cataracts 
in the second well conducted study, the multiple is at least 3.7x.  
To summarize, cataracts have been detected in multiple animals from two similar rat studies at mid‐to‐high 
doses.  In contrast, the finding of cataracts in one monkey study could not be confirmed in a follow‐up study.  
Thus, both cataracts and the testicular effects appear to be species‐limited. 
An overall summary of the findings from animal safety and toxicology studies is contained in Table 1. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 1: PA‐824 Animal Safety and Toxicology Findings 
 
Nervous system‐related effects.   
Rats given single oral PA‐824 doses had decreased body tone, touch responses and decreased grooming 
behavior at ≥150 mg/kg, which resolved within 24 hours.  Rats given repeated daily doses of PA‐824 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 
PA‐824 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 
Testicular degeneration/atrophy, occurred in rats with repeated doses of PA‐824 at ≥30 mg/kg/day but 
did not occur in monkeys at any dose level.  Testicular effects showed evidence of being partially reversible, 
albeit very slowly, in rats dosed for 7 days, but not in rats dosed for 14 days.  As would be expected, there 
was a dose‐related decrease in fertility in male rats at ≥30 mg/kg/day that was associated with decreased 
sperm numbers and motility. This effect on fertility in male rats was partially reversible. 
 
Cataracts 
Cataracts developed with prolonged daily dosing in rats at PA‐824 doses ≥100 mg/kg/day.  In one 13‐week 
study 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 study 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 
PA‐824 inhibited hERG current with IC50 values of approximately 6.2 µg/mL. Following a single PA‐824 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 PA‐824 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  PA‐824  doses  of 
≥150 mg/kg/day. 
 
 
 


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2.2.2.2. 
PA‐824 Clinical Studies 
Phase 1 
The safety, tolerability and pharmacokinetics of PA‐824 have been studied in 9 Phase 1 studies, which are 
summarized in Table 2. In these trials, PA‐824 has been administered in doses ranging from 50 to 1500mg, as 
50 or 200mg tablets or as an oral suspension.  PK parameters have largely been consistent in each study and 
can be summarized as follows:  
 
PA‐824  is  moderately  rapidly  absorbed,  with  median  Tmax  values  across  Subjects  and  dose  levels 
ranging from 4 to 7 hours.   
 
The mean half‐life for elimination (t½) across Subjects and dose levels was approximately 16 ‐ 25 hours.  
 
Exposure increased approximately linearly but less than dose‐proportionally, with increasing doses up 
to approximately 600 – 1000mg, while higher doses achieved minimal additional increases in either 
Cmax or AUC.   
Two studies using radiolabeled PA‐824 in an oral‐suspension formulation have been conducted to investigate 
the metabolism and excretion patterns of PA‐824 in humans: Study PA‐824‐CL‐004, which used [benzyl‐14C] 
PA‐824 and Study PA‐824‐CL‐008, which used [imidazooxazine‐14C] PA‐824. The mass balance results from the 
two studies were very similar.  In each study, the majority (53‐65%) of radioactivity was excreted in the urine; 
an additional 26‐38% was collected in the feces such that approximately 91% of the administered dose was 
ultimately recovered in the excreta.   
Radioprofiling and metabolite identification work have been completed on samples from the two human 
studies as well as from analogous work in rat and monkey using both radiolabeled PA‐824 preparations.  The 
metabolism of PA‐824 proceeds via a combination of reductive metabolism (~20 – 25% of the dose) and 
oxidative metabolism (remainder of the characterized metabolites). The metabolic profile of PA‐824 in vivo 
was qualitatively similar in the three species, with quantitative differences being minor. No human unique 
metabolites  were  detected  and  there  is  no  one  single  metabolic  path  that  can  be  considered  major. 
Furthermore, there are no major metabolites in human plasma.   
Study PA‐824‐CL‐006, a drug‐drug interaction study with midazolam to assess the extent of CYP3A inhibition 
by PA‐824, results indicate that dosing of PA‐824 400mg once daily for 14 days did not have a major effect on 
the exposure of midazolam or its major metabolite 1‐hydroxy midazolam.  For midazolam, the geometric mean 
ratio of Day 17 (midazolam+PA‐824) vs. Day 1 (midazolam alone) for Cmax was 0.84 and AUC was 0.85.  For 
the 1‐hydroxy midazolam metabolite, the corresponding geometric mean ratio for Cmax was 1.05 and AUC 
was 1.11.  The data suggests that PA‐824 does not cause clinically significant drugs interactions with drugs 
metabolized by CYP3A.  No drug‐drug interaction is anticipated between PA‐824 and either pyrazinamide or 
moxifloxacin. 
Two additional studies have recently been completed and are currently undergoing analysis: Study DMID 10‐
0058 (a Thorough QT study comparing PA‐824 and PA‐824 plus moxifloxacin to moxifloxacin alone) and Study 
ACTG 5603 (a drug‐drug interaction study evaluating the effects of concomitantly administered Efavirenz, 
Ritonavir‐Boosted Lopinavir or rifampicin on the PK parameters of PA‐824). The first study found that single 
doses of PA‐824 of 400mg and 1000mg had a small effect on the QTc interval (<5msec) and when PA‐824 at 
400mg is co‐administered with moxifloxacin (400mg) it did not increase the QTc prolongation substantially 
over what is seen with moxifloxacin alone. The second study found that when administered with Efavirenz, 
Ritonavir‐Boosted  Lopinavir,  or  Rifampin,  PA‐824  (200mg)  median  PA‐824  concentrations  (AUC0‐24h)  were 
reduced 35% by EFV, 17% by LPV/r, and 66% by rifampin. The clinical significance of these findings requires 
further investigation. 


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Study PA‐824‐CL‐009, a food effects study PA‐824 (200mg and 50mg), results indicate that the food effect 
observed is dependent on the PA‐824 dose administered.  When a single dose of PA‐824 was administered 
with  a  high  fat,  high  calorie  meal,  Cmax  and  AUC  of  the  50mg  dose  increased  1.40‐fold  and  1.45‐fold 
respectively, whereas for the 200mg dose, Cmax increased 1.76‐fold and AUC increased 1.88‐fold. 
Table 2: PA‐824 Phase 1 Clinical Studies 
Study 
Design 
PA‐824 Dose 
Enrolled 
Key Findings 
CL‐001 
Double‐blind, placebo‐
controlled, single‐
dose, dose‐escalating, 
PK and safety study  
0, 50, 250, 500, 750, 
1000, 1250, 1500 
53 
 
 
Well tolerated; no dose‐limiting AEs or 
abnormal laboratory results; no effects on ECG, 
vital signs, or PE.  
CL‐002 
Double‐blind, placebo‐
controlled 7‐day 
multidose, escalating, 
PK and safety study 
0, 200, 600, 1000 
24 
 
 
Well tolerated; no effects on ECG, vital signs, or 
PE. 
 
After 5 days’ dosing at 1000 mg/d, progressive 
moderate creatinine elevation: reversed during 
7‐day washout period.   
 
No consistent effect on BUN.   
 
A planned 1400‐mg cohort not enrolled. 
CL‐003 
Open‐label, single‐
dose, food effects 
1000 
16 
 
 
 
Well tolerated; no dose‐limiting AEs or 
abnormal laboratory results; no effects on ECG, 
vital signs, or PE. 
 
Treatment‐emergent AEs affecting more than 
one Subject occurred more frequently after 
dosing in the fed condition than the fasted 
condition, and more frequently among women 
than men. 
 
Bioavailability is 3.5‐to‐4.5‐fold higher when 
PA‐824 is administered within 30 minutes of a 
high‐fat, high‐calorie meal than when it is 
administered after an overnight fast. 
CL‐004 
Open‐label, single‐
dose, ADME 
~860, oral suspension 
[benzyl‐14C]PA‐824 
6 
 
 
Well tolerated; no dose‐limiting AEs or 
abnormal laboratory results; no effects on ECG, 
vital signs, or PE. 
 
No significant radioactivity captured as [benzyl‐
14C]CO2.   
 
~91% of dose recovered (~65% in urine; ~26% 
in feces) 
 
Plasma: parent drug and one major metabolite.  
 
Urine: little or no parent drug; multiple major 
metabolites. 
 
Feces: minimal unchanged parent drug; 
numerous low‐abundance metabolites. 


Global Alliance for TB Drug Development 
Protocol Number: NC‐005‐(J‐M‐Pa‐Z) 
Working Protocol Version: 1.1 (Final) 
Protocol Date: 19 September 2014 
 
 
 
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Study 
Design 
PA‐824 Dose 
Enrolled 
Key Findings 
CL‐005 
Double‐blind, 8‐day 
multidose, renal 
effects  
0, 800, 1000 
47 
 
 
Well tolerated; no dose‐limiting AEs or 
abnormal laboratory results; no effects on ECG, 
vital signs, or PE. 
 
As anticipated, serum/plasma creatinine levels 
increased significantly (up to ~ 40%) during 
treatment; reversed during 7‐day washout 
period. 
 
No effect during treatment on GFR, ERPF, FF, 
BUN or UA. 
CL‐006 
Open‐label, multidose, 
DDI 
400 
14 
 
Well tolerated; no dose‐limiting AEs.  
 
For midazolam, the geometric mean ratio of 
Day 17 (midazolam+Pa‐824) vs. Day 1 
(midazolam alone) for Cmax was 0.84 and AUC(0‐
infinity) was 0.85.  
 
For the 1‐hydroxy midazolam metabolite, the 
corresponding geometric mean ratio for Cmax 
was 1.05 and AUC(0‐infinity) was 1.11.  
CL‐008 
Open‐label, single‐
dose, ADME 
~1100, oral 
suspension 
[imidazooxazine‐14C]P
A‐824 
6 
 
 
Well tolerated; no dose‐limiting AEs or 
abnormal laboratory results; no effects on ECG, 
vital signs, or PE. 
 
No significant radioactivity captured as 
[imidazooxazine‐14C]CO2.   
 
~91% of dose recovered (~53% in urine; ~38% 
in feces) Plasma: parent drug. Urine: little or no 
parent drug; multiple major metabolites. 
 
Feces:  unchanged parent drug and numerous 
low‐abundance metabolites. 
CL‐009 
Open‐label, single‐
dose, food effects 
50 and 200 
32 
 
 
Well tolerated; no dose‐limiting AEs. 
 
In the presence of high fat, high calorie diet, 
Cmax and AUC of the 50‐mg dose increased 
1.40‐fold and 1.45‐fold respectively, whereas 
for the 200‐mg dose, Cmax increased 1.76‐
fold and AUC increased 1.88‐fold. 
A5306 
Antiretroviral DDI 
200 
48 
 
Based on preliminary data – the study is 
currently undergoing analysis. 
 
Co‐administration with Efavirenz resulted in a 
35% reduction in PA‐824 AUC. 
 
Co‐administration with Ritonavir‐Boosted 
Lopinavir resulted in a 17% reduction in PA‐824 
AUC. 
 
Co‐administration with rifampicin resulted in a 
66% reduction in PA‐824 AUC. 


Global Alliance for TB Drug Development 
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Working Protocol Version: 1.1 (Final) 
Protocol Date: 19 September 2014 
 
 
 
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Study 
Design 
PA‐824 Dose 
Enrolled 
Key Findings 
10‐
0058 
Thorough QT Study 
400 and 1000 
75 
 
PA‐824, alone and in combination with 
moxifloxacin, was well tolerated. 
 
PA‐824 doses of 400 mg and 1000 mg did not 
cause QT interval prolongation to a level of 
clinical concern as the upper limit of the 90% CI 
associated with any LS mean ΔΔQTcI value did 
not exceed 4.4 ms for the 400‐mg dose or 6.1 
ms for the 1000‐mg dose, and both were well 
below 10 ms. 
 
The effect of PA‐824 400 mg plus moxifloxacin 
400 mg on QTcI was similar to the effect of 
moxifloxacin administered alone. 
 
No Subject receiving PA‐824 or moxifloxacin 
alone had an observed QTcI value that 
exceeded 450 ms or experienced a change‐
from‐baseline in QTcI that exceeded 30 ms.   
 
The PK of PA‐824 was not affected by the co‐
administration of moxifloxacin. 
 
Phase 2 
Study PA‐824‐CL‐007, a 14 day monotherapy EBA study, indicated that all doses of PA‐824 (200, 600, 1000 and 
1200mg  a  day)  produced  a  measurable  and  equivalent  decrease  in  sputum  CFU  counts  over  the  14‐day 
treatment period. Study PA‐824‐CL‐010 was an EBA study with a similar design to study PA‐824‐CL‐007 except 
for the use of lower doses of PA‐824 (50, 100, 150 or 200 mg/day).  Results indicate that PA‐824 treatment 
resulted in a measurable dose‐dependent mycobactericidal activity, with the 50mg dose demonstrating less 
activity than the 100, 150 and 200mg doses, which were all equivalent.  
Study  NC‐001‐(J‐M‐Pa‐Z)  was  a  14  day  EBA  study  that  assessed  the  two‐week  EBA  of  the  following  drug 
combinations: PA‐824 plus pyrazinamide, PA‐824 plus pyrazinamide plus moxifloxacin, along with two other 
non‐PA‐824 containing combinations. Results indicate that the three drug combination of PA‐824 (200mg per 
day), moxifloxacin and pyrazinamide has potential as a treatment shortening regimen.  In the study this three 
drug combination has an EBA 0‐14, which is believed indicative of sterilizing activity, numerically better than 
the current 4‐drug intensive phase treatment of HRZE.   
The recently completed Phase 2b study, NC‐002, was a multi‐center open‐label partially randomized clinical 
trial with four treatment groups. Subjects with drug‐sensitive TB were randomized to receive moxifloxacin 
400mg plus PA‐824 100mg plus pyrazinamide 1500mg (M‐PA100‐Z) or moxifloxacin 400mg plus PA‐824 200mg 
plus pyrazinamide 1500mg (M‐PA200‐Z) or standard HRZE therapy. HRZE was included as a control arm for the 
drug‐sensitive treatments and for the laboratory methodology. Subjects with MDR‐TB received moxifloxacin 
400mg plus PA‐824 200mg plus pyrazinamide 1500mg (M‐PA200‐Z MDR). The study population included a 
total of up to 230 male and female newly diagnosed Subjects with drug‐sensitive or multi drug‐resistant, smear 
positive pulmonary tuberculosis aged 18 to 65 years (inclusive).  The primary efficacy endpoint was the rate 
of  change  in  the  logarithm  of  colony  forming  unit  (CFU)  (or  log[CFU])  count)  over  8  weeks  of  treatment 
analysed by a Joint Bayesian Non‐linear Mixed Effect (NLME) regression.  
Preliminary analyses indicate that a total of 207 Subjects were enrolled, with 60 randomized to M‐PA100‐Z, 
62 randomized to M‐PA200‐Z, and 59 to HRZE.  An additional 26 Subjects were treated in the M‐PA200‐Z MDR‐
TB arm.  Of note, more Subjects in the MDR‐TB arm did not complete the full 8 weeks of treatment, primarily 
because many were withdrawn as late‐exclusions (M. Tb resistant to pyrazinamide determined in culture after 
enrolment in the study). 21 MDR‐TB Subjects were in the study with active treatment through day 14 and 10 
were  in  the  study  through  the  full  8  weeks  of  treatment  (9  with  evaluable  results  for  the  primary 
microbiological  endpoint).    In  contrast,  the  following  number  of  Subjects  was  in  the  study  with  active 


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treatment through 8 weeks in the 3 randomized arms with evaluable results for the primary microbiological 
endpoint:  55 in the M‐PA100‐Z arm, 54 in the M‐PA200‐Z arm and 54 in the HRZE arm. For the primary 
endpoint, Subjects in the M‐PA200‐Z arm had a statistically significantly greater decline in the log CFU count 
over the 8 weeks, than the Subjects in the HRZE arm. 
Finally, PA‐824 has recently been studied in combination with Bedaquiline and other agents in a 2 week EBA 
study (NC‐003). Findings from this study form the basis for selecting the J‐Pa‐Z regimen for further study in the 
current clinical trial (NC‐005) and are discussed in detail in section 2.3 Regimens to be Studied. 


Global Alliance for TB Drug Development 
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Table 3: PA‐824 Phase 2 Studies 
 
 
 
 
 
 
 
 
 
 
Study 
Design 
PA‐824 
Doses 
Enrolled 
Key Findings 
CL‐007 
Partially double‐blinded (blinded as to 
PA‐824 dose), 14‐day multidose, 
extended early bactericidal activity. 
200, 
600, 
1000, 
1200 
69  
 
Overall well tolerated with relatively few 
AEs and no dose‐limiting AEs or laboratory 
findings.  No clinically significant effects on 
ECG, vitals, or PE noted. 
 
Two SAEs occurred during study, both were 
considered possibly related to TB disease 
(hemoptysis). 
 
PA‐824 treatment produced a measurable 
decrease in log CFU, with the magnitude of 
effect equivalent for all doses. 
CL‐010 
Partially double‐blinded (blinded as to 
PA‐824 dose), 14‐day multidose, 
extended early bactericidal activity. 
50,  100, 
150, 
200 
69  
 
Well tolerated. 
 
PA‐824 treatment produced a measurable 
decrease in log CFU with some evidence of 
dose dependence. 
NC‐
001 
 
Partially double‐blinded (blinded as to 
combination within Pa or J containing 
arms), 14‐day multidose, extended early 
bactericidal activity. 
200 
85 
 
Well tolerated. 
 
PA‐824 plus moxifloxacin plus pyrazinamide 
combination treatment produced a 
decrease in log CFU at least comparable to 
that of the Rifafour e‐275 control group. 
NC‐
003 
Multi‐center, open‐label, randomized 
clinical trial with seven parallel 
treatment arms.  Fifteen Subjects were 
enrolled in each of the following 
treatment arms: TMC207 plus PA‐824 
plus pyrazinamide plus clofazimine, 
TMC207 plus PA‐824 plus pyrazinamide, 
TMC207 plus PA‐824 plus clofazimine, 
TMC207 plus pyrazinamide plus 
clofazimine, pyrazinamide alone, 
clofazimine alone, and Rifafour e‐275®. 
200 
  105 
 
Based on preliminary results: 
 
The EBA results for Rifafour in this trial are 
similar to those reported in prior studies 
and validate the trial’s underlying 
mycobacterial methodology; the decrease 
in log(CFU) count over the 14‐day treatment 
period under Rifafour was similar to the 
decreases observed in previous studies. 
 
Among the regimens studied, the 
combination J‐PA‐Z demonstrated the 
highest EBA, with results at least 
comparable to the HRZE control. 
 
The treatments administered in this trial 
were well tolerated by the trial population. 
 
No deaths were reported in this trial.  
Serious AEs were reported for 1 Subject 
(1.0%) in the clofazimine alone arm: 
gastroenteritis, anemia, and deep vein 
thrombosis (none of which were considered 
to be related to the treatment).   


Global Alliance for TB Drug Development 
Protocol Number: NC‐005‐(J‐M‐Pa‐Z) 
Working Protocol Version: 1.1 (Final) 
Protocol Date: 19 September 2014 
 
 
 
TMP02‐A V1.0 
 
 
Page 39 of 112  Confidential 
 
Study 
Design 
PA‐824 
Doses 
Enrolled 
Key Findings 
NC‐
002  
 
Multi‐center open‐label partially 
randomized clinical trial in four 
treatment groups.  Subjects with drug‐
sensitive TB randomized to receive 
moxifloxacin 400 mg plus PA‐824 100 
mg plus pyrazinamide 1500 mg or 
moxifloxacin 400 mg plus PA‐824 200 
mg plus pyrazinamide 1500 mg or 
Rifafour e‐275.   
100, 200 
207 
 
Based on preliminary results: 
 
For the primary endpoint Subjects in the M‐
PA200‐Z arm had a statistically significantly 
greater decline in the log CFU count over 
the 8 weeks than the Subjects in the HRZE 
arm. 
 
For the exploratory endpoint all groups had 
a higher rate of conversion of sputum to a 
negative culture for M. Tb on solid culture 
than on liquid culture.  Subjects in both of 
the M‐Pa‐Z groups had substantially and 
statistically significantly greater rates of 
conversion to negative growth in liquid 
culture than the group on Rifafour (HRZE) 
 
Well tolerated overall, with  88% of all 
Subjects had a treatment emergent adverse 
event (TEAE), including 87% in the M‐
PA100‐Z group, 92% in the M‐Pa‐Z group, 
85% in the Rifafour group and 89% in the 
M‐Pa‐Z MDR group 
 
Eleven serious adverse events (SAEs) were 
reported in 9 Subjects, with one Subject in 
each of the M‐PA100‐Z and the Rifafour 
groups, and 7 Subjects in the M‐PA200‐Z 
group. The Subject in the M‐PA100‐Z group 
died of an unknown cause 39 days after a 
single dose of study drug regimen and the 
death was not considered related to study 
drug by the Investigator or the sponsor.  
Four other SAEs were considered not 
related to study drug, including a 
pneumothorax, a bone fracture, dyspnea 
requiring hospitalization, and second degree 
heart block SAEs considered possibly related 
or related to the study drug regimen 
included hyperuricemia likely secondary 
from pyrazinamide, drug‐induced hepatitis 
and elevated liver enzymes.  One Subject 
had an episode of agranulocytosis that 
resolved after the study drug regimen was 
stopped and one Subject had a seizure and 
was discontinued from the study. 


Global Alliance for TB Drug Development 
Protocol Number: NC‐005‐(J‐M‐Pa‐Z) 
Working Protocol Version: 1.1 (Final) 
Protocol Date: 19 September 2014 
 
  
TMP02‐B V1.0  
 
   
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2.2.2.3. 
Clinical Safety 
The overall safety profile determined from the clinical studies completed to date indicates PA‐824 is well 
tolerated in healthy adults and in TB Subjects when administered alone and in combination with moxifloxacin, 
pyrazinamide, bedaquiline and clofazimine.  Single doses ranging from 50 to 1500 mg in men and daily doses 
in men and women up to 1200 mg for up to 14 days were safe and resulted in generally minor adverse events 
(AEs).    Approximately  80%  of  AEs  were  mild,  with  most  of  the  remainder  as  moderate.    Among  healthy 
volunteers dosed to date, one severe AE and no serious adverse events (SAEs) have been observed.   
In Phase 1 trials at the clinical dose of 200mg or lower, the incidence of headache was approximately 20‐30% 
and similar to placebo.  At doses of 800mg and higher, usually in trials without a placebo or comparator arm, 
the incidence of headache reached 80%.  Headache occurrence was typically higher in studies with longer 
confinement periods.  Throughout the development program, other common TEAEs include elevated serum 
creatinine, stomach  discomfort  (including  nausea and other  gastrointestinal  symptoms such as flatulence 
and/or diarrhea), and skin and subcutaneous tissue disorders (including erythema, pruritus and rash).  Skin 
and subcutaneous tissue disorders, followed by stomach discomfort were the most commonly reported TEAEs 
in the Phase 2 monotherapy studies (PA‐824‐CL‐007 and PA‐824‐CL‐010).  Within Study PA‐824‐CL‐007, a 
higher incidence of PA‐824 TEAEs were observed in the higher PA‐824 dose groups (PA‐824 200mg: 7%; PA‐
824 600mg: 13%; PA‐824 1000mg: 31%; and PA‐824 1200mg: 33%).  The incidence of the TEAEs in the Rifafour® 
treated group was 25%.  Study PA‐824‐CL‐010, among the four PA‐824 treatment groups (50mg, 100mg, 
150mg, and 200mg) and the Rifafour® treatment group, a higher incidence of TEAEs was observed in the 50mg 
PA‐824 group (66.7%) when compared with Rifafour® (50.0%) and the other PA‐824 treatment groups. For the 
multidose, placebo‐controlled Studies PA‐824‐CL‐002 and PA‐824‐CL‐005, overall AE frequency tended to be 
greater among PA‐824 Subjects than among placebo Subjects, and tended to be higher in higher PA‐824 dose 
groups.   
Study PA‐824‐CL‐005 was undertaken to determine the mechanism responsible for the elevation in serum 
creatinine seen with PA‐824 dosing in studies PA‐824‐CL‐001 and PA‐824‐CL‐002.  This study explored the 
effects of PA‐824 on kidney function by measuring glomerular filtration rate (GFR), effective renal plasma flow 
(ERPF), filtration fraction (FF, calculated as GFR/ERPF), and creatinine clearance.   Subjects were dosed in 
blinded fashion with placebo, 800mg PA‐824, or 1000mg PA‐824 for 8 days.  Serum creatinine levels rose in 
both the 800‐ and 1000‐mg/day PA‐824 groups, by an average of 0.18 mg/dL (19%) and 0.25 mg/dL (27%) in 
the two groups respectively by Day 8; the largest individual increase was approximately 40% over baseline.  In 
this study, although serum creatinine levels rose, no meaningful effects were noted during the dosing period 
on  GFR,  ERPF,  BUN,  uric  acid  or  FF.    As  expected,  creatinine  clearance  was  reduced  concomitantly  with 
maximally elevated serum creatinine levels relative to baseline.  Taken together, these results indicate that 
PA‐824 does not negatively affect renal function.  Instead, the drug can be assumed to cause its effects on 
serum  creatinine  by  inhibiting  tubular  creatinine  secretion;  such  an  effect  has  been  reported  with  other 
approved drugs (e.g. cimetidine) and is not considered clinically significant.   
Across all studies, the great majority (>~95%) of AEs resolved without sequelae.  In Study PA‐824‐CL‐003, one 
Subject concluded the study with blurry/double vision that may have been related to childhood strabismus, 
while another Subject had ongoing swollen fingers on both hands at the end of the study.  In Study PA‐824‐
CL‐007, two Subjects exited the study with an ongoing AE (anemia [mild, unrelated] and rash [mild, related]) 
and the outcomes for three AEs in one Subject each (anemia [mild, possibly related], elevated LFT [moderate, 
unrelated], and Wolff‐Parkinson‐White syndrome [mild, unrelated] were not known due to loss to follow‐up.  
In Study PA‐824‐CL‐005, one Subject treated with 800mg PA‐824 was discharged with three ongoing AEs 
(proteinuria [nephrotic range during the study, but non‐nephrotic range in follow‐up], hypoalbuminemia, and 
iron deficiency).  The proteinuria and hypoalbuminemia were moderate in severity and the iron deficiency was 
mild.  This Subject substantially improved, and the Subject is seen periodically by a nephrologist.  A renal biopsy 
performed 20 months post‐study revealed focal segmental glomerulosclerosis likely secondary type, although 
the Subject remains fundamentally healthy with normal renal function indices and no signs of peripheral 
edema or hypertension.  A complete review of her screening and check‐in laboratory values suggests, in the 


Global Alliance for TB Drug Development 
Protocol Number: NC‐005‐(J‐M‐Pa‐Z) 
Working Protocol Version: 1.1 (Final) 
Protocol Date: 19 September 2014 
 
 
 
TMP02‐A V1.0 
 
 
Page 41 of 112  Confidential 
 
opinion of the Sponsor, that she might have had a pre‐existing undiagnosed clinical condition including atypical 
lipid profile, BUN below the lower limit of the normal range, and ALT and AST above the upper limit of normal 
range.  Furthermore, her eosinophil count was above‐normal at Screening at 6.7% and progressively rose 
during the study to 8.9% by Day 15 and she reported a personal and family history of allergies and rhinorrea.  
The Investigator considered this individual normal and meeting the protocol entry criteria, and enrolled this 
Subject.  In study PA‐824‐CL‐010 there were 5 mild events (papular rash, left bundle branch block, pruritis, 
pruritis general, peripheral neuropathy) in 5 Subjects being administered PA‐824 which were not resolved at 
study  completion.    In  addition,  there  were  3  moderate  events  (heart  rate  increased,  hyponatremia  and 
hemoglobin decreased) in 3 Subjects being administered PA‐824 which were not resolved, lost to follow up or 
improved, respectively.  There was a single event in one Subject being treated with Rifafour® (lens opacity) 
which was not resolved at study completion.   
Among the healthy volunteers tested, any concomitant therapy for AEs was generally palliative in nature.  
Occasionally,  pains  such  as  headaches,  sore  throat,  and  muscle  ache  were  treated  with  analgesics.    One 
instance of iron deficiency (deemed not related to study drug) was treated with an iron supplement.  In studies 
PA‐824‐CL‐007 and PA‐824‐CL‐010, multiple AEs, most of which were associated with ongoing TB disease, were 
treated  with  medications  or  other  interventions  including  hospitalization  (e.g.,  to  treat  hemoptysis, 
pneumonia and pneumothorax).  
In most of the completed Phase 2 studies, no Subjects discontinued from the study as a result of AEs.  In Study 
PA‐824‐CL‐002, dosing for all Subjects in the 1000mg dose group was discontinued on Day 5 in response to 
rising serum creatinine levels.  In Study PA‐824‐CL‐005, one Subject was discontinued for safety reasons in 
relation  to  a  severe  rash  that  developed  approximately  32  hours  after  the  8th  and  last  dose  of  PA‐824 
(1000mg).  The rash symptoms were treated with diphenhydramine, prednisone, and hydroxyzine at various 
points during the ensuing approximately 9 days until the symptoms completely resolved.  In Study PA‐824‐CL‐
007, two Subjects (one in the 200 mg/day PA‐824 group and one in the control arm) were discontinued as a 
result  of  disease‐related  hemoptysis.    Each  of  these  events  was  classified  as  an  SAE,  both  resolved  with 
treatment in hospital and neither was considered possibly related to the study drugs.  In Study PA‐824‐CL‐010, 
one  Subject  was  withdrawn  due  to  the  SAE  of  pneumothorax  after  4  days’  dosing,  which  resulted  in 
hospitalization and later resolved.  The SAE was deemed related to the Subject’s concurrent tuberculosis and 
unrelated to PA‐824.   
Post‐study  follow‐up  ophthalmic  examinations  were  performed  on  Subjects  and  Subjects  enrolled  in  two 
studies  (PA‐824‐CL‐005  [n=30]  and  PA‐824‐CL‐007  [n=46])  where  Subjects  received  the  highest  doses  of 
PA‐824 for the longest duration among the clinical studies conducted to date.  Male and female healthy 
volunteers were treated at doses up to 1000 mg/day for 8 days in study PA‐824‐CL‐005, and male and female 
TB Subjects were treated at doses up to 1200 mg/day for 14 days in study PA‐824‐CL‐007.  Two ocular events 
were reported, one cataract was among the 12 Subjects from the 1200 mg PA‐824 group in study PA‐824‐CL‐
007 and the other cataract was from among the 5 Subjects within the HRZE group.  
In NC‐001‐(J‐M‐Pa‐Z), five Subjects were discontinued prior to completion of their treatment with a PA‐824 
containing arm.  One Subject receiving PA‐824 (200mg), moxifloxacin (400mg), and pyrazinamide (dosed by 
weight) experienced an SAE considered by the Investigator unrelated  to the drug  combination.   The  SAE 
consisted of convulsion as well as aggressive and violent behaviors.  After a CT scan, the Subject was diagnosed 
with neurocysticercosis.  A second Subject receiving PA‐824 (200mg), moxifloxacin (400mg), and pyrazinamide 
(dosed by weight) was withdrawn on Treatment Day 5 based on a protocol specified criterion of an increase 
from baseline in QTcF and QTcB greater than 60 msec on repeated ECGs and accompanied by clinically relevant 
T‐wave morphology changes.  On Day 5, the Subject had prolonged QTc values (>60 msec) on the pre‐dose 
ECG; however, on repeat ECGs, the QTc values stabilized satisfactorily.  Five hours post‐dose on Day 5, ECG 
QTc values were again increased (>60 msec) from baseline and repeat ECGs also revealed T‐wave changes.  The 
Subject was, therefore, withdrawn from the study as specified in the protocol.  In addition, two Subjects 
receiving PA‐824 (200mg), and pyrazinamide (dosed by weight) were withdrawn due to Grade 3 ALT levels, 
although the elevation in ALT in one of these Subjects occurred prior to the first dose of study medication.  


Global Alliance for TB Drug Development 
Protocol Number: NC‐005‐(J‐M‐Pa‐Z) 
Working Protocol Version: 1.1 (Final) 
Protocol Date: 19 September 2014 
 
 
 
TMP02‐A V1.0 
 
 
Page 42 of 112  Confidential 
 
One  Subject  receiving  PA‐824  (200mg)  and  bedaquiline  (400mg)  was  withdrawn  due  to  a  Grade  3  ALT 
elevation.  Overall in the trial, 53% of the 15 Subjects in the PA‐824 + pyrazinamide  treatment arm experienced 
treatment‐emergent adverse events, as compared with 53% of the 15 Subjects in the PA‐824 + pyrazinamide 
+ moxifloxacin arm and 25% of the 8 Subjects in the HRZE (control) arm.  All of these adverse events were 
rated by the Investigator as mild or moderate.  7% of Subjects in the PA‐824 + pyrazinamide treatment arm 
experienced  liver  enzyme  elevations,  as  compared  with  20%  of  Subjects  in  the  PA‐824  +  pyrazinamide  + 
moxifloxacin arm and 0% in the Rifafour® arm, accounting for most of the imbalance between groups.  All liver 
enzyme elevations were < 3x ULN except for two cases.   
Also in NC‐001‐(J‐M‐Pa‐Z), changes in QT interval were assessed pre‐dose and at 2hrs and 5 hrs post‐dose on 
each day of the study for the PA‐824 + pyrazinamide and PA‐824 + pyrazinamide + moxifloxacin treatment 
arms.  On Day 14, the last dosing day, no Subject in either treatment group had a corrected QT interval (QTcF) 
> 450 msec.  One Subject in the PA‐824 + pyrazinamide arm had a QTcF increase of between 30 and 60 msec; 
no Subject had a QTcF increase > 60 msec.  No Subjects in the PA‐824 + pyrazinamide + moxifloxacin had a 
QTcF increase > 30 msec. 
Preliminary data analyses of the study NC‐002 indicate that a total of 207 Subjects were enrolled, with 60 
randomized to M‐PA100‐Z, 62 randomized to M‐PA200‐Z, and 59 to HRZE.  An additional 26 Subjects were 
treated in the M‐PA200‐Z MDR‐TB arm.  In this study 88% of all Subjects had a treatment emergent adverse 
event (TEAE), including 87% in the M‐PA100‐Z group, 92% in the M‐PA‐Z group, 85% in the HRZE group and 
89% in the M‐PA‐Z MDR‐TB group.  Adverse events were graded according to the NIH Division of Microbiology 
and Infectious Diseases Adult Toxicity Table.   
Eleven serious adverse events (SAEs) were reported in 9 Subjects, with one Subject in each of the M‐PA100‐Z 
and the HRZE groups, and 7 Subjects in the M‐PA200‐Z group. The Subject in the M‐PA100‐Z group died of an 
unknown cause 39 days after a single dose of study drug regimen and the death was not considered related 
to study drug by the Investigator or the Sponsor.  Four other SAEs were considered not related to study drug, 
including a pneumothorax, a bone fracture, dyspnea requiring hospitalization, and second degree heart block 
considered on evaluation to be existing prior to entry in to the trial.  SAEs considered possibly related or related 
to the study drug regimen included hyperuricemia likely secondary from pyrazinamide, drug‐induced hepatitis 
and elevated liver enzymes.  One Subject had an episode of agranulocytosis that resolved after the study drug 
regimen was stopped and one Subject had a seizure witnessed by the family and was discontinued from the 
study. 
The protocol required that Subjects with hepatic enzyme ALT or AST elevations greater than 3X the Upper limit 
of Normal (ULN) must have study drug discontinued.  Consequently, 25 Subjects were withdrawn from the 
study across the study arms for elevations in hepatic enzymes.  The distribution of elevations in ALT across the 
study arms is presented in Table 4.  While more Subjects in the M‐PA200‐Z group had elevations in ALT >3 – 
5X ULN, those with elevations >5X ULN or >8X ULN were fairly evenly distributed across the groups of Subjects 
with drug‐sensitive M. Tb. 
 
Table 4: NC‐002 Elevations in Alanine Aminotransferase 
Note: Groups are not mutually exclusive:  >3X includes >5X and >8X; >5X includes >8X 
ALT 
Statistic 
 
M‐PA100‐Z 
(N=60) 
M‐PA200‐Z 
(N=62) 
HRZE Control 
(N=59) 
M‐PA200‐Z MDR 
(N=26) 
> 3X ULN 
 N (%) 
7 
10 
5 
3 
> 5X ULN 
 N (%) 
4 
5 
4 
2 
> 8X ULN 
 N (%) 
2 
4 
3 
1 


Global Alliance for TB Drug Development 
Protocol Number: NC‐005‐(J‐M‐Pa‐Z) 
Working Protocol Version: 1.1 (Final) 
Protocol Date: 19 September 2014 
 
 
 
TMP02‐A V1.0 
 
 
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Ophthalmologic Evaluations – All Subjects received ophthalmologic evaluations using the AREDS2 grading 
system across a range of 0‐4 including visual acuity testing and slit lamp examinations at baseline and 3 months 
after completion of study drug dosing. All Subjects enrolled with the required zero score grade for all regions 
of the lens except for 1 Subject who was blind in one eye.  Among all Subjects in the trial, 4 Subjects had lens 
evaluations with a grade of greater than zero.  One Subject in the M‐PA100‐Z group and 3 Subjects in the M‐
PA200‐Z group had grades of 0.5 or 1.0 in a single eye in one of the 3 zones of the lens.  It is unlikely these 
findings represent a drug‐induced lens opacity given the low incidence, the unilateral nature of all findings and 
the differing zone locations of the findings.  It is common in persons with no clinical abnormalities to have 
grades of 0.5 – 1.0+ in the AREDS2 rating on a slit lamp evaluation. 
Reproductive  Hormone  Evaluations  –  In  study  NC‐002  men  were  evaluated  with  plasma  samples  for  the 
reproductive hormones LH, FSH and Testosterone at baseline and at the end of the dosing period.  If the study 
drug  regimen  caused  testicular  toxicity,  the  most  sensitive  measure  from  these  hormones  would  be  an 
increase in levels of FSH.  Among Subjects in the M‐PA100‐Z group the mean baseline FSH was 9.027 U/L which 
decreased to 8.338 U/L at the end of therapy.  Among Subjects in the M‐PA200‐Z group the mean baseline 
FSH was 6.531 U/L at baseline and this decreased to a mean of 6.061 at the end of therapy.  Men in the 
Rifafour group had a mean baseline of 7.394 U/L which decreased to 6.714 at the end of therapy.  This gives 
relative reassurance that the M‐Pa‐Z regimen is not likely to cause testicular toxicity in men.  
Electrocardiographic  Conduction  Interval  Changes  –  Subjects  in  NC‐002  had  supine  resting  ECGs  taken  at 
baseline, Day 4 and weekly through the 8 week dosing period and 2 weeks after the end of dosing.  All ECGs 
were read by a central cardiology service.  No Subjects had a corrected QT interval (QTcF) greater than 500 
msec during the study. A small number of Subjects had asymptomatic increases in QTcF from baseline over 60 
msec:  Two in the M‐PA100‐Z group, 4 in the M‐PA200‐Z group, none in the Rifafour group and 2 in the M‐
PA200‐Z MDR group.  An evaluation of the mean change from baseline across all post‐baseline ECGs notes 
increases of 11.1 msec in the Rifafour group, 11.1 in the M‐PA100‐Z group, 17.8 msec in the M‐PA200‐Z group 
and 6.7 in the M‐PA200‐Z MDR‐TB group.  Of note, many Subjects were tachycardic at baseline with their 
active pulmonary M. Tb and had heart rates decrease over the first week of therapy.  This fact complicates 
interpretation of the data based on the QT correction factors that are imperfect when correcting for heart 
rates that change over time.  
PA‐824  has  been  studied  in  combination  with  bedaquiline  in  study  NC‐003;  the  results  of  this  study  are 
presented in detail in section 2.3 Regimens to be Studied. 
2.2.3. Moxifloxacin 
Moxifloxacin (M) is an 8‐methoxyquinolone whose oral formulation (which will be used in this study) has been 
approved in most countries around the world for the treatment of acute bacterial sinusitis, acute bacterial 
exacerbation of chronic bronchitis, community‐acquired pneumonia, and skin and soft tissue infections.  It 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 400mg.  Clinical studies have been carried out in additional 
indications (urinary tract infections, pelvic infections, pharyngitis/tonsillitis, and tuberculosis).  
Studies  in  murine  models  of  TB  and  in  TB  Subjects  have  shown  that  moxifloxacin  has  significant 
mycobactericidal activity (26‐35).    These include EBA studies as well as four 8‐week treatment period Phase 2b 
studies in which moxifloxacin was substituted for either isoniazid or ethambutol in the standard, first‐line, TB 
treatment  regimen  (see  Table  5).    Currently,  a  Phase  3  trial,  REMoxTB,  is  ongoing  in  which  moxifloxacin 
replaces either isoniazid or ethambutol in first‐line treatment and is administered in combination with the 
other first‐line drugs for four months, with the expectation that total treatment duration of drug‐sensitive TB 
can be shortened to four months.  The dose of moxifloxacin employed in these TB clinical trials and the NC‐
001, NC‐002and NC‐003 studies is 400mg daily, the registered dose (for other indications as stated above)  and 


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the dose that is commonly used as second line therapy for TB (e.g., in MDR‐TB Subjects). This is the same dose 
we plan to use in the proposed study. 
2.2.3.1. 
Moxifloxacin Clinical Studies 
Moxifloxacin is commonly used as second line therapy for TB in Subjects (e.g. MDR‐ TB), and has also been 
evaluated in several clinical studies of Subjects with TB, including four 8‐week treatment period Phase 2b 
studies (see Table 5 below).  
Table 5: Summary of Phase 2b studies in which moxifloxacin were administered as part of a four‐drug 
regimen during the intensive phase of treatment (total treatment duration: 2 months) 
Study 
Design 
Objective 
 Subjects (N) 
Status 
Study 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 
Study 
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) 
Study 
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 
Study 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 
 
2.2.3.2. 
Moxifloxacin Clinical Safety 
In Study 27 (32), 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 study treatment.  Subjects 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 Subjects in both groups completed study 
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 study (33), AEs and SAEs occurred with equal frequency in the four treatment arms.  The most 
frequent  AEs  were  raised  amylase  (in  41%  of  Subjects  due  to  HIV  infection),  raised  transaminase  (10%), 
arthralgia (9%), anemia (7%), hypokalemia (6%) and vomiting (5%).  No Subject was withdrawn from the study 
due to an adverse event.  There were 4 deaths in the study: 2 in the control group, 1 each in the moxifloxacin 
and  ofloxacin  arms.    Importantly,  Subjects  in  this  study  who  received  moxifloxacin  and  pyrazinamide  in 
addition to isoniazid and rifampin had more rapid sputum clearance than Subjects on the four standard first 


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line  drugs  (isoniazid,  rifampin,  pyrazinamide  and  ethambutol).  This  difference  was  evident  14  days  after 
initiation of treatment. 
In the JHU study (34), AEs did not differ by treatment group. There were 16 SAEs (8 in each group) in 12 Subjects. 
Only 1 event was judged related to study drug (grade 3 cutaneous reaction in the ethambutol group). Eight 
Subjects died during the study, including 1 in each group still receiving study phase treatment. No death was 
attributed to study treatment. Only 5 Subjects discontinued treatment because of toxic effects; 2 Subjects in 
the  moxifloxacin  group  stopped  because  of  grade  2  nausea  and  vomiting  and  1  because  of  grade  2 
paraesthesias and ataxia. Two Subjects 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 Study 28  (35), the proportions of Subjects 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 study treatment during 
the first 2 months occurred among the moxifloxacin group and two in the isoniazid group.  Seven Subjects died 
during the study including 3 Subjects receiving the moxifloxacin treatment regimen and 4 Subjects receiving 
the isoniazid treatment regimen. All 3 moxifloxacin Subjects died during the intensive phase of TB treatment. 
Two Subjects died from advanced pulmonary TB judged not related to study treatment and 1 Subject (who 
developed diabetic ketoacidosis considered possibly related to study treatment) died from possible acute 
pulmonary embolus unrelated to study treatment. The 4 isoniazid deaths occurred during the continuation 
phase, and all 4 were considered unrelated to study treatment.  Nausea was more common among Subjects 
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 Subjects 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 Subjects with TB (Trial NC001) 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 (36) and the manufacturer’s package insert (37). 
2.2.4. Pyrazinamide  
Pyrazinamide, the pyrazine analogue of nicotinamide, is an approved anti‐tuberculosis agent. Pyrazinamide is 
indicated for the initial treatment of active tuberculosis in adults and children when combined with other anti‐
tuberculosis agents and it contributes significantly to the sterilization of lesions and thus, treatment shortening 
(38). 
The current study is being conducted as part of the clinical development of PA‐824 and bedaquiline‐based 
combinations  to  treat  TB.    In  mouse  model  studies  of  TB,  the  combination  of  PA‐824  and  pyrazinamide 
displayed anti‐tuberculosis activity that was equivalent to that of the first‐line regimen of rifampicin, isoniazid 
and pyrazinamide (39). Murine studies have also demonstrated that pyrazinamide potentiates the bactericidal 
effect of bedaquiline and is a key contributor to the efficacy of many combination regimens. Thus, the novel 
pyrazinamide containing regimens in this study, which contain neither isoniazid nor rifampicin, may have the 
potential to (1) shorten the duration of TB chemotherapy and (2) treat both drug‐sensitive and multi drug‐
resistant TB.   
Pyrazinamide  has  been  used  in  standard  regimens  to  treat  TB  for  a  number  of  years  and  is  commonly 
administered to Subjects with drug‐sensitive TB for the intensive first 2 months of a regimen in combination 
with isoniazid, ethambutol and rifampicin.  Pyrazinamide has been evaluated in two EBA studies of two and 
14 days, respectively (2, 41). Both studies showed that there is little activity against tuberculosis in the first two 
days.  However, in a study of 9 Subjects taking 2 grams daily of pyrazinamide, the daily average logCFU count 
decreased to a similar amount as Subjects in other trial arms who were taking rifampicin, streptomycin or INH 
as monotherapy (41).   


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Pyrazinamide monotherapy has been evaluated in a 14 day EBA study in Subjects with DS‐TB (study NC‐003‐
(C‐J‐Pa‐Z). In this study, the pyrazinamide monotherapy arm demonstrated modest EBA over the 14 days of 
the  study,  consistent  with  earlier  studies.  NC‐003  also  included  the  combinations  of  pyrazinamide  and 
bedaquiline and those results will be summarized below in section 2.3 Regimens to be Studied. 
Risks associated with the use of pyrazinamide are highlighted in section 2.5.3. 
2.3. 
Regimens to be Studied 
The regimens included in this study (J‐Pa‐Z and J‐Pa‐M‐Z) have been selected based on the performance of J‐
Pa‐Z in clinical study NC‐003 and mouse models of pulmonary TB. The regimen J‐M‐Pa‐Z will be administered 
only to MDR‐TB Subjects enrolled into the study; moxifloxacin has been added to the J‐Pa‐Z regimen for these 
Subjects because of the high rate of pyrazinamide resistance seen in MDR‐TB Subjects in the NC‐002 study. It 
essentially provides protection against the development of new resistance to the J‐Pa‐Z study drugs. These 
regimens have the potential to shorten TB treatment to less than 4 months for Subjects sensitive to the 
individual drugs in the regimens, including some MDR‐TB Subjects. These are 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. 
The key data supporting the progression of J‐Pa‐Z into Phase 2b (NC‐005) are the results of clinical study NC‐
003, which is described below. 
2.3.1. Non‐clinical Studies 
In the murine model of TB, addition of J to HRZ results in accelerated clearance of M.Tb (12,13) when compared 
to HRZ alone. There appears to be a synergistic interaction with Z: 100% of mice were culture negative after 8 
weeks  of  treatment  with  J  and  Z  compared  to  0%  of  mice  treated  with  the  standard  regimen  of  HRZ 
(18).   Collectively, these findings in the mouse model have led to the suggestion that regimens containing J and 
Z could be effective in the treatment of both DS and MDR‐TB and shorten treatment duration in patients.  
While the combination of J and Pa in the murine model of TB appeared somewhat antagonistic relative to J 
alone, it was as active as the triple combination of HRZ (18) and in a subsequent study it was more active in the 
mouse model than HRZ (19). Thus a novel regimen with a J plus Pa core could be effective in the treatment of 
MDR‐TB by providing two novel drugs for which there is no known pre‐existing resistance.  Indeed, while JPaZ 
was less effective than the JZ regimen in CFU reduction in the first month of therapy due to the antagonism 
between  J  and  Pa,  the  JPaZ  regimen  resulted  in  a  treatment  duration  of  3  months  in  the  murine  model 
compared to the 6 months required for the standard of care, HRZ. 
Prior to the use of PA‐824 in combination with J in clinical study NC‐001, a preclinical cardiovascular safety 
pharmacology study 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 J 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 Pa on Day 7. The effect of PA‐824 dosing alone on QT interval appeared to be 
due to discomfort related to the subcutaneous route of administration and not related to the plasma exposure.  
2.3.2. Clinical Study NC‐003 – Preliminary Results 
Efficacy 
In the 14 day EBA study NC‐003‐(C‐J‐Pa‐Z) two monotherapy and four different combinations of J, Pa, Z and C 
were evaluated in DS‐TB Subjects. Fifteen Subjects were randomized into 7 treatment arms: C, Z, J‐Pa‐Z‐C, J‐
Pa‐Z, J‐Pa‐C, J‐Z‐C, and HRZE control. This study demonstrated no EBA for the clofazimine monotherapy arm 
and  modest  EBA  for  the  pyrazinamide  monotherapy  arm.  However,  all  of  the  experimental  regimens 
demonstrated EBA. In general, adding clofazimine to the various agents resulted in either no increase in EBA, 
or  a  decrease  when  compared  to  a  similar  regimen  that  did  not  include  clofazimine.  In  this  study,  the 


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experimental regimen with the best EBA was J‐Pa‐Z which demonstrated a rate of decrease in both logCFU 
and logTTP that was at least as good as the HRZE control. The daily logCFU results are presented in Table 6. 
Similar results were found when TTP was used to calculate the BA(0‐14). 
Table 6: NC‐003 Efficacy Results: Daily BAlogCFU(0‐14) 
Arm 
logCFU 
JPaZC 
.124 
JPaZ 
.180 
JPaC 
.086 
JZC 
.098 
Z 
.036 
C 
‐.025 
Rifafour 
.152 
 
Safety 
In the 14 day EBA study NC‐003‐(C‐J‐Pa‐Z) two monotherapy and four different combinations of J, Pa, Z and C 
were evaluated in DS‐TB Subjects. Generally, the regimens in this study were well tolerated. Table 7 provides 
a list of the overall safety findings. The only SAE experienced in the study was in a Subject in the clofazimine 
monotherapy arm. Otherwise, the rates of treatment emergent AEs (TEAEs) were similar across the treatment 
arms.  One  Subject  withdrew  from  the  study  due  the  an  adverse  event:  in  the  J‐Pa‐Z  arm  a  Subject  had 
increased liver function tests (ALT, AST and GGT) and was withdrawn from the study.  
Table 7: NC‐003 Safety Data 
  
JPaZC 
JPaZ 
JPaC 
JZC 
Z 
C 
HRZE 
Total 
N 
15 
15 
15 
15 
15 
15 
15 
105 
Subjects with: 
TEAEs 
11 
9 
8 
10 
10 
9 
8 
65 
TEAEs leading to death: 
Serious TEAEs 
  
  
  
  
  
1 
  
1 
TEAES leading to early 
withdrawal 
  
1 
  
  
  
  
  
1 
TEAEs leading to 
discontinuation of study drug 
  
1 
  
  
  
  
  
1 
Drug‐related TEAES 
8 
5 
7 
3 
5 
6 
5 
39 
Serious, drug‐related TEAEs 
  
  
  
  
  
  
  
  
Grade III AEs 
  
2 
1 
2 
  
1 
  
6 
Grade IV AEs 
  
1 
1 
  
  
  
  
2 
Grade II/IV AEs 
  
2 
1 
2 
  
1 
  
6 
 


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QT Prolongation 
Because bedaquiline and clofazimine are both known to prolong the QT interval, intensive ECG monitoring 
was included in the study endpoints. The mean change from baseline in QTcB and QTcF tended to be larger at 
5 hours than at 10 hours post‐dose in the (J‐Pa‐Z‐C) arm and in the (J‐Pa‐C) arm.  No QTcB or QTcF ≥500 ms 
were reported.  An increase from baseline to Visit 5 and subsequent visits of ≥60 ms in QTcB was reported for 
2 Subjects in the (J‐Pa‐C) arm and for 1 Subject in the clofazimine alone arm.  An increase from baseline to 
Visit 5 and subsequent visits of ≥60 ms in QTcF was reported for 4 Subjects in the (J‐Pa‐C) arm and for 1 Subject 
in the clofazimine alone arm.  For both QTcB and QTcF, the (J‐Pa‐Z‐C) arm and the (J‐Pa‐C) arm showed the 
largest increase from baseline. In the current study (NC‐005), clofazimine will not be used in any treatment 
arms. 
2.4. 
Control: HRZE 
The HRZE combination is indicated and commonly used for the treatment of drug‐sensitive TB.  One cohort of 
Subjects in this study will be given standard weight‐adjusted doses of HRZE tablets as a control for the BA 
quantitative mycobacteriology and to evaluate whether HRZE in this population gives similar BA results to that 
demonstrated in prior studies with this combination.  Please see the HRZE package insert for more information 
(40).  
2.5. 
Known and Potential Risks and Benefits of the Investigational Medicinal Product/s 
2.5.1. Bedaquiline 
In  the  clinical  studies  conducted  to  date,  a  total  of  approximately  645  Subjects  (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  subjects  received  bedaquiline  in  a 
monotherapy  EBA  study  of  14  days  (study  TMC207‐CL001)  45  Subjects  received  bedaquiline,  either  as 
monotherapy (J) or in combination with other agents (J‐Pa or J‐Z) in study NC‐001 and 45 more in study NC‐
003 (J‐Pa‐Z, J‐Pa‐C, J‐Pa‐Z‐C). In these studies, bedaquiline has been shown to be an effective treatment for 
Subjects with both DS and MDR‐TB. Specifically, the regimen J‐Pa‐Z was demonstrated to have efficacy at least 
as good as the HRZE control in study 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 studies, 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 ADRs in the 
Any  bedaquiline  group  (>  10.0%  of  Subjects)  were  nausea  (36  [35.3%]  Subjects),  arthralgia  (30  [29.4%] 
Subjects), headache (24 [23.5%] Subjects), vomiting (21 [20.6%] Subjects), and dizziness (13 [12.7%] Subjects). 
In the placebo group, nausea was reported in 27 (25.7%) Subjects, arthralgia in 21 (20.0%) Subjects, headache 
in  12  (11.4%)  Subjects,  vomiting  in  24  (22.9%)  Subjects,  and  dizziness  in  12  (11.4%)  Subjects.  A  greater 
percentage of Subjects 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).  A  greater 
percentage of Subjects in the Any Placebo group compared to the Any bedaquiline group (difference > 5.0%) 
had diarrhea (11.4% versus 5.9%, respectively). 
Mortality 
In the 120‐week C208 Stage 2 trial where bedaquiline was administered for 24 weeks in combination with a 
background  regimen,  more  deaths  occurred  in  the  bedaquiline  group  than  in  the  Placebo  group.  After 
enrolment, 10 Subjects died in the bedaquiline treatment group (N = 79) compared to 3 Subjects in the placebo 
group (N = 81). One death occurred during administration of bedaquiline. The median time to death for the 
remaining 9 Subjects was 344 days after last intake of bedaquiline. One of the 10 deaths in the bedaquiline 


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group occurred after the week 120 window. In the bedaquiline group, the most common cause of death as 
reported by the Investigator was TB (5 Subjects). For all 5 deaths due to TB, the Subject’s last microbiological 
outcome was either failure to convert or relapse. The causes of death in the remaining bedaquiline Subjects 
varied. 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. 
Cardiovascular safety 
During clinical trials 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 study, 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 Subject’s M. Tb 
strain  is  resistant  to  pyrazinamide.  ECG  assessments  will  be  performed  on  all  Subjects  at  baseline,  each 
treatment visit and during the follow‐up visit on Day 70. 
Hepatic safety 
Increases  in  transaminases  were  seen  in  clinical  trials  during  administration  of  bedaquiline  with  the 
background regimen. Subjects should be monitored during treatment. 
Other hepatotoxic medicinal products and alcohol should be avoided while taking bedaquiline, especially in 
Subjects with diminished hepatic reserve. 
2.5.2. PA‐824 
In the thirteen clinical studies (9 Phase 1 and 4 Phase 2) completed to date, a total of 289 healthy volunteers 
(163 in Phase 1 studies conducted by TB Alliance and 126 in a thorough QT study conducted by the NIH) and 
315 Subjects with TB have taken PA‐824. Multiple dosing has extended for as long as 8 weeks. In montherapy 
EBA studies, PA‐824 has been shown to have bactericidal activity and in efficacy studies of up to 8 weeks in 
duration, regimens containing PA‐824 have demonstrated activity either better than, or at least as good as, 
the HRZE control regimen (studies NC001, NC002 and NC003). PA‐824 is a new drug with a novel mechanism 
of action with no pre‐existing resistance making it suitable to treat both DS‐ and MDR‐TB. It also has the 
potential, when used as part of a multi‐drug regimen, to shorten the duration of treatment for TB. The most 
common side effects or AEs associated with PA‐824 exposure include: 
 
Headache 
 
Benign, isolated and reversible elevations of serum creatinine 


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 
Stomach discomfort (nausea, vomiting, flatulence, and/or diarrhea) 
 
Skin and subcutaneous tissue disorders 
Cataracts 
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 NC‐005. These examinations 
are to follow up on the finding of cataracts in rats exposed to PA‐824 in preclinical studies. 
Testicular Toxicity 
Although all clinical evaluations of potential testicular toxicity in NC‐002 failed to demonstrate any effect, all 
male Subjects in NC‐005 will have baseline and periodic assays done of follicular stimulating hormone (FSH) as 
a sensitive test of early testicular damage.  
Central Nervous System 
The PA‐824 pre‐clinical program identified potential CNS‐related toxicities and one Subject treated with PA‐
824 in clinical study NC‐002 experienced a seizure while on treatment. Close surveillance will be in place to 
identify any seizures or significant central nervous system (CNS) signs or symptoms during study NC‐005. 
Hepatic Safety 
Hepatic enzyme increases have been seen in Subjects 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, study NC‐005 will include specific monitoring of hepatic enzymes. 
2.5.3. Pyrazinamide 
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  (42)  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 (12,13,23).  
Pyrazinamide enhanced the bactericidal activity of both bedaquiline and PA‐824 in Study NC‐001‐(J‐M‐Pa‐Z) 
as noted by decreases over 14 days in the CFU counts in sputum among Subjects. 
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 (42). 
2.5.4. Moxifloxacin 
Moxifloxacin is currently marketed globally for a variety of acute infectious diseases and has been studied for 
the treatment of tuberculosis in multiple clinical studies. The inclusion of moxifloxacin in a novel regimen (PA‐
M‐Z) to treat both DS and MDR‐TB has resulted in bactericidal activity in both 14 day and 8 week efficacy 
studies. Furthermore, moxifloxacin is currently used as a second‐line agent to treat MDR‐TB and in this study 
it will be used as a component of the regimen used in the MDR‐TB treatment arm. The following list of known 
and potential risks is based on the warnings and precautions and adverse reactions sections of the current 
package label (37). 


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Warnings and Precautions 
 
Increased risk of tendinitis and tendon rupture. This risk is further increased in older patients usually 
over 60 years of age, in patients taking corticosteroids, and in patients with kidney, heart or lung 
transplants. Discontinue if pain or inflammation in a tendon occurs.  
 
Prolongation of the QT interval and isolated cases of torsade de pointes has been reported. Avoid 
use in patients with known prolongation, hypokalemia, and with drugs that prolong the QT interval. 
Use caution in patients with proarrhythmic conditions such as clinically significant bradycardia or 
acute myocardial ischemia.   
 
Serious and sometimes fatal hypersensitivity reactions, including anaphylactic reactions, may occur 
after first or subsequent doses. Discontinue drug use at first sign of skin rash, jaundice or any other 
sign of hypersensitivity.  
 
Central nervous system (CNS) events including dizziness, confusion, hallucination, depression, and 
rarely suicidal thoughts or acts may occur after first dose. Use caution in patients with known or 
suspected CNS disorders that may predispose to seizures or lower the seizure threshold.   
 
Clostridium difficile‐associated diarrhea: Evaluate if diarrhea occurs.   
 
Peripheral neuropathy: Discontinue if symptoms occur. 
 Adverse reactions 
Most common reactions (≥3%) were nausea, diarrhea, headache, and dizziness.  
2.6. 
Overall Benefit/Risk Assessment 
Subjects in this study will be given regimens for 56 days that are not fully proven for the long term treatment 
of pulmonary TB.  However these drugs, individually and in combination are known to have anti‐tuberculosis 
activity and a delay of treatment with the full standard regimen of 56 days is not expected to have an adverse 
impact on the ultimate cure of TB in these Subjects. Subjects in this study will have their TB infection carefully 
characterized, with drug sensitivity profiles established, and they will receive treatment with study drugs that 
have demonstrated activity against M. Tb.  Subjects will receive individualized medical attention; this will allow 
a continuous monitoring of the health conditions of each Subject, any of whom can be withdrawn at any stage 
of the trial and removed from study 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 subjects with risk factors that might predispose them to cardiac arrhythmias, screening all subjects 
for evidence of existing cardiac disease and monitoring all subjects with ECGs throughout the study.  
 The  regimens  to  be  tested  in  this  study  have  all  demonstrated  efficacy  in  the  treatment  of  pulmonary 
tuberculosis in non‐clinical and clinical studies. Specifically, the regimen J‐Pa‐Z was generally well‐tolerated 
and demonstrated bactericidal activity in a 14 day EBA study. The potential risks associated with the study 
drugs and regimen has been identified and will be monitored carefully throughout the conduct of the study. 
3. TRIAL RATIONALE AND OBJECTIVES 
3.1. 
Trial Rationale 
This trial seeks to establish the anti‐tuberculosis effect (bactericidal activity (BA)) of the study drugs on serial 
TTP of M.Tb in sputum over 56 days (8 weeks) of therapy. The combinations of drugs in this study have all 
demonstrated good microbicidal and sterilizing activity in mouse models of TB infection and a 14 day EBA 
study and this study will determine the effects of these combinations in patients with DS and MDR‐TB over 56 


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days.  These regimens have the potential to substantially shorten the current duration of regimens for both 
DS and MDR‐TB.   
3.2. 
Study Design Rationale 
This study will be a 56 day BA design incorporating 4 parallel treatment groups. This design allows comparison 
of the results of this study with similar prior studies of treatments for TB. The study will be open label, as the 
primary endpoint related to TTP is objective and will therefore not be subject to bias. The mycobacteriology 
laboratory personnel will remain blinded to the study arm assignment until closure of the BA results.  All 
Subjects who undergo randomization (DS‐TB treatment arms) or assignment (MDR‐TB treatment arm) will be 
selected  according  to  the  study  inclusion  and  exclusion  criteria  thereby  ensuring  that  all  Subjects  are 
appropriate for inclusion in any of the 4 treatment arms. No placebo treatment is included in this study – all 
Subjects  will  be  given  either  active  study  treatment  or  HRZE  control.  Given  the  availability  of  effective 
treatment  for  TB,  and  the  serious  consequences  of  allowing  TB  to  go  untreated,  inclusion  of  a  placebo 
treatment arm would be unethical. 
Upon treatment completion, the DS‐TB Subjects will be given sufficient doses of standard of care TB treatment, 
as appropriate, to cover the time period from attending their last visit at the study clinic until their scheduled 
visit at the TB clinic. All Subjects will immediately be referred to the National TB Treatment Program local TB 
clinic.  
3.3. 
Dose Rationale 
3.3.1. Bedaquiline 
In one of the experimental treatment arms (J(loading dose/t.i.w.)PaZ), bedaquiline will be administered at the MDR‐
TB registered dose (i.e. registered in some countries) of 400mg once daily for Days 1‐14 followed by 200mg 
three times per week for Days 15‐56. In another experimental treatment arm (J(200mg daily)PaZ), bedaquiline will 
be administered at 200mg once daily for Days 1‐56 in order to compare the efficacy and safety of these two 
dosing schemes. The two week loading dose followed by a t.i.w dose has been shown to be an effective 
treatment  for  MDR‐TB,  but  is  complex  and  difficult  to  administer  in  standard  TB  treatment  clinics.  By 
administering bedaquiline at a fixed daily dose of 200mg, the overall exposure to the drug over a 3‐ or 4‐month 
regimen will not be substantially greater than if it were administered using the loading dose/t.i.w dosing 
scheme over 6 months, and should provide similar efficacy and safety. Over the course of this 8 week study, 
Subjects in the J(loading dose/t.i.w.) arm will receive a total cumulative dose of 9.2 gm while Subjects in the J(200mg daily) 
arm will receive a total of 11.2 gm. However, based on PK modeling, the highest Cmax and AUC exposures will 
occur in the J(loading dose/t.i.w.) arm at the end of the first 2 weeks of dosing. Given that the Subjects in the J(200mg 
daily) arm will never achieve exposures greater than those in the J(loading dose/t.i.w.)  arm, yet will receive slightly 
more total drug, it is likely that the daily dosing scheme will not result in increased tolerability or safety 
problems and will achieve good anti‐tuberculosis activity. As this is a clinical trial, the Subjects will be closely 
monitored for safety and improvement/worsening of their underlying TB disease. 
3.3.2. PA‐824 
PA‐824 has demonstrated good microbicidal activity at the 200mg daily dose as monotherapy in studies PA‐
824‐CL‐007 and PA‐824‐CL‐010, in combination with either bedaquiline or pyrazinamide over 14 days in the 
EBA  Study  NC‐001‐(J‐M‐Pa‐Z)  and  in  combination  with  either  bedaquiline  and/or  pyrazinamide  and/or 
clofazimine over 14 days in the EBA Study NC‐003‐(C‐J‐Pa‐Z).  In the EBA Study PA‐824‐CL‐010 the 100mg dose 
demonstrated  similar  microbicidal  activity  to  the  150  and  the  200mg  daily  dose  over  14  days.    However 
because sterilizing relapse‐free cure of TB may ultimately require a regimen with higher drug exposures, the 
200mg dose has been chosen for this study. 
 
 


Global Alliance for TB Drug Development 
Protocol Number: NC‐005‐(J‐M‐Pa‐Z) 
Working Protocol Version: 1.1 (Final) 
Protocol Date: 19 September 2014 
 
 
 
TMP02‐A V1.0 
 
 
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3.3.3. Moxifloxacin 
The standard dose of moxifloxacin for a multitude of indications is 400mg daily. This is the dose that has been 
studied in clinical studies NC‐001 and NC‐002 and is the dose of moxifloxacin in the on‐going REMox TB study. 
3.3.4. Pyrazinamide 
Pyrazinamide is currently dosed in the marketplace according to weight, although specific weight bands and 
the number of weight bands vary by country. Mixing weight‐banded and non‐weight‐banded drugs in the same 
marketed TB treatment regimen, if the drugs are co‐packaged or made into fixed dose combination tablets, 
would pose significant challenges for distribution channels in the developing world because the number of 
presentations required would be large. TB Alliance therefore worked with colleagues at Glaxo SmithKline to 
determine whether weight banding of pyrazinamide in a new regimen is expected to be necessary, either for 
safety or efficacy reasons, and determined that it is not (43).  
Targeting the 25th to 90th percentiles of exposure (AUC) in Subjects dosed in 3 key weight bands, various fixed 
doses of pyrazinamide were investigated in this model and the fixed dose of 1500mg was chosen as optimal 
for producing exposure in this range for the TB Subject population.  In addition, the literature on hepatotoxicity 
of pyrazinamide was reviewed. The incidence of hepatotoxicity was found to be only partially explained by 
exposure (or dose), but, to be conservative in the modeling, hepatotoxicity was assumed to be entirely related 
to exposure. Even with this assumption, it was found that a fixed 1500mg dose of pyrazinamide is expected to 
approximately double the number of Subjects above the 90th percentile of exposure when dosed using 3 
weight bands, but the incidence of hepatotoxicity is predicted to rise only by <1%. From these analyses it was 
concluded that pyrazinamide can safely and reasonably be tested in clinical trials at a fixed 1500mg dose.   
Pyrazinamide  has  demonstrated  microbicidal  activity  at  the  1500mg  daily  dose  as  monotherapy  and  in 
combination with either bedaquiline and/or PA‐824 and/or clofazimine over 14 days in the EBA Study NC‐003‐
(C‐J‐Pa‐Z).  As  described  above,  the  combination  J‐PA‐Z,  with  Z  dosed  at  a  fixed  dose  of  1500mg  daily, 
demonstrated  good  efficacy  in  this  study.  Furthermore,  study  NC002  included  two  arms  containing  the 
1500mg  fixed  daily  dose  of  pyrazinamide  (PA(100)‐M‐Z  and  PA(200)‐M‐Z),  both  of  which  demonstrated  good 
efficacy compared to the HRZE control with pyrazinamide dosed using the standard weight‐banding. In the 
NC002  study,  both  arms  containing  pyrazinamide  dosed  at  the  1500mg  fixed  dose  were  generally  well‐
tolerated with no increase in the number of subjects with significant increases (>5X ULN) in hepatic enzyme 
elevations. Taken together, these studies confirm the PK model results – that a daily, fixed pyrazinamide dose 
of 1500mg offers equal efficacy and no significant increase in hepatotoxicity. 
3.3.5. HRZE Combination Tablets 
HRZE combination tablets will be used at standard weight‐adjusted doses.  
3.4. 
Trial Objectives 
The primary objective of this study is to evaluate the bactericidal activity, safety, and tolerability of J‐Pa‐Z in 
drug‐sensitive TB and J‐M‐Pa‐Z in MDR TB. Secondary objectives include evaluating the bactericidal activity, 
safety and tolerability of bedaquiline dosed using two different schemes (the loading dose/t.i.w schedule and 
200mg a day). Additional key secondary objectives are to evaluate the population PK characteristics of J, M, 
Pa and Z when administered as a part of 3‐ and 4‐drug regimens in adults with TB, and investigation of the 
methodology of sputum sampling by comparing CFU counts and TTP results, quantified from both Coached 
Spot Sputum and Overnight Sputum samples. 
 
 
 
 


Global Alliance for TB Drug Development 
Protocol Number: NC‐005‐(J‐M‐Pa‐Z) 
Working Protocol Version: 1.1 (Final) 
Protocol Date: 19 September 2014 
 
 
 
TMP02‐A V1.0 
 
 
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4. TRIAL DESIGN 
4.1. 
Summary 
This is a Phase 2, multi‐center, open‐label, partially randomized clinical trial in four parallel treatment groups.  
The trial will be performed at multiple centres globally.  Specific sites will be identified to enrol MDR‐TB 
Subjects and/or take part in the PK sub‐study. 
A total of approximately 240 male and female, newly diagnosed Subjects with drug‐sensitive or multi drug‐
resistant, smear positive pulmonary tuberculosis aged 18 to 75 years (inclusive) will be enrolled. A total of 180 
DS‐TB Subjects (60 per treatment arm) will be randomized. Up to 60 MDR‐TB Subjects will be assigned. In the 
event of the DS‐TB treatment arms being fully recruited (i.e. 60 Subjects in each of the three treatment arms) 
before the MDR‐TB treatment arm has enrolled 60 Subjects, the Sponsor may elect to close the study for all 
treatment arms, or close the DS‐TB treatment arms and continue the study with MDR‐TB recruitment while 
analyzing the DS‐TB data. 
All Subjects will have up to a maximum of 9 days screening, receive 8 weeks of treatment, and have follow‐up 
visits performed at 2 and 12 weeks after study treatment completion with Telephonic Survival Follow Up for 
survival data at 6 (Month 8), 12 (Month 14), 18 (Month 20) and 24 months (Month 26) after completion of 
IMP. Subjects who withdraw after < 14 days of IMP should attend a follow‐up visit 2 weeks after the last dose 
of IMP, while Subjects who withdraw after > 15 days of IMP should complete  all the scheduled Follow Up.  
Subjects with Drug‐Sensitive (DS) TB will be randomized to receive:  
 
J(loading dose/t.i.w.)PaZ or  
 
J(200mg)PaZ or  
 
HRZE 
Subjects with Multi Drug‐Resistant (MDR) TB will receive:  
 
J(200mg)MPaZ  
The HRZE treatment arm is included as a control for the drug‐sensitive treatments (both efficacy and safety 
assessments) and the quantitative laboratory mycobacteriology testing.  


Global Alliance for TB Drug Development 
Protocol Number: NC‐005‐(J‐M‐Pa‐Z) 
Working Protocol Version: 1.1 (Final) 
Protocol Date: 19 September 2014 
 
  
TMP02‐B V1.0  
 
   
Page 55 of 112  Confidential          
Figure 1: Trial Schematic 
 
 
Visit 
Day 
‐9  
to 
‐3 
‐2 
‐1 
1 
4 
8 
15 
21 
29 
36 
43 
50 
57 
70 
140 
M6 
SFU 
M12 
SFU 
M18
SFU 
M24 
SFU 
Week 
or 
Month 
Wk ‐1 
Wk 1 
Wk 2 
Wk 3 
Wk 4 
Wk 5 
Wk 6 
Wk 7 
Wk 8 
Wk 
10 
Wk 
20 
M8 
M14 
M20 
M26 
 
Screening 
Treatment 
Follow Up 
Telephonic Survival Follow Up 
 
 
 
DS 
 
J (loading dose / t.i.w.) PaZ 
 
 
 
 
 
DS 
 
J (200mg) PaZ 
 
 
 
 
 
DS 
 
HRZE 
 
 
 
 
 
 
 
 
 
 
MDR 
J (200mg) MPaz 
 
 
 
Note: PK Sub‐study Subjects will attend additional Visits on Days 14 and 56 
 
 
4.2. 
Trial Endpoints 
The Overnight Sputum Samples will be used to determine the primary outcome of the study. 
4.2.1. Primary Endpoint 
The Bactericidal Activity (BATTP(0‐56)) as determined by the rate of change in time to sputum culture positivity 
(TTP) over 8 weeks of treatment in the Mycobacterial Growth Indicator Tube system, represented by the 
model‐fitted log(TTP) results as calculated by the regression of the observed log(TTP) results over time. 
4.2.2. Secondary Endpoints 
4.2.2.1. 
Efficacy: 
 
The BATTP(0‐2) and BATTP(14‐56) as determined by the rate of change in time to sputum culture positivity 
(TTP) over Days 0 to 2, and Days 14 to 56 treatment, represented by the model‐fitted log(TTP) as calculated 
by the regression of the observed log(TTP) counts over time. 
 
The BACFU(0‐56), BACFU(0‐2) and BACFU(14‐56) as determined by the  rate of change in colony forming units 
(CFU) over 8 weeks of treatment represented by the model‐fitted log(CFU) results as calculated by the 
regression of the observed log(CFU) results over time. 


Global Alliance for TB Drug Development 
Protocol Number: NC‐005‐(J‐M‐Pa‐Z) 
Working Protocol Version: 1.1 (Final) 
Protocol Date: 19 September 2014 
 
 
 
TMP02‐A V1.0 
 
 
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 
Time  to  sputum  culture  conversion  using  data  from  weekly  cultures  through  8  weeks  of  treatment 
(separately, on solid and liquid media). 
 
Proportion of Subjects with sputum culture conversion at 4, 6 and 8 weeks (separately, on solid and liquid 
media). 
 
The BACFU(0‐56, 0‐2 and 14‐56) and BATTP(0‐56, 0‐2 and 14‐56) of J(loading dose/t.i.w.)PaZ compared to J(200mg)PaZ 
from DS‐TB treatment arms. 
 
Investigation of the methodology of sputum sampling by comparing CFU counts and TTP results, each 
quantified in both Coached Spot Sputum and Overnight Sputum samples; however Overnight Sputum 
Samples are considered the reference samples. 
4.2.2.2. 
Safety and Tolerability: 
 
Incidence of Treatment Emergent Adverse Events (TEAEs) will be presented by severity (DMID Grade), 
drug relatedness and seriousness, leading to early withdrawal and leading to death, by group.   
 
Quantitative and qualitative clinical laboratory result measurements, including observed and change from 
baseline will be presented and summarized by group. 
 
Quantitative and qualitative measurement of ECG results (heart rate, RR interval, PR interval, QRS interval, 
QT interval and QTc interval), including observed and change from baseline will be presented. QT/QTc 
intervals, including post baseline and change from baseline will also be categorized and presented, by 
group. 
 
Descriptive statistics will be presented for ophthalmology slit lamp examination data (age related eye 
disease study 2 [AREDS2] lens opacity classification and grading) and listed by Subject. Categorical data for 
lens opacity will be summarized in a frequency table for the left and right eye, respectively, including 
change from baseline, and summarized by group. 
 
Descriptive statistics will be presented for serum FSH measurements (mean and median at baseline, 4, 8 
and 10 weeks and mean change from baseline at 4, 8 and 10 weeks) by group.  
 
Other safety variables will be presented by group and listed by Subject. 
 
These data will be presented as descriptive analyses, and no inferential tests will be carried out. 
4.2.2.3. 
Pharmacokinetics / Pharmacokinetics‐Pharmacodynamics (PK‐PD):   
Pharmacokinetics will consist of two separate schedules:  
 
All Subjects: 
 
Pre‐dose sampling at Days 1, 4, 8, 15, 22, 29, 36, 43, 50 and during the site visit on Days 57 and 70 to 
measure Ctrough levels of J, J metabolite M2, M, Pa and Z as per the table below. 
 
PK Sub‐study Subjects:    
In addition to the general PK samples, there will be intense PK sampling on Days 14 and 56 at pre‐
dose, 1, 2, 4, 8 and 24 hours after dosing in a sub‐group of 15 Subjects in each treatment arm across 
selected sites.  
Pharmacokinetic Analysis: 
All measured PK concentrations will be listed. 
For the Ctrough samples, only descriptive statistics will be prepared (average Ctrough) derived for each analyte on 
Days 4, 8, 15, 22, 29, 36, 43, 50, 57 and 70 as follows: 
Table 8 : PK Analyte/s Per Treatment Arm 
Treatment Arm 
Analyte/s 
Subject Population
J(loading dose/t.i.w.)PaZ  
J, J metabolite M2, Pa, Z 
DS‐TB 
J(200mg)PaZ 
J, J metabolite M2, Pa, Z 
DS‐TB 


Global Alliance for TB Drug Development 
Protocol Number: NC‐005‐(J‐M‐Pa‐Z) 
Working Protocol Version: 1.1 (Final) 
Protocol Date: 19 September 2014 
 
 
 
TMP02‐A V1.0 
 
 
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J(200mg)MPaZ 
J, J metabolite M2, M, Pa, Z 
MDR‐TB 
HRZE 
Z 
DS‐TB 
For the PK sub‐study samples, the following PK parameters will be estimated from the individual (per Subject) 
PK plasma concentrations: minimum observed PK plasma concentration (Cmin), maximum observed PK plasma 
concentration(Cmax),  time  to  reach  Cmax  obtained  without  interpolation  (Tmax),  area  under  the  PK  plasma 
concentration  time  (t)  curve  from  zero  to  the  last  quantifiable  PK  plasma  concentration  prior  to  the 
subsequent dose, using the linear trapezoidal rule (AUC(0‐t)), area under the PK plasma concentration time (t) 
curve from zero to 24 hours (AUC(0‐24)). These will be derived for each analyte, on Days 14 and 56, as follows: 
Table 9 : PK Analyte/s Per Treatment Arm 
Treatment Arm 
Analyte/s 
Subject Population
J(loading dose/t.i.w.)PaZ  
J, J metabolite M2, Pa, Z 
DS‐TB 
J(200mg)PaZ 
J, J metabolite M2, Pa, Z 
DS‐TB 
J(200mg)MPaZ 
J, J metabolite M2, M, Pa, Z 
MDR‐TB 
HRZE 
Z 
DS‐TB 
J(200mg)PaZ compared to J(loading dose/t.i.w.)PaZ and J(200mg)MPaZ :  
In order to compare the effects of the two J dosing schemes on bedaquiline exposure, the Cmax, Cmin and AUC 
of J and M2 will be compared using PK sub‐study data from days 14 and 56 from the J(loading dose/t.i.w.)PaZ and 
J(200mg)PaZ DS‐TB arms. A secondary comparison of the PK parameters from the sub‐study parameters of J and 
M2 between the J(200mg)PaZ  DS‐TB and J(200mg)MPaZ MDR‐TB arms will also be performed. 
Another comparison of J and M2 exposure will be performed using the Ctrough data from the J(loading dose/t.i.w.)PaZ 
and J(200mg)PaZ DS‐TB arms, with a secondary comparison between the J(200mg)PaZ  DS‐TB and J(200mg)MPaZ   MDR 
arms. 
Pharmacokinetics‐Pharmacodynamics (PK‐PD):   
Pearson  correlation  coefficients  will  be  reported  for  the  correlation  analysis  of  all  relevant  PK‐PD  and 
exploratory PK‐PD endpoints. 
Descriptive summary statistics for TMIC will be presented. 
Exploratory PK‐PD Endpoints: 
 
Correlations between Ctrough plasma drug concentrations, efficacy and safety findings will be performed 
in an exploratory fashion. 
 
Comparison of TMIC (based on data from the PK sub‐study parameters) for J between J(loading dose/t.i.w.)PaZ 
and J(200mg)PaZ in DS‐TB treatment arms. 
 
Correlations between plasma drug concentrations and efficacy and safety findings will be performed in 
an exploratory fashion, as follows: 
BATTP(0‐56) and BATTP(14‐56) versus the following PK variables (at Day 14 and Day 56) will be presented 
for J, Pa and M: 
o Cmax 
o AUC(0‐24) 
o Time over Minimum inhibitory concentration (TMIC) of J, Pa and M, both with and without 
taking protein binding shift into account. 
 
 


Global Alliance for TB Drug Development 
Protocol Number: NC‐005‐(J‐M‐Pa‐Z) 
Working Protocol Version: 1.1 (Final) 
Protocol Date: 19 September 2014 
 
 
 
TMP02‐A V1.0 
 
 
Page 58 of 112  Confidential 
 
4.2.2.4. 
Exploratory Endpoints: 
 
Sub‐analysis of the primary and secondary efficacy endpoints of the MDR‐TB pyrazinamide resistant 
Subjects compared to the MDR‐TB sensitive Subjects. 
 
Sub‐analysis of the primary and secondary efficacy endpoints of the H or R mono‐resistant Subjects will 
be evaluated as separate sub‐groups. 
4.2.2.5. 
General Mycobacteriology: 
Overnight Sputum and Coached Spot Sputum Samples will be obtained at all scheduled visits, except the 
Screening Visit when only a Coached Spot Sputum  Sample will  be collected. Sputum samples will not  be 
collected at Early Withdrawal Visits. Cultures will be grown from all Overnight Sputum and Coached Spot 
Sputum  Samples  collected  from  Day  ‐2  onwards.  The  Overnight  Sputum  Samples  will  be  considered  the 
reference samples.  
The following mycobacteriology assays will be carried out: 
Table 10 : General Mycobacteriology 
Sample 
Type 
Assessments 
Comments 
Screening 
Coached 
Spot 
Sputum 
Sample 
 
Direct microscopy for acid‐fast bacilli 
 
Molecular assay for identification of M. Tb and 
drug susceptibility (such as GeneXpert or 
MTBDRplus) to confirm the diagnosis of TB and 
distinguish between DS‐TB and MDR‐TB 
 
Molecular test for fluoroquinolone resistance 
(such as MTBDRsl) for MDR‐TB Subjects to 
establish susceptibility to moxifloxacin 
All to be performed at 
the Trial 
Appointed Laboratory. 
Baseline 
Overnight 
Sputum 
Samples 
named Day ‐2 
and ‐1 
Overnight 
Sputum 
Sample 
 
Direct microscopy for acid‐fast bacilli 
 
Molecular / antigen test to confirm M. Tb 
 
Culture: MGIT and Solid Media (quantitative for 
CFU) 
 
DST : SIRE, Z 
 
MIC: J, Pa, M 
 
DNA for pncA Sequencing 
Z DST resistance must 
be repeated to 
confirm. 
Baseline 
Coached Spot 
Sputum 
Samples 
named Day ‐2 
and ‐1 
Coached 
Spot 
Sputum 
Sample 
 
Culture: MGIT and Solid Media (quantitative for 
CFU) 
For determination of 
logCFU and logTTP 
rates of change for 
comparison to 
cultures from 
Overnight Sputum 
Sample. 


Global Alliance for TB Drug Development 
Protocol Number: NC‐005‐(J‐M‐Pa‐Z) 
Working Protocol Version: 1.1 (Final) 
Protocol Date: 19 September 2014 
 
 
 
TMP02‐A V1.0 
 
 
Page 59 of 112  Confidential 
 
Sample 
Type 
Assessments 
Comments 
Overnight 
Sputum 
Samples 
named Days 1, 
3, 7, 14, 21, 
28, 35, 42, 49 
and 56 
Overnight 
Sputum 
Sample 
 
Culture: MGIT and Solid Media (quantitative for 
CFU) 
 
The last positive sample from withdrawn Subjects 
who have not converted to culture negative status 
OR Subjects who are still culture positive at 8 
weeks OR the first positive sample after 
conversion to culture negative status for subjects 
who have ‘relapsed’*: 
o 
DST: SIRE, Z 
o 
MIC: J, Pa, M 
 
 
Coached Spot 
Sputum 
Samples 
named Days 1, 
3, 7, 14, 21, 
28, 35, 42, 49, 
and 56 
Coached 
Spot 
Sputum 
Sample 
 
Culture: MGIT and Solid Media (quantitative for 
CFU) 
 
For determination of 
logCFU and logTTP 
rates of change for 
comparison to 
cultures from 
Overnight Sputum 
Sample. 
 
The above assays will be carried out according to procedures described in the Laboratory Manual.  
 
The Coached Spot Sputum Sample can be used for all assays, except CFU and TTP, if results cannot be 
obtained from the Overnight Sputum Sample. 
 
pncA sequencing and MIC isolates can be batched at the end of the study.  
 
*If the Subject was treated with study medication for less than 9 days, the mycobacteriology testing will 
be performed on the Day ‐2 sample isolate only. 
 
*Culture negativity is defined as the first of two consecutive negative cultures, except for the week 8 
time point, where a singular negative is acceptable.  
4.3. 
Trial Population 
4.3.1. Inclusion Criteria  
Subjects are required to meet all of the following inclusion criteria in order to be randomized. 
1. Provide written, informed consent prior to all trial‐related procedures. Male or female, aged between 18 
and 75 years inclusive. 
2. Body weight (in light clothing and with no shoes) between 35 and 100 kg, inclusive. 
3. Tested at the trial appointed laboratory: M. Tb positive on molecular test (e.g. GeneXpert or Hain) and 
sputum  smear‐positive  pulmonary  TB  on  direct  microscopy  for  acid‐fast  bacilli  (at  least  1+  on  the 
IUATLD/WHO scale (Appendix 1)).  
For  DS‐TB  treatment  arms  (defined  as  sensitive  to  rifampicin  based  on  molecular  sensitivity  testing), 
Subjects should be:  
a. either newly diagnosed or untreated for at least 3 years after cure from a previous episode 
(Subject can give a history of cure and previous treatment); AND 
b. Previous TB treatment must be discontinued as per exclusion criteria 16.  
For MDR‐TB treatment arm (defined as resistant to rifampicin based on molecular sensitivity testing), 
Subjects should be: 
a. sensitive to moxifloxacin by molecular sensitivity testing; AND 


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b. either newly diagnosed or could have previously been treated for DS‐TB and/or MDR‐TB (< 7 
days  of  treatment).  Previous  MDR‐TB  treatment  must  be  discontinued  as  per  exclusion 
criteria 17.  
4. A chest X‐ray picture which in the opinion of the Investigator is compatible with TB. 
5. Ability to produce an adequate volume of sputum as estimated from a screening Coached Spot Sputum 
Sample assessment (estimated 10 ml or more overnight production).  
6. Be of non‐childbearing potential or using effective methods of birth control, as defined below: 
Non‐childbearing potential: 
a. Subject ‐ not heterosexually active or practises sexual abstinence; or  
b. Female  Subject/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 Subject/sexual partner ‐ vasectomised or has had a bilateral orchidectomy minimally 
three months prior to screening. 
Effective birth control methods:  
A double contraceptive method should be used as follows: 
a. Double barrier method which can include any 2 of the following: a male condom, diaphragm, 
cervical cap, or female condom (male and female condoms should not be used together); or  
b. Barrier method (one of the above) combined with hormone‐based contraceptives or an intra‐
uterine device for the female Subject/partner; 
and are willing to continue practicing birth control methods throughout treatment and for 6 months (both 
male  and  female  Subjects)  after  the  last  dose  of  study  medication  or  discontinuation  from  study 
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 Subjects or female partners of male Subjects to 
prevent pregnancy).  
4.3.2. Exclusion Criteria  
Subjects will be excluded from participation if they meet any of the following criteria. 
Medical Criteria 
1. Evidence of clinically significant (as judged by the Investigator), metabolic, gastrointestinal, cardiovascular, 
musculoskeletal,  ophthalmological,  pulmonary,  neurological,  psychiatric  or  endocrine  diseases, 
malignancy, or other abnormalities (other than the indication being studied) including malaria. A rapid 
test for malaria may be carried out if indicated. 
2. Karnofsky performance status score of < 60% (Appendix 4). 
3. Poor  general  condition  where  any  delay  in  treatment  cannot  be  tolerated  per  discretion  of  the 
Investigator. 
4. Clinically  significant  evidence  of  extrathoracic  TB  (e.g.  miliary  TB,  abdominal  TB,  urogenital  TB, 
osteoarthritic TB, TB meningitis), as judged by the Investigator. 
5. History of allergy or hypersensitivity to any of the study Investigational Medicinal Products or related 
substances. 
6. Known or suspected current alcohol and/or drug abuse (positive urine drug screen) or history thereof 
within the past 2 years that is, in the opinion of the Investigator, sufficient to compromise the safety 
and/or cooperation of the Subject.   
7. For HIV infected Subjects: 
a. having a CD4+ count <100 cells/µL;  
b. with an AIDS‐defining opportunistic infection or malignancies (except pulmonary TB); 


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c. currently  treated  with  or  will  need  to  initiate  antiretroviral  therapy  (ART)  which  is  not 
compatible  with  the  allowed  ARTs  and  is  not  considered  an  appropriate  candidate  for 
switching to a regimen of ARVs which is allowed as follows: 
o Triple nucleoside reverse transcriptase inhibitor (NRTI) based regimen consisting of 
zidovudine, lamivudine, and abacavir; 
o Nevirapine based regimen consisting of nevirapine in combination with any NRTIs; 
o Lopinavir/ritonavir (Aluvia™) based regimen consisting of lopinavir/ritonavir 
(Aluvia™) in combination with any NRTIs; 
o Raltegravir in combination with nucleoside reverse transcriptase inhibitors (NRTIs); 
d.  cannot ensure a 2 week interval between commencing IMP and the start of ART.  
8. Having participated in other clinical study/ies with investigational agent/s within 8 weeks prior to trial 
start. 
9. Significant cardiac arrhythmia requiring medication. 
10. Subjects with the following at screening (per measurements and reading done by Central ECG): 
a. Marked prolongation of QT/QTc interval, e.g. confirmed demonstration of QTcF (Fridericia 
correction) or QTcB (Bazett correction) interval >450 ms at screening; 
b. History of additional risk factors for Torsade de Pointes, e.g. heart failure, hypokalemia, family 
history of Long QT Syndrome; 
c. Use of concomitant medications that are known to prolong the QT/QTc interval (see exclusion 
criteria 19 as well as list of restricted medication in Section 4.8.1); 
d. Any clinically significant, in the opinion of the Investigator, ECG abnormality.  
11. Females who are pregnant, breast‐feeding, or planning to conceive a child during the study or within 6 
months of cessation of treatment.  Males planning to conceive a child during the study or within 6 months 
of cessation of treatment. 
12. Diabetes Mellitus resulting in hospitalization in the past year. 
13. Evidence of lens opacity on slit lamp ophthalmologic examination as defined by a grading of >1+ on the 
AREDS2 grading system. 
14. For males, any history of a clinically significant abnormality in the reproductive system.  
Specific Treatments 
15. Previously received treatment with PA‐824, bedaquiline or moxifloxacin as part of a clinical trial. 
16. For the DS‐TB treatment arms: treatment with any drug active against M. Tb within the 3 years prior to 
Day 1 (including but not limited to isoniazid, ethambutol, amikacin, bedaquiline, clofazimine, cycloserine, 
fluoroquinolones,  rifabutin,  rifampicin,  streptomycin,  kanamycin,  para‐aminosalicylic  acid,  rifapentine, 
pyrazinamide, thioacetazone, capreomycin, thioamides, metronidazole). Exceptions include the use of 
fluoroquinolones  and  metronidazole  as  short‐term  treatment  (<2  weeks)  for  Non‐M.Tb  infections. 
Treatment should have been discontinued at least 3 months prior to Day 1. Subjects 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.  
17. MDR‐TB Subjects may have previously been treated for DS‐TB with first‐line TB drugs (isoniazid, rifampicin, 
ethambutol,  pyrazinamide  and/or  streptomycin)  and/or  received  <  7  days  MDR‐TB  treatment, 
provided that treatment is/was discontinued at least 7 days prior to randomization. It should be confirmed 
that the MDR‐TB treatment can be safely stopped and the screening period is long enough to allow for a 
washout period of 5 times the longest half‐life of the drugs.  
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 acute gout, allergy to any TB drug, their component or to the IMP.  
19. Use of any drug within 30 days prior to dosing known to prolong QTc interval (including but not limited to 
amiodarone,  bepridil,  chloroquine,  chlorpromazine,  cisapride,  cyclobenzaprine,  clarithromycin, 
disopyramide  dofetilide,  domperidone,  droperidol,  erythromycin,  halofantrine,  haloperidol,  ibutilide, 
levomethadyl,  mesoridazine,  methadone,  pentamidine,  pimozide,  procainamide,  quinidine,  sotalol, 
sparfloxacin, thioridazine). Exceptions may be made for Subjects that have received 3 days or less of one 


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of these drugs or substances, if there has been a wash‐out period before administration of IMP equivalent 
to at least 5 half‐lives of that drug or substance. Subjects who have taken drugs with long elimination half‐
lives such as amiodarone should be discussed with the Sponsor. 
20. Use of any drugs or substances within 30 days prior to dosing known to be strong inhibitors or inducers of 
cytochrome P450 enzymes (including but not limited to quinidine, tyramine, ketoconazole, fluconazole, 
testosterone, 
quinine, 
gestodene, 
metyrapone, 
phenelzine, 
doxorubicin, 
troleandomycin, 
cyclobenzaprine, erythromycin, cocaine, furafylline, cimetidine, dextromethorphan).  Exceptions may be 
made for Subjects that have received 3 days or less of one of these drugs or substances, if there has been 
a wash‐out period before administration of IMP equivalent to at least 5 half‐lives of that drug or substance.  
21. Any ARVs other than allowable ARVs detailed in exclusion criteria no. 7 above. 
Based on Laboratory Abnormalities: 
22. Subjects 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): 
a. serum magnesium and calcium (corrected for albumin) levels outside of the laboratory’s reference 
range 
b. lipase grade 3 or greater (>2.0 x ULN); 
c. creatinine grade 2 or greater (>1.5 x ULN); 
d. hemoglobin grade 4 (<6.5 g/dL); 
e. platelets >grade 2 (under 50x109 cells/L); 
f. 
serum potassium less than the lower limit of normal for the laboratory; 
g. aspartate aminotransferase (AST) grade 3 or greater (≥3.0 x ULN)  to be excluded; 
h. alanine aminotransferase (ALT) grade 3 or greater (≥3.0 x ULN) to be excluded; 
i. 
alkaline phosphatase (ALP) grade 4 (>8.0 x ULN) to be excluded, grade 3 (≥3.0 – 8.0 x ULN) must be 
discussed with and approved by the Sponsor Medical Monitor; 
j. 
total bilirubin grade 3 or greater (>2.0 x ULN, or >1.50 x ULN when accompanied by any increase in 
other liver function test) to be excluded, grade 2 (>1.50 x ULN, or >1.25 x ULN when accompanied by 
any increase in other liver function test) must be discussed with and approved by the Sponsor Medical 
Monitor; 
Any laboratory value which excludes the Subject may be repeated to confirm eligibility. 
All inclusion and no 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, and receiving approval from the Sponsor Medical Monitor. 
4.4. 
Treatment Plan:  Schedule of Assessments 
The trial consists of four periods, as follows: 
 
Screening Period (Day ‐9 to Day ‐1); 
 
Treatment Period (Day 1 to Day 57); 
 
Follow‐Up Period (Day 70 to Day 140); 
 
Telephonic Survival Follow Up Contact at 6, 12, 18 and 24 months after last dose of IMP (Month 8, Month 
14, Month 20 and Month 26). 
Refer to: 
 
Study Flow Chart (Section 1.2) for the timing of all procedures and laboratory samples to be done at each 
visit.   
 
Trial Procedures (Section 6) for details regarding specific procedures or laboratory tests. 
 
 


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4.4.1. Screening Period (Days ‐9 to Day ‐1) 
 
Naming of Overnight Sputum Samples for the Trial Period Days ‐3 to Day 1: The day Overnight 
Sputum Sample collection ends reflects the day to which that sample applies e.g. a sample where 
collection starts on Day ‐3 and ends on Day ‐2, is designated as the Day ‐2 Overnight Sputum Sample 
and results are also referred to as Day ‐2 results.  
 
Naming of Coached Spot Sputum Samples for the Trial Period Days ‐9 to Day 1: The Day ‐9 to ‐3 
Coached Spot Sputum Sample/s will be named ‘screen’ (note, there is no matching Overnight Sputum 
Sample). The naming of Coached Spot Sputum Samples for Days ‐2, ‐1 and 1 will be designated as Day 
‐2, ‐1 and 1 respectively and results are also referred to as Day ‐2, ‐1 and 1 results.  
4.4.1.1. 
Day ‐9 to ‐3 
Prior to this visit, Subjects must have a history of a positive molecular test (e.g. GeneXpert or Hain) or TB 
sputum smear microscopy result from their TB clinic or site of initial diagnosis. 
The following information will be collected and procedures performed: 
 
Written Informed Consent (Main study, HIV testing and PK sub‐study if applicable); 
 
Eligibility Assessment; 
 
Demographic Data; 
 
Medical and Treatment History; 
 
Single 12‐lead ECG (the ECG should be done before any other assessments); 
 
Laboratory Safety Assessments (including serum FSH for male Subjects); 
 
Urine Pregnancy Test, (women of child bearing potential only, whether they are sexually active or not);  
 
HIV test and CD4 count; if an HIV test was performed within 1 month prior to trial start, it need not be 
repeated as long as documentation can be provided [ELISA and/or Western Blot]). Subjects may be on 
current antiretroviral therapy (ART) or commence ART during the study if required, provided there is at 
least a 2 week interval between commencing IMP and the start of ART. For ART which is allowed in 
conjunction with IMP please refer to section 4.8.1.2; 
 
Urine Drug Screen; 
 
Karnofsky Score; 
 
Tuberculosis Symptom Profile (TSP) Questionnaire; 
 
Chest X‐ray (may be performed at Day ‐2 or ‐1 if not performed at Day ‐9 to ‐3 or if performed within 7 
days prior to signing consent, the X‐ray does not need to be repeated if the report and X‐ray are available 
for review and interpretation); 
 
Vital Signs including weight; 
 
Physical Examination (full) including height;  
 
Ophthalmology Examination (may be performed at Day ‐2 or Day ‐1 if not performed at Day ‐9 to ‐3); 
 
Overnight Sputum Sample (starts +/‐ 4 pm on Day ‐3 ends on Day ‐2, named ‘Day ‐2’), all isolates from 
positive cultures should be stored until study completion;  
 
Screening Coached Spot Sputum Sample (named ‘screen’);  
 
Concomitant Medication(s)/Other Treatment(s); 
 
Adverse Events. 
 
The screening visit (Day ‐9 to ‐3) may occur over a number of days i.e. all screening procedures do not 
have to be performed on the same day. All isolates from positive cultures should be stored until study 
completion. 
 
 


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4.4.1.2. 
Day ‐2 
 
If not already performed at Day ‐9 to ‐3: 
o Chest X‐ray or if performed within 7 days prior to signing consent, the X‐ray does not need to be 
repeated if the report and X‐ray are available for review and interpretation; 
o Ophthalmologic Examination; 
 
Overnight Sputum Sample: 
o Day ‐2 ends – named ‘Day ‐2’ 
o Day ‐1 starts +/‐ 4 pm 
o all isolates from positive cultures should be stored until study completion;  
 
Coached Spot Sputum Sample (named ‘Day ‐2’), all isolates from positive cultures should be stored until 
study completion;  
 
Concomitant Medication(s)/Other Treatment(s); 
 
Adverse Events. 
4.4.1.3. 
Day ‐1 
The following information will be collected and procedures performed: 
 
Laboratory Safety Assessment: FSH only (male subjects); 
 
If not already performed at Day ‐9 to ‐3: 
o Chest X‐ray or if performed within 7 days prior to signing consent, the X‐ray does not need to be 
repeated if the report and X‐ray are available for review and interpretation; 
o Ophthalmologic Examination; 
 
Vital Signs including weight; 
 
Randomization/Treatment Assignment; 
 
Overnight Sputum Sample 
o Day ‐1 ends – named ‘Day ‐1’  
o Day 1 starts +‐ 4 pm 
o all isolates from positive cultures should be stored until study completion;  
 
Coached Spot Sputum Sample (named ‘Day ‐1’), all isolates from positive cultures should be stored until 
study completion;  
 
Concomitant Medication(s)/Other Treatment(s); 
 
Adverse events. 
4.4.2. Treatment Period (Day 1 to Day 57) 
 
Hospitalization: 
o Not  required  for  study  participation,  however  may  be  considered  when  necessary  per  local 
guidelines (e.g. for MDR‐TB if required) and only for a limited period of time, after approval by the 
Sponsor on a case by case basis.  
o Subjects  do  not  need  to  be  hospitalized  for  the  intensive  PK  sampling,  but  may  remain  as 
outpatients at the clinic for the applicable day, and return the following morning for their 24hour 
post dosing sample collection. 
 
 
Investigational Medicinal Product (IMP) Administration:  
o The Subject should be instructed to: 
 
Take IMP orally once daily for 8 weeks (56 days), preferably around breakfast time, with 
a glass of water (approximately 240ml); 
 
Subjects on the HRZE treatment arm should not take IMP with a meal (generally, no closer 
to meals than 1 hour before or 2 hours after a meal) and should take the Vitamin B6 
supplement with the HRZE dose; 


Global Alliance for TB Drug Development 
Protocol Number: NC‐005‐(J‐M‐Pa‐Z) 
Working Protocol Version: 1.1 (Final) 
Protocol Date: 19 September 2014 
 
 
 
TMP02‐A V1.0 
 
 
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 
Subjects on the bedaquiline containing arms should take IMP with a meal (generally allow 
the Subjects a window of 30 minutes before to 30 minutes after a meal); 
 
When Subjects return for clinic visits or are hospitalized, they will be dosed on site; 
 
For the J(loading dose/t.i.w.) DS‐TB treatment arm: The bedaquiline dosing schedule is 400mg 
daily on days 1‐14, and then 200mg 3x per week. The 3x per week doses must be given on 
the following specific days to accommodate the PK sampling: Days 15, 17, 20, 22, 24, 27, 
29, 31, 34, 36, 38, 41, 43, 45, 48, 50, 53 and 56. 
 
Overnight Sputum Sample: 
o The Subject should be instructed to: 
 
Collect  the  sample  from  approximately  4pm  the  afternoon  prior  to  the  visit  and  for 
approximately 16 hours overnight for each of the sampling days.  
 
Collection must be finished prior to the administration of the next day’s IMP, which will 
be administered at the study site.   
o Naming of Overnight Sputum Samples for the Trial Period Days ‐3 to Day 1: The day Overnight 
Sputum Sample collection ends reflects the day to which that sample applies e.g. a sample where 
collection starts on Day ‐3 and ends on Day ‐2, is designated as the Day ‐2 Overnight Sputum 
Sample and results are also referred to as Day ‐2 results.  
o Naming  of  Overnight  Sputum  Samples  for  the  Trial  Period  Days  3  to  57:  The  day  Overnight 
Sputum Sample starts reflects the day to which that sample applies e.g. a sample where collection 
starts on Day 3 and ends on Day 4, is designated as the Day 3 Overnight Sputum Sample and results 
are also referred to as Day 3 results.  
o The Coached Spot Sputum Sample can be used for all assays if results cannot be obtained from 
the Overnight Sputum Sample.  
o All isolates from positive cultures should be stored until study completion.  
 
Coached Spot Sputum Collection: 
o The Coached Spot Sputum Sample can be used for all assays, except CFU and TTP, if results cannot 
be obtained from the Overnight Sputum Sample.  
o Naming of Coached Spot Sputum Samples for the Trial Period Days ‐9 to Day 1: The Day ‐9 to ‐3 
Coached Spot Sputum Sample/s will be named ‘screen’ (note, there is no matching Overnight 
Sputum  Sample). The naming of Coached Spot Sputum Samples for Days ‐2, ‐1 and 1 will be 
designated as Day ‐2, ‐1 and 1 respectively and results are also referred to as Day ‐2, ‐1 and 1 
results.  
o Naming  of  Coached  Spot  Sputum  Samples  for  the  Trial  Period  Days  3  to  57:  The  naming  of 
Coached  Spot Sputum Samples  will match the  naming of  Overnight Sputum Samples for that 
period, i.e. the Coached Spot Sputum Sample collected on Visit Day 4 will be named Day 3 etc. and 
results are referred to as Day 3 results.  
o All isolates from positive cultures should be stored until study completion.  
 
Timing of Assessments 
o During the treatment period, all assessments must be done prior to dosing and the ECG must be 
completed before any laboratory or clinical procedures are carried out. 
o Laboratory Safety Assessments must be taken before IMP dosing. 
o Pharmacokinetics: 
 
Pharmacokinetics will consist of two separate schedules:  
All Subjects: 
Pre‐dose sampling at Days 1, 4, 8, 15, 22, 29, 36, 43, 50 and during the site visit   on 
Days 57 and 70, to measure Ctrough levels of J, J metabolite M2, M, Pa and Z as per Table 
8. 
PK Sub‐study Subjects:  


Global Alliance for TB Drug Development 
Protocol Number: NC‐005‐(J‐M‐Pa‐Z) 
Working Protocol Version: 1.1 (Final) 
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In Addition to the general PK samples, there will be intense PK sampling on Days 14 
and 56 at pre‐dose, 1, 2, 4, 8 and 24 hours after dosing in a sub‐group of 15 Subjects 
in each of the treatment arms across selected sites. 
 
Subjects  do  not  need  to  be  hospitalized  for  the  PK  sampling,  but  may  remain  as 
outpatients at the clinic for the applicable day and return the following morning for their 
24 hour post dosing sample collection.  
 
PKs are to be collected at the specified time points within the allowed applicable window 
periods as follows: Pre‐dose: 0‐5 minutes before dose; 1‐8 hours post‐dose: +/‐ 5 minutes 
of dosing time; 24 hours post‐dose: +/‐ 15 minutes of dosing time and prior to next dose. 
 
The site staff should attempt to take the PK samples at the same time of day for each 
timepoint.    
 
Timing of Visits 
o Up to and including Day 15 ‐ No visit window (in order to accommodate PK sampling); 
o Day 14 must occur on Day 14, relative to Day 1 (in order to accommodate PK sampling for PK sub‐
study Subjects only); 
o Days 22 to 50 +/‐ 2 days; 
o Days 56 and 57 must occur on Days 56 and 57, relative to Day 1 (in order to accommodate PK 
sampling. The Day 56 visit is for PK sub‐study Subjects only); 
o Day 70 (or 2 weeks after last dose of IMP in the case of early withdrawal) +/‐ 3 days; 
o Day 140 (or 12 weeks after last dose of IMP in the case of early withdrawal) +/‐ 14 days; 
o The 8, 14, 20 and 26 Month Telephonic Survival Follow Up Contact will be 6, 12, 18 and 24 months, 
respectively, after study treatment completion +/‐ 14 days;   
 
Please Note 
 : IMP dosing should not exceed 56 days even if visit windows are utilized; 
 
 
: If a visit window is utilized, the next visit must be scheduled relative to Day 1.  
4.4.2.1. 
Day 1  
The following information will be collected and procedures performed pre‐dosing: 
 
Eligibility Assessment; 
 
Triplicate 12‐lead ECG (the ECG should be done before any other assessments); 
 
Laboratory Safety Assessments (excluding serum FSH); 
 
Pharmacokinetic sampling (pre‐dose for all Subjects); 
 
Vital Signs including weight; 
 
Physical Examination (full); 
 
If not already performed at Day ‐1: Randomization/Treatment Assignment; 
 
Overnight Sputum Sample: 
o Day 1 ends, named ‘Day 1’ 
o Subject given a sputum pot to start next Overnight Sputum Sample on Day 3 
 
Coached Spot Sputum Sample (named ‘Day 1’); 
 
Investigational Medicinal Product (IMP) Administration; 
 
Concomitant Medication(s)/Other Treatment(s); 
 
Adverse events. 
4.4.2.2. 
Day 4 
The following information will be collected and procedures performed pre‐dosing: 
 
Pharmacokinetic sampling (pre‐dose for all Subjects); 
 
Vital Signs including weight; 
 
Physical Examination (limited); 
 
Investigational Medicinal Product (IMP) Administration;  


Global Alliance for TB Drug Development 
Protocol Number: NC‐005‐(J‐M‐Pa‐Z) 
Working Protocol Version: 1.1 (Final) 
Protocol Date: 19 September 2014 
 
 
 
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 
Overnight Sputum Sample: 
o Day 3 ends, named ‘Day 3’; 
o Subject given a sputum pot to start next Overnight Sputum Sample on Day 7 
 
Coached Spot Sputum Sample (named ‘Day 3’); 
 
Concomitant Medication(s)/Other Treatment(s); 
 
Adverse events. 
4.4.2.3. 
Day 8; 22; 36 and 50 (+/‐ 2 days window for Visits on Days 22, 36 and 50) 
The following information will be collected and procedures performed pre‐dosing: 
 
Laboratory Safety Assessments (excluding serum FSH); 
 
Pharmacokinetic sampling (pre‐dose for all Subjects); 
 
Vital Signs including weight; 
 
Physical Examination (limited); 
 
Investigational Medicinal Product (IMP) Administration;  
 
Overnight Sputum Sample: 
o Day 7 ends, named ‘Day 7’, Day 21 ends, named ‘Day 21’, Day 35 ends, named ‘Day 35’, Day 
49 ends, named ‘Day 49’ respectively);  
o Subject given a sputum pot to start next Overnight Sputum Sample on the day preceding the 
next visit ‐ excluding the Day 14 and 56 Visits;   
 
Coached Spot Sputum Sample Collection (named ‘Day 7’, ‘Day 21’, ‘Day 35’ and ‘Day 49’ respectively); 
 
Concomitant Medication(s)/Other Treatment(s); 
 
Adverse events. 
4.4.2.4. 
Day 14 
 
Intensive Pharmacokinetic Sub‐study (for 15 Subjects in each treatment arm across selected sites) at pre‐
dose and 1, 2, 4, 8 and 24 hours after dosing; 
 
Investigational Medicinal Product (IMP) Administration;  
 
Concomitant Medication(s)/Other Treatment(s); 
 
Adverse events. 
4.4.2.5. 
Day 15 and 43 (+/‐ 2 days window for Visit on Day 43) 
The following information will be collected and procedures performed pre‐dosing: 
 
Triplicate 12‐lead ECG (the ECG should be done before any other assessments); 
 
Laboratory Safety Assessments (excluding serum FSH); 
 
Tuberculosis Symptom Profile (TSP) Questionnaire (performed on Day 15 only); 
 
Pharmacokinetic sampling (pre‐dose for all Subjects); 
 
Vital Signs including weight; 
 
Physical Examination (limited); 
 
Investigational Medicinal Product (IMP) Administration;  
 
Overnight Sputum Sample: 
o Day 14 ends, named ‘Day 14’, Day 42 ends, named ‘Day 42’ respectively 
o Subject given a sputum pot to start next Overnight Sputum Sample on the day preceding the 
next visit;   
 
Coached Spot Sputum Sample (named ‘Day 14’ and ‘Day 42’ respectively); 
 
Concomitant Medication(s)/Other Treatment(s); 
 
Adverse events. 
 
 


Global Alliance for TB Drug Development 
Protocol Number: NC‐005‐(J‐M‐Pa‐Z) 
Working Protocol Version: 1.1 (Final) 
Protocol Date: 19 September 2014 
 
 
 
TMP02‐A V1.0 
 
 
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4.4.2.6. 
Day 29 (+/‐ 2 days window) 
The following information will be collected and procedures performed: 
 
Triplicate 12‐lead ECG (pre‐dose and 2 hours (+ 15 minutes) post‐dose, the ECG should be done before 
any other assessments); 
 
Laboratory Safety Assessments (including serum FSH for male Subjects); 
 
Urine Pregnancy Test, (women of child bearing potential only, whether they are sexually active or not); 
 
Tuberculosis Symptom Profile (TSP) Questionnaire; 
 
Pharmacokinetic Sampling (pre‐dose for all Subjects); 
 
Vital Signs including weight; 
 
Physical Examination (limited); 
 
Investigational Medicinal Product (IMP) Administration;  
 
Overnight Sputum Sample: 
o Day 28 ends, named ‘Day 28’;  
o Subject given a sputum pot to start next Overnight Sputum Sample on the day preceding the 
next visit; 
 
Coached Spot Sputum Sample (named ‘Day 28’); 
 
Concomitant Medication(s)/Other Treatment(s); 
 
Adverse events. 
4.4.2.7. 
Day 56 
 
Intensive Pharmacokinetic Sub‐study (for 15 Subjects from each treatment arm across selected sites) at 
pre‐dose 1, 2, 4, 8 and 24 hours after dosing; 
 
Investigational Medicinal Product (IMP) Administration;  
 
Concomitant Medication(s)/Other Treatment(s); 
 
Adverse events. 
4.4.2.8. 
Day 57  
The following information will be collected and procedures performed: 
 
Triplicate 12‐lead ECG (the ECG should be done before any other assessments); 
 
Laboratory Safety Assessments (including serum FSH for male Subjects); 
 
Urine Pregnancy Test (women of child bearing potential only, whether they are sexually active or not); 
 
Tuberculosis Symptom Profile (TSP) Questionnaire; 
 
Pharmacokinetic Sampling (for all Subjects);  
 
Vital Signs including weight; 
 
Physical Examination (full);  
 
Overnight Sputum Sample ends (named ‘Day 56’);  
 
Coached Spot Sputum Sample (named ‘Day 56’); 
 
Concomitant Medication(s)/Other Treatment(s); 
 
Adverse events; 
 
Referral to National TB Treatment Program. 
Upon treatment completion, the DS‐TB Subjects will be provided with sufficient doses of standard of care 
TB treatment, as appropriate, to cover the time period from attending their last visit at the study clinic 
until their scheduled visit at the TB clinic. All DS‐TB and MDR‐TB Subjects will be referred to the local 
community TB clinics for standard anti‐tuberculosis chemotherapy according to National TB Guidelines. 
The Subjects will be provided with a referral letter to take with them to the TB Clinic.  A follow‐up call will 
be made by the study site staff to the clinic to determine if the Subject attended the clinic on the date as 
arranged. 


Global Alliance for TB Drug Development 
Protocol Number: NC‐005‐(J‐M‐Pa‐Z) 
Working Protocol Version: 1.1 (Final) 
Protocol Date: 19 September 2014 
 
 
 
TMP02‐A V1.0 
 
 
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4.4.2.9. 
Early Withdrawal 
If the Investigator considers it necessary to withdraw a Subject from treatment or the study, this should be 
discussed with the Sponsor and their approval should be obtained. In case of early withdrawal during the 
treatment period of the study (prior to Day 56), 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: 
 
Triplicate 12‐lead ECG (the ECG should be done before any other assessments); 
 
Laboratory Safety Assessments (including serum FSH for male Subjects); 
 
Urine Pregnancy Test (women of child bearing potential only, whether they are sexually active or not); 
 
Tuberculosis Symptom Profile (TSP) Questionnaire; 
 
Pharmacokinetic Sampling (all Subjects, pre‐dose if IMP is administered); 
 
Vital Signs including weight; 
 
Physical Examination (full); 
 
Concomitant Medication(s)/Other Treatment(s); 
 
Adverse events; 
 
Referral to National TB Treatment Program: 
Upon early withdrawal of IMP, the DS‐TB Subjects will be provided with sufficient doses of standard of 
care TB treatment, as appropriate, to cover the time period from attending their last visit at the study 
clinic until their scheduled visit at the TB clinic. All DS‐TB and MDR‐TB Subjects will be referred to the local 
community TB clinics for standard anti‐tuberculosis chemotherapy according to National Guidelines. The 
Subjects will be provided with a referral letter to take with them to the TB Clinic.  A follow‐up call will be 
made by the study site staff to the clinic to determine if the Subject attended the clinic on the date as 
arranged. 
 
Subjects who withdraw after <14 days of IMP administration are to return for the first follow‐up visit (i.e. 
2 weeks after last dose of IMP) only, while Subjects who withdraw after >15 days of IMP administration 
are to return for the first follow‐up visit (2 weeks after last dose of IMP) and the second follow‐up visit (12 
weeks after last dose of IMP). 
4.4.3. Follow‐Up Period (Day 70 to Day 140) 
4.4.3.1. 
Day 70 or 2 Weeks after Last Dose of IMP (+/‐ 3 days window) 
The following information will be collected and procedures performed: 
 
Triplicate 12‐lead ECG (the ECG should be done before any other assessments); 
 
Laboratory Safety Assessments (including serum FSH for male Subjects); 
 
Urine Pregnancy Test, (women of child bearing potential only, whether they are sexually active or not); 
 
Pharmacokinetic sampling (during the site visit for all Subjects); 
 
Vital Signs including weight; 
 
Physical Examination (limited); 
 
Concomitant Medication(s)/Other Treatment(s); 
 
Adverse events (all AEs and SAEs to be collected up to the end of the Day 70 Visit). 
4.4.3.2. 
Day 140 or 12 Weeks after Last Dose of IMP (+/‐ 14 days window) 
The following information will be collected and procedures performed pre‐dosing: 
 
Urine Pregnancy Test, (women of child bearing potential only, whether they are sexually active or not);  
 
Ophthalmology Examination Day 140 or at least 90 days post the last dose of study medication; 
 
Adverse events (ophthalmologic AEs and all SAEs to be collected up to the end of the Day 140 
Visit). 


Global Alliance for TB Drug Development 
Protocol Number: NC‐005‐(J‐M‐Pa‐Z) 
Working Protocol Version: 1.1 (Final) 
Protocol Date: 19 September 2014 
 
 
 
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4.4.4. Telephonic Survival Follow Up Contact for Survival Data at 6, 12, 18 and 24 months after 
  Last Dose of IMP (+/‐ 14 day window) i.e. Month 8, Month 14, Month 20 and Month 26 
The following information will be collected during the telephonic follow‐up: 
 
Establish and document whether the Subject remains alive or not; 
 
If the Subject has died, collect the date of death, cause of death and also if the death was related to TB or 
not. 
4.5. 
Treatment Discontinuation and Subject Withdrawal  
If the Investigator considers it necessary to withdraw a Subject from treatment or the study, this should be 
discussed with the Sponsor and their approval should be obtained. A Subject should immediately discontinue 
treatment and be prematurely withdrawn from the trial for the following reasons: 
 
Withdrawal of informed consent; 
 
Investigator  considers that for safety reasons, it is  in the best interest of the Subject that he/she be 
withdrawn; 
 
Specific Toxicities as described in section 7.3; 
 
Diagnosed with malaria during the treatment period. The Sponsor would recommend that Subjects who 
require treatment for malaria with drugs that have a potential of QTc prolongation should be withdrawn 
from study treatment and treated for malaria. Refer to Section 4.8.1.1 Recommendations for Concomitant 
use of Anti‐Malarials; 
 
Serious Adverse Event (SAE); 
 
Pregnancy; 
 
At the specific request of the Sponsor or termination of the study by the Sponsor; 
 
Subject who, in the opinion of the Investigator or Sponsor, fails to comply with the Protocol. 
Subjects (DS‐TB and MDR‐TB) who withdraw from the trial after having received IMP will not be replaced.  
Upon discontinuation of IMP, the DS‐TB Subjects will be provided with sufficient doses of standard of care TB 
treatment, as appropriate, to cover the time period from attending their last visit at the study clinic until their 
scheduled visit at the TB clinic. All DS‐TB and MDR‐TB Subjects will be referred to the local community TB 
clinics for standard anti‐tuberculosis chemotherapy according to National Guidelines. The Subjects will be 
provided with a referral letter to take with them to the TB Clinic.  A follow‐up call will be made by the study 
site staff to the clinic to determine if the Subject attended the clinic on the date as arranged. 
Any Subject who received at least one dose of IMP and is withdrawn or withdraws early from the study during 
the treatment phase will undergo an early withdrawal visit and will be requested to return for the applicable 
follow‐up visits: 
 
Subjects who withdraw after 14 days or less of IMP administration are to return for the first follow‐
up visit (i.e. 2 weeks after last dose of IMP) only. 
 
Subjects who withdraw after >15 days of IMP administration are to complete all the scheduled 
Follow Ups (i.e. up to and including Month 26). 
4.6. 
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.  Subjects currently on treatment will receive an appropriate regimen and 


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all Subjects will be referred as soon as possible to the National TB Treatment Program in each participating 
country. 
4.7. 
Subject Progress Definitions 
4.7.1. Enrollment 
 Screening Failure 
Subjects  from  whom  informed  consent  is  obtained  and  documented  in  writing  (that  is,  Subject  signs  an 
informed consent form), but who’s not randomized/assigned to study treatment. 
 Enrolled 
Subjects from whom informed consent is obtained and is documented in writing (that is, subject signs an 
informed consent form), and who are randomized / assigned to treatment. 
4.7.2. Completed Treatment 
Subjects who complete the treatment visits through to the Day 57 visit. 
4.7.3. Early Withdrawal 
 
During Treatment ‐ Subjects who are assigned treatment and withdraw/are withdrawn from the trial 
prior to completion of treatment visits.  
 
During Follow‐up ‐ Subjects who are randomized / assigned to and complete treatment, however 
withdraw/are withdrawn from the trial prior to completion of all scheduled follow‐up. 
4.7.4. Completed Trial 
 
Subjects who are randomised / assigned to treatment and complete Treatment and Follow‐Up. 
4.8. 
Restrictions 
4.8.1. Prior and Concomitant Medications and Other Treatments 
Concomitant Medication is defined as any medication taken within 30 days prior to IMP administration or 
during the trial until Day 70. These, plus any other relevant treatment, will be recorded onto the electronic 
Case Report Form (eCRF). 
Concomitant treatments should be kept to a minimum during the trial.  However, if concomitant treatments 
are considered to be necessary for the Subject’s welfare and are unlikely to interfere with the investigational 
medication, they may be given at the discretion of the Investigator.  For any concomitant therapy given as a 
treatment for: 
 
An  existing  condition  before  signing  of  the  informed  consent  form  (ICF),  the  condition  must  be 
documented on the Medical History pages of the eCRF. 
 
A new condition or a worsening of an existing condition occurring after signing of the ICF, the condition 
must be documented on the Adverse Event pages of the eCRF. 
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: 
 
Subjects  on  the  HRZE  and  J‐M‐Pa‐Z  treatment  arm:  Any  aluminium‐containing  antacids  should  be 
taken/administered at least one hour after the IMP dose. 
 
Subjects  on  the  J‐M‐Pa‐Z  arm:  antacids,  sucralfate,  multivitamins  and  other  products  containing 
multivalent cations, warfarin and didanosine are prohibited. 


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The following medicinal products are prohibited from Days ‐9 to ‐3 until after Day 57 or early withdrawal visit, 
unless part of study treatment: 
 
The systemic use of CYP3A4 inhibitors (e.g., azole antifungals: ketoconazole, voriconazole, itraconazole, 
fluconazole; ketolides such as telithromycin; and macrolide antibiotics other than azithromycin) for more 
than 3 consecutive days; 
 
The systemic use of CYP3A4 inducers (e.g., phenytoin, carbamazepine, phenobarbital, St. John’s wort, 
rifamycins and systemic dexamethasone); 
 
Medications of the statin class of compounds; 
 
Tricyclic  antidepressants  and  related  compounds,  including  amitriptyline,  doxepin,  desipramine, 
imipramine, clomipramine, cyclobenzaprine; 
 
Nonsedating antihistamines astemizole and terfenadine; 
 
The neuroleptics – phenothiazines, thioridazine, haloperidol, chlorpromazine, trifluoperazine, percyline, 
prochlorperazine, fluphenazine, sertindole and pimozide; 
 
The prokinetic cisapride; 
 
Quinoline antimalarials (e.g., chloroquine and quinacrine); 
 
Diuretics that deplete potassium; 
 
Medicinal products used to treat pulmonary TB (other than IMP):  including but not limited to isoniazid, 
ethambutol,  amikacin,  bedaquiline,  clofazimine,  cycloserine,  fluoroquinolones,  rifabutin,  rifampicin, 
streptomycin, 
kanamycin, 
para‐aminosalicylic 
acid, 
rifapentine, 
pyrazinamide, 
thioacetazone, 
capreomycin, thioamides, metronidazole; 
 
Subjects may be treated with levofloxacin for a defined time period of <2 weeks, provided it was not given 
for TB and the diagnosis is known and documented.  
 
Use  of  any  drug  known  to  prolong  QTc  interval  (including  but  not  limited  to  amiodarone,  bepridil, 
chloroquine,  chlorpromazine,  cisapride,  cyclobenzaprine,  clarithromycin,  disopyramide  dofetilide, 
domperidone, droperidol, erythromycin, halofantrine, haloperidol, ibutilide, levomethadyl, mesoridazine, 
methadone, pentamidine, pimozide, procainamide, quinidine, sotalol, sparfloxacin, thioridazine).  
4.8.1.1. 
Recommendations for Concomitant Use of Anti‐Malarials 
The  following  treatments  for  malaria  are  recommended  for  concomitant  use  with  the  IMP,  should  it  be 
necessary: 
 
Proguanil/atovaquone for J(loading dose/t.i.w.)PaZ, J(200mg)PaZ or J(200mg)MPaZ treatment arms  (NOT  for 
Subjects on the HRZE treatment arm); 
 
Artesunate plus sulfadoxine‐pyrimethamine for the HRZE, J(loading dose/t.i.w.)PaZ, J(200mg)PaZ or J(200mg)MPaZ  
treatment arms. 
These recommendations are based on the potential for QT prolongation by bedaquiline, moxifloxacin and 
many  anti‐malarials.  Due  to  the  extended  half‐life  of  bedaquiline  commencing  anti‐malarial  treatment, 
containing  drugs  that  could  prolong  the  QT  interval,  shortly  after  discontinuing  bedaquiline,  is  not 
recommended.  
4.8.1.2. 
Concomitant Use of Antiretroviral Therapy 
For Subjects who are HIV positive, and are either taking or commencing ART, the following restrictions must 
be followed due to potential DDI with IMP: 
 
Antiretroviral therapy is prohibited except: 
o 
Triple nucleoside reverse transcriptase inhibitor (NRTI) based regimen consisting of zidovudine, 
lamivudine, and abacavir; 
o 
Nevirapine based regimen consisting of nevirapine in combination with any NRTIs; 
o 
Lopinavir/ritonavir (Aluvia™) based regimen consisting of lopinavir/ritonavir (Aluvia™) in 
combination with any NRTIs; 


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o 
Raltegravir (an integrase inhibitor) in combination with nucleoside reverse transcriptase inhibitors 
(NRTIs). 
Subjects on all four treatment arms, who are commencing ART, may be entered onto the study provided there 
is at least a 2 week interval between commencing IMP and the start of ART.  
5. INVESTIGATIONAL MEDICINAL PRODUCT 
5.1. 
Trial Treatments 
Subjects will receive oral, once‐daily dosing for 8 weeks.  Table 11 details the four treatment arms and their 
applicable Subject population. 
Table 11 : Treatment Groups 
Treatment Group 
Subject Population 
1. 
 
bedaquiline 400mg once daily Days 1‐14, 200mg three times per week (2 x 
bedaquiline 100 mg tablets to be taken 3 times a week on specific study days 
as per section 5.3) Days 15‐56; plus 
 
PA‐824 200mg once daily Days 1‐56; plus 
 
pyrazinamide 1500mg once daily Days 1‐56. 
DS‐TB 
2. 
 
bedaquiline 200mg once daily Days 1‐56; plus 
 
PA‐824 200mg once daily Days 1‐56; plus 
 
pyrazinamide 1500mg once daily Days 1‐56. 
DS‐TB 
3. 
 
HRZE (isoniazid 75mg plus rifampicin 150mg plus pyrazinamide 400mg plus 
ethambutol 275mg combination tablets): Days 1‐56 with the daily dose per 
the Subject’s weight as follows: 
30‐37kg: 2 tablets; 
38‐54kg: 3 tablets; 
55 – 70kg: 4 tablets; 
71kg and over: 5 tablets. 
Vitamin B6 25mg one tablet daily Days 1‐56 should be taken with the HRZE 
dose. 
DS‐TB 
4. 
 
bedaquiline 200mg once daily Days 1‐56; plus 
 
moxifloxacin 400mg once daily Days 1‐56; plus 
 
PA‐824 200mg once daily Days 1‐56; plus 
 
pyrazinamide 1500mg once daily Days 1‐56. 
MDR‐TB 
5.2. 
Method of Assigning Subjects to Treatment Groups 
Eligible Subjects who have given written, informed consent will be enrolled onto the trial during Days ‐9 to 
Day ‐3 and will be identified by a study generated Subject identification code for anonymity (Subject number). 
Subjects who meet all of the inclusion criteria and none of the exclusion criteria will be randomized per their 
DS‐ or MDR‐TB status, and assigned a treatment number once all of the screening results are available. 
The Investigational Medicinal Product will be centrally randomized by persons not directly involved with the 
trial.  All treatment arms are open‐label. Subjects, study Investigators and staff, site pharmacists/dispensers, 
including laboratory staff, sponsor staff and applicable CROs will know what treatment a Subject is randomized 
to receive.  A treatment pack will be available for each Subject which will be identified by a treatment number.  


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In order to ensure there is no bias in treatment assignment, the study medication will be retained by the site 
pharmacist/registered dispenser.  The person responsible for assigning study treatment will not be directly 
involved in Subject care responsibilities.  
On  initial  randomization  the  site  will  request  the  site  pharmacist/registered  dispenser  to  assign  an  IMP 
treatment  pack  to  the  Subject  dependent  on  their  DS‐  or  MDR‐TB  status  (refer  to  Table  12).  The  site 
pharmacist/registered dispenser will assign to the Subject the next available applicable treatment pack, in a 
sequential basis starting from the lowest unused treatment number.   
This process will be fully documented.  Randomization/assignment by the pharmacist/registered dispenser 
may occur once all the screening results are available and the Investigator has determined that the Subject is 
eligible for the trial.  
5.3. 
IMP Administration 
The Subject should be instructed to: 
 
Take IMP orally once daily for 8 weeks (56 days), preferably around breakfast time, with 
a glass of water (approximately 240ml); 
 
When Subjects return for clinic visits or are hospitalized, they will be dosed on site; 
 
Subjects on the HRZE treatment arm should not take IMP with a meal (generally, no closer 
to meals than 1 hour before or 2 hours after a meal) and should take the Vitamin B6 25mg 
supplement with the HRZE dose;   
 
Subjects on the bedaquiline containing arms should take IMP with a meal (generally allow 
the Subjects a window of 30 minutes before to 30 minutes after a meal); 
 
When Subjects return for clinic visits or are hospitalized, they will be dosed on site; 
 
For the J(loading dose/t.i.w.) DS‐TB treatment arm: The bedaquiline dosing schedule is 400mg daily on days 1‐
14, and then 200mg 3x per week. The 3x per week doses must be given on the following specific days to 
accommodate the PK sampling: Days 15, 17, 20, 22, 24, 27, 29, 31, 34, 36, 38, 41, 43, 45, 48, 50, 53 and 
56. 
5.4. 
Subject Compliance 
During site clinic visits or hospitalization, the IMP will be administered by the Investigator/designated site 
personnel.  During the study, sites will be responsible for ensuring Subjects are taking the IMP correctly and 
are fully trained on how IMP is to be taken. When possible, Subjects 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 mouth of the Subject will be checked to ensure that the Subject has swallowed 
the IMP). 
5.5. 
Blinding and Procedures for Breaking the Blind 
This is an open label study.  There is no need for blinding or procedures to break the blind.   
5.6. 
IMP Packaging and Labeling 
The  complete  formulations  of  the  bedaquiline,  moxifloxacin  and  PA‐824  are  found  in  the  applicable 
Investigator Brochures  (12, 13, 23, 36). The complete formulations of the Pyrazinamide and HRZE combination 
tablets are found in the applicable Package Insert (11, 37, 40, 42).  
5.6.1. Packaging 
IMP will be supplied as: 
 
Bedaquiline 100mg Tablets; 
 
Moxifloxacin 400mg Tablets; 
 
PA‐824 200mg Tablets; 
 
Pyrazinamide 500mg Tablets;  


Global Alliance for TB Drug Development 
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 
HRZE Tablets (Isoniazid 75mg plus Rifampicin 150mg plus Pyrazinamide 400mg plus Ethambutol 275mg 
combination tablets). 
Subjects  will  receive  the  following  daily  trial  medication,  depending  on  which  group  they  are 
randomized/assigned to (see Table 12 below). 
Table 12: Investigational Medicinal Product Details 
Treatment Group 
Active 
Subject Population 
J(loading dose/t.i.w.)PaZ  
Days 1‐14  : 4 x bedaquiline 100mg tablets then 
Days 15‐56 : 2 x bedaquiline 100mg tablets to be 
taken 3 times a week on specific study days; Days 
15, 17, 20, 22, 24, 27, 29, 31, 34, 36, 38, 41, 43, 
45, 48, 50, 53 and 56 plus 
Days 1‐56  : 1 x  PA‐824 200mg tablet plus 
Days 1‐56  : 3 x pyrazinamide 500mg tablets 
DS‐TB 
J(200mg)PaZ 
Days 1‐56  : 2 x bedaquiline 100mg tablets plus 
Days 1‐56  : 1 x  PA‐824 200mg tablet plus 
Days 1‐56  : 3 x pyrazinamide 500mg tablets 
DS‐TB 
J(200mg)MPaZ 
Days 1‐56  : 2 x bedaquiline 100mg tablets plus 
Days 1‐56  : 1 x  moxifloxacin 400mg tablet plus 
Days 1‐56  : 1 x  PA‐824 200mg tablet plus 
Days 1‐56  : 3 x pyrazinamide 500mg tablets 
MDR‐TB 
HRZE 
Days 1‐56  : 
Dosing per weight: 
30‐37 kg 
2 tablets
38‐54 kg 
3 tablets
55‐70 kg 
4 tablets
71 kg and over
5 tablets
DS‐TB 
 
 
 
 
 
 
5.6.2. Labeling 
The  test  product containing treatment arms will be packaged in an individual treatment  pack. The outer 
packaging of each treatment pack will be labeled with, at a minimum, the following information: 
 
Name, address and telephone number of the Sponsor 
 
Name of medication, dosage, quantity and method of administration 
 
Reference/Lot Number 
 
Protocol number and space for completion of name of Investigator, site number, treatment number and 
visit number 
 
Directions for use 
 
The statement “For Clinical Trial Use Only” 
 
Storage conditions 
 
Expiry date 
 
The statement “Keep out of reach of children” 
 
The inner packaging of each treatment pack will be labeled with, at a minimum, the following information: 
 
Name, address and telephone number of the Sponsor 
 
Name of medication, dosage, quantity and method of administration 
 
Reference/Lot Number 


Global Alliance for TB Drug Development 
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Working Protocol Version: 1.1 (Final) 
Protocol Date: 19 September 2014 
 
 
 
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 
Protocol number and space for completion of name of Investigator, site number, treatment number and 
visit number 
 
Directions for use 
 
The statement “For Clinical Trial Use Only” 
 
Storage conditions 
 
Expiry date 
 
The statement “Keep out of reach of children” 
The control product will be commercially purchased and labeled as per the randomization code and the above 
requirements. 
5.7. 
Storage 
All study medication will be kept securely stored by the site pharmacist/registered dispenser in a secured area 
with limited access to designated site personnel only.  
Test product containing treatment arms will be stored in the supplied containers (thereby protected from light 
and moisture), between 15 to 30 degrees Celsius.  
Control product will be stored per the manufacturers Package Insert, i.e. not exceeding 25 degrees Celsius in 
the tightly closed container that it is supplied in, protected from light. 
5.8. 
Dispensing and Accountability 
The site pharmacist/ delegated dispenser will be responsible for dispensing the IMP.  Accurate accountability 
records will be kept by the site to assure that the IMP will not be dispensed to any person who is not a Subject 
under the terms and conditions set forth in this protocol i.e. delivery to site, inventory at site, use by Subject, 
destruction etc.  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. 
The Investigator undertakes to use the trial medication only as indicated in this protocol. 
5.9. 
Returns and Destruction  
Upon completion or termination of the trial, all unused and/or partially used IMPs must be returned to Sponsor 
(or designated vendor) who will arrange for destruction after final accountability has been confirmed. If no 
supplies remain, this fact will be indicated in the drug accountability section of the final report. 
 
 


Global Alliance for TB Drug Development 
Protocol Number: NC‐005‐(J‐M‐Pa‐Z) 
Working Protocol Version: 1.1 (Final) 
Protocol Date: 19 September 2014 
 
 
 
TMP02‐A V1.0 
 
 
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6. TRIAL VARIABLES AND PROCEDURES  
6.1. 
Demographic and Baseline Variables and Procedures 
The following demographic and background variables will be collected at the time points described in the trial 
flow chart: 
 
Written Informed Consent (including HIV and PK sub‐study). 
 
Eligibility criteria. 
 
Demographic data:  Date of birth, race and gender. 
 
Medical and treatment history.  
 
Laboratory  parameters:  The  Safety  and  Mycobacteriology  Laboratory  sampling  methodology  and 
requirements will be described in a separate document, the Laboratory Manual/s, which will be provided 
prior to the trial start. The following analyses will be performed: 
o Screening Coached Spot Sputum Sample: 
 
Direct microscopy for acid‐fast bacilli. 
 
Molecular assay for identification of M. Tb and drug susceptibility (such as GeneXpert or 
MTBDRplus) to confirm the diagnosis of TB and distinguish between DS‐TB and MDR‐TB. 
 
Molecular test for fluoroquinolone resistance (such as MTBDRsl) for MDR‐TB Subjects to 
establish susceptibility to moxifloxacin. 
 
Estimation of adequate sputum production. 
o Overnight Sputum Sample (Days ‐1 and ‐2 only): 
 
Direct microscopy for acid‐fast bacilli. 
 
Molecular / antigen test to confirm M. Tb. 
 
Speciation of infecting organism. 
 
Culture: MGIT and Solid Media (quantitative for CFU). 
 
DST of M. Tb isolate: SIRE, Z. 
 
MIC of J, Pa, M. 
o Urine: 
 
Urine drug screen. 
 
Urine pregnancy test: women of child‐bearing potential only, whether they are sexually 
active or not. 
o Serology: 
 
HIV and CD4 count.  
Approval for this to be performed will be obtained from Subjects in the written informed 
consent process. If an HIV test was performed within 1 month prior to trial start, it should 
not be repeated as long as documentation can be provided (ELISA and/or Western Blot). 
Prior to HIV testing and on receipt of the results, Subjects will be counseled on HIV by 
trained counselors if they have indicated as such on the HIV consent form (if approved by 
the relevant Ethics Committees). If requested by the Subject, HIV counseling provided to 
the  Subject  by  the  study  site  should  be  clearly  documented  in  the  Subject’s  medical 
records/source.   
 
In the countries and at the sites where subjects have the right to decline to know or 
receive their HIV test results, this decision should be clearly documented in the Subject’s 
medical records/source. For the purpose of this study each individual site has to adhere 
to  its  site  specific  SOPs;  country  and/or  applicable  Ethics  Committee’s  specific 
requirements regarding HIV counseling and HIV result communication. 
 
Karnofsky Score. 
 
Tuberculosis Symptom Profile (TSP) Questionnaire. 
 
Chest X‐ray: A chest x‐ray picture will be obtained from the clinic appointed radiology department.  The 
Investigator is responsible for review and analysis. 


Global Alliance for TB Drug Development 
Protocol Number: NC‐005‐(J‐M‐Pa‐Z) 
Working Protocol Version: 1.1 (Final) 
Protocol Date: 19 September 2014 
 
 
 
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 
Concomitant Medications/Other Treatments. 
 
Height (meters (m)). 
 
Method of Birth Control: Male and Female Subjects and their partners. 
 
Verify Post‐Trial Treatment TB Programme Attendance: attendance at the local TB clinic, inclusion onto 
the National TB Treatment Program. 
6.2. 
Efficacy Variables and Procedures 
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 efficacy variables will be 
collected at the time points, and as described, in the trial flow chart: 
 
Overnight Sputum Sample: 
o TTP (liquid media);   
o Number of CFU per ml sputum (solid media); 
o MIC of J, Pa, M; 
o Direct microscopy for acid‐fast bacilli positive/negative and Day; 
o DST of the M. Tb isolate: SIRE, Z; 
o Speciation of infecting organism. 
 
 
Coached Spot Sputum Sample Collection: 
o TTP (liquid media);   
o Number of CFU per ml sputum (solid media). 
 
Using these observed variables the following derived variables will be assessed for evaluation of the efficacy 
endpoints: 
o The rate of change over timeframes in TTP in liquid and solid media (change in TTP per day); 
o The rate of change over timeframes in number of sputum CFU of M. Tb on solid media (change in 
logCFU per day); 
o Time to Sputum Culture Conversion; 
o Number of Subjects with Sputum Culture Conversion. 
6.3. 
Safety and Tolerability Variables and Procedures 
The following safety and tolerability variables will be collected at the time points described in the trial flow 
chart 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 Hematology  (hemoglobin,  hematocrit,  red  blood  cell  count,  white  blood  cell  count  with 
differential, platelet count);  
o Clinical Chemistry (albumin, BUN, creatinine, direct, indirect and total bilirubin, uric acid, total 
protein, alkaline phosphatase, aspartate aminotransferase (AST), alanine aminotransferase (ALT), 
gamma‐glutamyl transferase (GGT), lactic dehydrogenase (LDH), total amylase, lipase,  phosphate, 
sodium,  potassium,  calcium  (corrected  for  albumin),  chloride,  magnesium,  random/fasting 
glucose, bicarbonate/CO2, creatine phosphokinase (CPK) and CK‐MB).   
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.  
o Serum Endocrinology: follicle‐stimulating hormone (FSH) male Subjects only.  
 
12‐lead Electrocardiogram (ECG): 


Global Alliance for TB Drug Development 
Protocol Number: NC‐005‐(J‐M‐Pa‐Z) 
Working Protocol Version: 1.1 (Final) 
Protocol Date: 19 September 2014 
 
 
 
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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 Subjects and will 
be described in a separate document which will be provided prior to the trial start; 
 
ECGs should be recorded prior to other assessments and administration of IMP; 
 
Subjects should be lying down (recumbent) for at least 5 minutes prior to each 12‐lead 
ECG evaluation; 
 
ECGs are to be recorded for 10 seconds; 
 
Screening ECG to be performed in single, and all other ECGs to be performed in triplicate. 
 
Vital signs: Supine systolic and diastolic blood pressure (SBP and DBP), heart rate, respiratory rate (RR), 
body temperature, weight. Using the observed variables weight and height, calculated body mass index 
(BMI) will be derived. 
 
Physical Examination: 
o Height is measured at Screening only. 
o Full and Limited (pulmonary, cardiovascular and abdominal) examinations. 
 
Ophthalmology Examination. The ophthalmology methodology and requirements will be described in a 
separate document, the Ophthalmology Guideline, which will be provided prior to the trial start. The 
following analyses will be performed: 
o Ophthalmology History; 
o Visual Acuity Test – Corrected. Near and Distance Vision; 
o AREDS2 opacity typing and grading. 
 
Adverse Events 
o All AEs and SAEs – through to the end of Day 70 Visit;   
o Only ophthalmologic related adverse events and all serious adverse events ‐ from Day 70 Visit 
through to Day 140 Visit. 
o Deaths will be reported during the Survival Follow Up Period. 
 
Concomitant Medication/Other Treatments. 
o Collected up to Day 70 visit. 
6.4. 
Pharmacokinetic Variables and Procedures  
Pharmacokinetics: 
Pharmacokinetics will consist of two separate schedules:  
 
All Subjects: 
 
Pre‐dose sampling at Days 1, 4, 8, 15, 22, 29, 36, 43, 50 and during the site visit on Days 57 and 70 to 
measure Ctrough levels of J, J metabolite M2, M, Pa and Z as per the table 13 below. 
 
PK Sub‐study Subjects:    
In addition to the general PK samples, there will be intense PK sampling on Days 14 and 56 at pre‐
dose, 1, 2, 4, 8 and 24 hours after dosing in a sub‐group of 15 Subjects in each treatment arm across 
selected sites. 
Pharmacokinetic Analysis: 
All measured PK concentrations will be listed. 
For the Ctrough samples, only descriptive statistics will be prepared (average Ctrough) derived for each analyte on 
Days 4, 8, 15, 22, 29, 36, 43, 50, 57 and 70 as follows: 


Global Alliance for TB Drug Development 
Protocol Number: NC‐005‐(J‐M‐Pa‐Z) 
Working Protocol Version: 1.1 (Final) 
Protocol Date: 19 September 2014 
 
 
 
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Table 13 : PK Analyte/s per Treatment Arm 
Treatment Arm 
Analyte/s 
Subject Population 
J(loading dose/t.i.w.)PaZ  
J, J metabolite M2, Pa, Z 
DS‐TB 
J(200mg)PaZ 
J, J metabolite M2, Pa, Z 
DS‐TB 
J(200mg)MPaZ 
J, J metabolite M2, M, Pa, Z 
MDR‐TB 
HRZE 
Z 
DS‐TB 
For the PK sub‐study samples, the following PK parameters will be estimated from the individual (per Subject) 
PK plasma concentrations: minimum observed PK plasma concentration (Cmin), maximum observed PK plasma 
concentration(Cmax),  time  to  reach  Cmax  obtained  without  interpolation  (Tmax),  area  under  the  PK  plasma 
concentration  time  (t)  curve  from  zero  to  the  last  quantifiable  PK  plasma  concentration  prior  to  the 
subsequent dose, using the linear trapezoidal rule (AUC(0‐t)), area under the PK plasma concentration time (t) 
curve from zero to 24 hours (AUC(0‐24)). These will be derived for each analyte, on Days 14 and 56, as follows: 
Table 14 : PK Analyte/s per Treatment Arm 
Treatment Arm 
Analyte/s 
Subject Population 
J(loading dose/t.i.w.)PaZ  
J, J metabolite M2, Pa, Z 
DS‐TB 
J(200mg)PaZ 
J, J metabolite M2, Pa, Z 
DS‐TB 
J(200mg)MPaZ 
J, J metabolite M2, M, Pa, Z 
MDR‐TB 
HRZE 
Z 
DS‐TB 
 
J(200mg)PaZ compared to J(loading dose/t.i.w.)PaZ and  J(200mg)MPaZ:  
In order to compare the effects of the two J dosing schemes on bedaquiline exposure, the Cmax, Cmin and AUC 
of J and M2 will be compared using PK sub‐study data from days 14 and 56 from the J(loading dose/t.i.w.)PaZ and 
J(200mg)PaZ DS‐TB arms. A secondary comparison of the PK parameters from the sub‐study parameters of J and 
M2 between the J(200mg)PaZ  DS‐TB and J(200mg)MPaZ MDR‐TB arms will also be performed. 
Another comparison of J and M2 exposure will be performed using the Ctrough data from the J(loading dose/t.i.w.)PaZ 
and J(200mg)PaZ DS‐TB arms, with a secondary comparison between the J(200mg)PaZ  DS‐TB and J(200mg)MPaZ   MDR‐
TB treatment arms. 
Pharmacokinetics‐Pharmacodynamics (PK‐PD):   
Pearson  correlation  coefficients  will  be  reported  for  the  correlation  analysis  of  all  relevant  PK‐PD  and 
exploratory PK‐PD endpoints. 
Descriptive summary statistics for TMIC will be presented. 
6.5. 
Mycobacteriology Characterization Variables and Procedures 
The  Mycobacteriology  characteristics  of  the  Subjects’  M.  Tb  strains  will  be  assessed  at  the  time  points 
described in the trial flow chart.  
Overnight Sputum and Coached Spot Sputum Samples will be collected at all scheduled visits, except the 
Screening Visit when only a Coached Spot Sputum  Sample will  be collected. Sputum samples will not  be 
collected at Early Withdrawal Visits. Cultures will be grown from all Overnight Sputum and Coached Spot 
Sputum Samples collected after Day ‐2. The Overnight Sputum  Samples will  be considered the reference 
samples. The following mycobacteriology assays will be carried out: 
 
 


Global Alliance for TB Drug Development 
Protocol Number: NC‐005‐(J‐M‐Pa‐Z) 
Working Protocol Version: 1.1 (Final) 
Protocol Date: 19 September 2014 
 
 
 
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Table 15 : General Mycobacteriology 
Sample 
Type 
Assessments 
Comments 
Screening 
Coached 
Spot 
Sputum 
Sample 
 
Direct microscopy for acid‐fast bacilli 
 
Molecular assay for identification of M. Tb and 
drug susceptibility (such as GeneXpert or 
MTBDRplus) to confirm the diagnosis of TB and 
distinguish between DS‐TB and MDR‐TB 
 
Molecular test for fluoroquinolone resistance 
(such as MTBDRsl) for MDR‐TB Subjects to 
establish susceptibility to moxifloxacin 
All to be performed at 
the Trial 
Appointed Laboratory. 
Baseline 
Overnight 
Sputum 
Samples 
named Day     
‐2 and ‐1 
Overnight 
Sputum 
Sample 
 
Direct microscopy for acid‐fast bacilli 
 
Molecular / antigen test to confirm M. Tb 
 
Culture: MGIT and Solid Media (quantitative for 
CFU) 
 
DST : SIRE, Z 
 
MIC : J, Pa, M 
 
DNA for pncA Sequencing 
Z DST resistance must 
be repeated to 
confirm. 
Baseline 
Coached Spot 
Sputum 
Sample 
named Day ‐2 
and ‐1 
Coached 
Spot 
Sputum 
Sample 
 
Culture: MGIT and Solid Media (quantitative for 
CFU) 
For determination of 
logCFU and logTTP 
rates of change for 
comparison to 
cultures from 
Overnight Sputum 
Sample. 
Overnight 
Sputum 
Sample 
named Days 1, 
3, 7, 14, 21, 
28, 35, 42, 49 
and 56 
Overnight 
Sputum 
Sample 
 
Culture: MGIT and Solid Media (quantitative for 
CFU) 
 
The last positive sample from withdrawn Subjects 
who have not converted to culture negative status 
OR Subjects who are still culture positive at 8 
weeks OR the first positive sample after 
conversion to culture negative status for Subjects 
who have ‘relapsed’*: 
o 
DST : SIRE, Z 
o 
MIC : J, Pa, M 
 
Coached Spot 
Sputum 
Sample Days 
1, 3, 7, 14, 21, 
28, 35, 42, 49 
and  56 
Coached 
Spot 
Sputum 
Sample 
 
Culture: MGIT and Solid Media (quantitative for 
CFU) 
 
For determination of 
logCFU and logTTP 
rates of change for 
comparison to 
cultures from 
Overnight Sputum 
Sample. 
 
The above assays will be carried out according to procedures described in the Laboratory Manual.  


Global Alliance for TB Drug Development 
Protocol Number: NC‐005‐(J‐M‐Pa‐Z) 
Working Protocol Version: 1.1 (Final) 
Protocol Date: 19 September 2014 
 
 
 
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 
The Coached Spot Sputum Sample can be used for all assays, except CFU and TTP, if results cannot be 
obtained from the Overnight Sputum Sample. 
 
pncA sequencing and MIC isolates can be batched at the end of the study.  
 
*If the Subject was treated with study medication for less than 9 days, the mycobacteriology testing will 
be performed on the Day ‐2 sample isolate only.  
 
*Culture negativity is defined as the first two consecutive negative cultures, except for the week 8 time 
point, where a singular negative is acceptable.  
7. ADVERSE EVENTS 
The Investigators are responsible for eliciting adverse events by observing the Subject and recording adverse 
events observed by him/her or reported by the Subject during the trial.  
Adverse events will be collected by the Investigator from the time a Subject signs the Informed Consent Form 
until the Subject has completed their last follow‐up as follows: 
 
All AEs and SAEs – through to the end of the Day 70 Visit;   
 
Only ophthalmologic related AEs and all SAEs ‐ from Day 70 through to Day 140 Visit 
 
Deaths will be reported during the Survival Follow Up period. 
7.1. 
Definitions 
7.1.1. Adverse Event (AE) 
Any untoward medical occurrence in a patient or clinical investigation Subject administered a pharmaceutical 
product and which does not necessarily have a causal relationship with this treatment. An adverse event can 
therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a medicinal product, whether or not related to the medicinal 
product. 
7.1.2. Serious Adverse Event (SAE) 
Any untoward medical occurrence that at any dose: 
 
results in death; 
 
is life threatening (any event in which the Subject 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 hospitalization or prolongation of existing hospitalization; 
 
results in persistent or significant disability/incapacity;  
 
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 hospitalization, but may jeopardize the Subject 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 hospitalization, 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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7.1.3. Unlisted (Unexpected) Adverse Event 
An adverse reaction, the nature or severity of which is not consistent with the applicable product information 
(e.g., Investigator’s Brochure for an unapproved investigational product or package insert/summary of product 
characteristics for an approved product). 
7.1.4. Life threatening 
Any event in which the Subject 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. 
7.1.5. Associated with the Use of the Drug 
An adverse event is considered associated with the use of the drug (Adverse Drug Reaction) if the attribution 
is possible, probable or very likely. 
7.1.6. Attribution/Causality 
The definitions for rating attribution/causality will be as described in Table 16. 
Table 16: 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).   
7.1.7. Severity 
Severity rating is to be made per the DMID Adult Toxicity Table (Appendix 2). For abnormalities NOT found 
elsewhere in the Toxicity Tables the scale described in Table 17 below is to be used to estimate grade of 
severity: 
Table 17: Adverse Event Severity Ratings 
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. 


Global Alliance for TB Drug Development 
Protocol Number: NC‐005‐(J‐M‐Pa‐Z) 
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Grade 
Severity Rating 
Definition 
GRADE 4 
Potentially Life‐
threatening 
Extreme limitation in activity, significant assistance 
required; significant medical intervention/therapy required, 
hospitalization or hospice care probable. 
7.1.8. Other AE Definitions 
The following definitions will be used for Adverse Event Reporting: 
Action Taken with IMP 
 
IMP unchanged 
 
IMP interrupted 
 
IMP stopped 
 
Not applicable (Follow‐up period) 
Other Action Taken 
 
None 
 
Medication given 
 
Hospitalization or prolongation of hospitalization 
 
Therapeutic or diagnostic procedure 
Outcome 
 
Resolved 
 
Improved 
 
Unchanged 
 
Worse 
 
Fatal 
 
Unknown 
Occurrence  
 
Once 
 
Intermittent  
 
Continuous 
7.2. 
Reporting 
7.2.1. Adverse Event (AE) 
Adverse events will be collected by the Investigator from the time a Subject signs the Informed Consent Form 
as follows: 
 
All AEs and SAEs will be collected through to the end of the Day 70 Visit; 
 
Only ophthalmologic related AEs and all SAEs from the Day 70 Visit through to the end of the Day 140 Visit. 
Any AE (serious or non‐serious) observed by the Investigator or reported by the Subject will be recorded on 
the Adverse Event Case Report Form.  The Investigator will review each AE and assess its relationship to drug 
treatment based on all available information at the time of the completion of the case report form.  The 
following information will be recorded for each Adverse Event reported (definitions section 7.1): 
 
Diagnosis of the AE, if possible.  In the case where an overall diagnosis cannot be made, each specific sign 
and/or symptom will be recorded as individual AEs; 
 
Date of onset; 
 
Stop Date (duration) if applicable; 
 
Severity;   


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 
Action Taken with IMP; 
 
Other Action Taken; 
 
Outcome; 
 
Relationship to IMP; 
 
Occurrence; 
 
Seriousness. 
7.2.2. Serious Adverse Event (SAE) 
Any AE that occurs which is serious must be reported by the Investigator to the study monitor and copied to 
the Sponsor Medical Monitor within 24 hours of the site first being aware of the SAE, whether or not the 
serious event is deemed associated with the use of the drug.   
Serious Adverse events will be collected by the Investigator from the time a Subject signs the Informed Consent 
Form as follows: 
 
All AEs and SAEs will be collected through to the end of the Day 70 Visit; 
 
Only ophthalmologic related AEs and all SAEs from the Day 70 Visit through to the end of the Day 140 Visit; 
 
Deaths will be reported during the Survival Follow Up period. 
In  addition,  the  Investigator  will  provide  a  detailed,  signed,  written,  and  complete  SAE  report  form  that 
addresses  the  Investigator’s  estimates  of  the  attribution/causality  of  the  AE  to  the  study  drug  and  the 
seriousness of the AE in question to the study monitor and medical monitor within 24 hours of becoming 
aware of the SAE. 
The study monitor will confirm receipt of the SAE Form with the Investigator and review the initial information 
on the SAE for diagnosis, consistency and completeness of data.   
For submission of updated or additional information on a previously reported SAE, the Investigator will provide 
the study monitor and medical monitor with a newly completed Serious Adverse Event Form, designated as a 
follow‐up report.  This will be submitted to the study monitor and medical monitor within 24 hours of the 
Investigator receiving the information. 
The study monitor will query for additional information from the Investigator, if necessary, to complete the 
profile of the SAE reported. 
The Sponsor/Investigator/designee will inform Regulatory Authorities and/or IEC/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 IEC/IRB. 
7.2.3. Follow up of Adverse Events 
All AEs 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.   
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.  
 
 


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7.2.4. Post‐Trial Adverse Events 
Any new SAEs reported by the Subject to the Investigator that occur after the last scheduled contact, and are 
determined by the Investigator to be possible, probable or certainly related to the use of the IMP, will be 
reported to the Sponsor, IEC/IRB and regulatory authorities on an expedited basis as required in accordance 
with local requirements and ICH guidelines for GCP. 
7.2.5. 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 Subject.  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 Subject, it is considered to be an adverse event. 
7.2.6. Disease under Study 
Symptoms of the disease under study (Pulmonary Tuberculosis) experienced by the Subject while on the study 
will be assessed by the Investigator.  If the symptom has: 
 
worsened while the Subject is in the study; 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 Subject’s TB; and  
 
not clinically significant; 
it will not be recorded as an AE and this will be noted in the Subject’s source documentation.  
All TB related symptoms that meet SAE criteria will be recorded and reported as a SAE. 
7.2.7. Overdose 
Overdose  of  IMP  experienced  by  the  Subject  while  on  the  study,  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 Subject’s source documentation.  
7.2.8. Drug Interaction 
If the Investigator becomes aware that the Subject has experienced a drug interaction which has resulted in 
an adverse event, it will be recorded as an adverse event.  
7.2.9. 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.   


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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) for the following time‐periods: 
 
During the trial; 
 
Within 6 months after last dose of IMP. 
If pregnancy is suspected while the Subject 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  Subject  withdrawn  from  the  trial.  Protocol‐required  procedures  for  trial 
discontinuation and follow‐up will be performed unless contraindicated by the pregnancy. 
Should the female partner of a male Subject become pregnant during the study or in the 6 months after the 
completion  of  IMP  and  the  Investigator  becomes  aware  that  this  situation  has  occurred,  consent  will  be 
requested from the female partner for collection of information on her pregnancy history and for information 
on the current pregnancy and birth. 
Pregnancy reporting will follow the same time lines and reporting structures as for a SAE (see above). SAE 
reporting will also occur if the pregnancy outcome is a congenital anomaly.  This will follow the reporting 
procedures described above for SAE reporting plus an additional clinical report compiled by the applicable 
company.  
7.3. 
Monitoring and Safety for Specific Toxicities 
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, Subjects should have a confirmatory measurement within 48 hours 
where possible. This management scheme is for confirmed lab abnormalities and not for isolated events. 
Monitoring  for  specific  toxicities  is  based  upon  target  organs  defined  in  preclinical  toxicity  studies 
(Investigator’s Brochures (12, 13, 23, 36) and Package Inserts (11, 37, 40, 42)). 
7.3.1. ALT and AST 
> 1.0 to < 5.0 x ULN AST or ALT elevation: 
Management will be at the discretion of the Investigator, according to generally accepted medical practice 
standards, and Subjects may continue IMP.  Subjects should be followed until resolution (return to baseline) 
or stabilization of AST/ALT elevation. 
> 5.0 x ULN or Grade 4 (> 8.0 x ULN ) AST or ALT elevation: 
Subjects will permanently discontinue IMP and be withdrawn from the trial.  It is recommended that the 
Investigator contacts the Sponsor to discuss the case of AST or ALT elevation.  Subjects should be followed 
until resolution (return to baseline) or stabilization of AST/ALT elevation. 
7.3.2. Amylase elevation 
Grade 1 (> 1.0 to ≤ 1.5 x ULN) or Grade 2 (> 1.5 to ≤ 2.0 x ULN): 
Subjects may continue IMP and should be carefully evaluated and followed closely. 
Grade 3 (> 2.0 to ≤ 5.0 x ULN): 
Further  testing  such  as  pancreatic  amylase  and  trypsin‐like  immunoreactivity  should  be  considered  after 
consultation with the Sponsor Medical Monitor. 
Grade 4 (> 5.1 x ULN): 


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Subjects with confirmed Grade 4 elevations of total amylase will permanently discontinue study medication 
and be withdrawn from the trial.  
7.3.3. Lipase elevation 
Grade 1 (> 1.0 to ≤ 1.5 x ULN) or Grade 2 (> 1.5 to ≤ 2.0 x ULN): 
Management will be at the discretion of the Investigator, according to generally accepted medical practice 
standards. Subjects may continue IMP and should be carefully evaluated and followed closely. 
Grade 3 (> 2.0 to ≤ 5.0 x ULN) or Grade 4 (> 5.1 x ULN): 
Subjects with confirmed Grade 3 or 4 elevations of lipase will permanently discontinue IMP and be withdrawn 
from the trial. 
7.3.4. Musculo‐skeletal System and Cardiac Muscle 
Myalgia 
Grade 1 (mild with no limitation of activity): 
Subjects may continue IMP and should be carefully evaluated and followed closely. 
Grade 2 (muscle tenderness at site other than injection site or with moderate impairment of activity) or 
Grade 3 (severe muscle tenderness with marked impairment of activity) or Grade 4 (frank myonecrosis): 
Subjects will permanently discontinue IMP and be withdrawn from the trial.  CPK should be fractionated for 
CK‐MB subunit.  
Subjects having Grade 3 (3.1 to 6 x ULN) or Grade 4 (> 6 x ULN) elevation in CK‐MB subunit will permanently 
discontinue IMP and be withdrawn from the trial.  
7.3.5. LDH  
For Subjects with LDH elevation >2.5 x ULN, LDH isoenzymes will be assessed. 
7.3.6. Cardiac Rhythm Disturbances 
Grade  1  (asymptomatic)  or  Grade  2  (asymptomatic,  transient  rhythm  abnormality  not  requiring  any 
treatment) cardiac rhythm disturbances: 
Subjects may continue IMP and should be carefully evaluated and followed closely. 
Grade  3  (recurrent,  persistent,  symptomatic  arrhythmia  requiring  treatment)  or  Grade  4  (unstable 
dysrhythmia requiring treatment) cardiac rhythm disturbances: 
Subjects will permanently discontinue IMP and be withdrawn from the trial. 
QTc prolongation  
 A Subject will be withdrawn if: 
 
the mean QTcF of their triplicate recordings is equal to or greater than 500 msec, or  
 
if a single recording has a QTcF > 500msec, the ECG should be repeated. If the second ECG also has a 
QTcF of > 500msec the Subject should be withdrawn after consultation with the Sponsor, or 
 
they  develop  a  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 withheld until the reading has been 
confirmed by the central cardiologist and the Subject is to be treated per the Investigators clinical judgment. 
If it is confirmed by the central cardiologist the Subject is to be withdrawn. 


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7.3.7. Other toxicities  
Grade 1 or 2 
Subjects who develop grade 1 or 2 AE or laboratory toxicity may continue intake of IMP. 
Grade 3 or 4 
Subjects who develop grade 3 or 4 AE or laboratory toxicity (see Appendix 2 for specifics) will be carefully 
evaluated by the Investigator.  Subjects may continue intake of IMP or be withdrawn from the trial if, in the 
opinion of the Investigator, the AE or laboratory toxicity poses a significant risk for the Subject in case of 
continued participation in the trial.  Subjects should be followed as appropriate until resolution of the AE or 
toxicity. 
7.4. 
Safety Monitoring by the Data Safety Monitoring Committee 
A DSMC will be appointed for the study. The primary responsibility of the DSMC will be to act in an advisory 
capacity to the Sponsor to safeguard the interests of trial Subjects by monitoring Subject safety, assess Subject 
risk  versus  benefit,  assess  data  quality  and  general  evaluation  of  the  trial  progress.  It’s  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 study 
team. It will comprise at least 3 voting members.  The DSMC may have an organizational meeting prior to 
commencement of the trial. The DSMC will have one meeting where it will review unblinded data during a 
closed session. This meeting is planned to occur once 33% of the planned Subjects’ complete treatment.  The 
Sponsor  or  the  DSMC  may  convene  ad  hoc  meetings  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.   
8. STATISTICAL ANALYSIS  
The statistical analysis plan (SAP), which will contain details of the analyses described generally in this section, 
will be written and signed off prior to Clinical Database Lock.  
8.1. 
Analysis Population 
Efficacy Analysis Populations will contain all Subjects included in the safety analysis population for whom 
corresponding  efficacy  data  are  available  and  had  no  major  protocol  violations/deviations  defined  as 
violations/deviations affecting the integrity of the efficacy data. 
The analysis populations will be defined in the SAP. 
In particular, the Safety analysis population will contain all Subjects who were randomized to study drug and 
received at least one administration of study drug. The Efficacy analysis populations will contain all Subjects 
included in the Safety analysis population for whom corresponding efficacy data are available and had no 
major protocol violations/deviations defined as violations/deviations affecting the integrity of the efficacy 
data.  Pyrazinamide  resistant  subjects  will  be  excluded  from  the  general  efficacy  analyses,  except  for  the 
exploratory analyses associated with the comparison of MDR‐TB pyrazinamide resistant subjects to MDR‐TB 
sensitive subjects. 
8.2. 
Sample Size 
The objective of this trial is to evaluate the bactericidal activity, safety, tolerability and pharmacokinetics of 
combinations of bedaquiline, PA‐824, moxifloxacin and pyrazinamide after 8 weeks of treatment. 
Sixty subjects will be randomized to each DS treatment group. It is expected that at least 50 subjects per 
treatment group would have valid data for the assessment of BATTP(0‐56) as per primary efficacy analysis. 


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A fixed number of MDR subjects to be assigned is not pre‐specified. The analysis of such MDR subjects is 
exploratory and no formal statistical analysis will therefore be performed for the MDR treatment group.   
Formal sample size calculations will not be performed due to the exploratory nature of the trial (no formal 
statistical hypothesis is therefore to be tested). Provided the assumption that a sample size of 50 subjects in 
each DS treatment group will be included, and using a two sample t‐test with a 0.05 two‐sided significance 
level (alpha) with common standard deviation (SD) of 0.008, the study will have 90% statistical power to detect 
a mean group difference in BATTP(0‐56) of 0.00524. 
8.3. 
Interim Analyses 
No formal interim analyses will be done for this study. The survival follow‐up analysis will be included as an 
Addendum to the final CSR. 
8.4. 
Primary Endpoint Analysis 
The primary efficacy analysis of the primary efficacy endpoint, i.e. BATTP(0‐56), as determined by the rate of 
change in the log TTP in sputum over 8 weeks of treatment, will be analyzed using non‐linear mixed effects 
(NLME) regression modeling.  
Sensitivity analyses may be performed using different model assumptions for the NLME regression model. 
Subgroup analyses, such as by site and human immunodeficiency virus (HIV) status, may be performed as 
exploratory analyses. 
No multiplicity adjustments for alpha will be done as this is an exploratory trial. 
8.5. 
Secondary Endpoint Analysis 
8.5.1. Efficacy 
The secondary efficacy endpoints and analyses are as follows: 
 
The BACFU(0‐56), BACFU(0‐2) and BACFU(14‐56) as determined by the rate of change in log colony forming 
units (CFUs) over Days 0 to 2 and Days 14 to 56 treatment, represented by the model‐fitted log(CFU) 
counts as calculated by the regression of the observed log(CFU) counts over time. 
 
The  BATTP(0‐2) and BATTP(14‐56) as determined by the  rate of change in log time of sputum culture 
positivity  (TTP)  over  8  weeks  of  treatment  in  the  Mycobacterial  Growth  Indicator  Tube  system, 
represented by the model‐fitted log(TTP) results as calculated by the regression of the observed log(TTP) 
results over time. 
 
Time  to  sputum  culture  conversion  using  data  from  weekly  cultures  through  8  weeks  of  treatment 
(separately, on solid and liquid media). 
o The time to sputum culture conversion will be analyzed using Kaplan‐Meier analysis, and will be 
depicted in figures. Time to sputum culture conversion is defined as the sampling day at which 
first of two consecutive negative cultures are obtained (except for the week 8 time point where a 
singular negative sample is sufficient). The log‐rank test will be used for the comparison of the 
median time to sputum culture conversion. 
 
Proportion of subjects with sputum culture conversion at 4, 6 and 8 weeks (separately, on solid and liquid 
media). 
o The proportion of Subjects with sputum culture conversion at each time point will be compared 
pairwise between treatment groups using a Chi‐Square test. 
 
The BACFU(0‐56, 0‐2 and 14‐56) and BATTP(0‐56, 0‐2 and 14‐56)  of J(loading dose/t.i.w.)PaZ compared to J(200mg)PaZ 
from DS‐TB treatment arms. 
 
Investigation of the methodology of sputum sampling by comparing CFU counts and TTP results, quantified 
by both coached spot and overnight sputum samples. 
 
All analyses of the CFU an TTP data obtained by overnight sputum sampling will also be performed for CFU 
and TTP data obtained on the coached spot sputum samples. 


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8.5.2. Safety and Tolerability Analysis 
 
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 by treatment group for further medical analysis: 
o Incidence of TEAEs; 
o Incidence of TEAEs by Severity; 
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. 
 
Cardiovascular Safety (see Appendix 3).  ECGs will be centrally read. QT intervals will be adjusted using 
Fridericia’s correction and Bazett’s correction. QT/QTc values and changes from pre‐dose (average of 
Screening and Day 1 values) at each time point will be summarized using descriptive statistics by group 
and time of collection.  For IMP containing treatment arms, the potential correlations between the plasma 
concentration of IMP and the change from baseline of QT interval corrected by Fridericia’s method (QTcF) 
and change from baseline of QT interval corrected by Bazett’s method (QTcB) with respect to time for the 
different treatment groups will be explored.  These will be presented as descriptive analyses, and no 
inferential tests will be carried out. 
o Post‐baseline QT/QTc intervals will be classified into the following categories:   
 
QT/QTc < 450 msec 
 
450 msec < QT/QTc < 480 msec 
 
480 msec < QT/QTc < 500 msec 
 
QT/QTc > 500 msec   
o QTc changes from baseline will be classified into the following categories: 
 
increase < 30 msec,  
 
> 30 msec and < 60 msec, and  
 
increase > 60 msec.  
o Frequency counts will be used to summarize the number of Subjects at each time point according 
to the above categories. 
o ECG results will be classified as normal or abnormal (investigator assessment) and summarized 
using frequency counts by dose group and time of collection. 
o Tukey honestly significant difference (HSD) analysis of the mean change from baseline in QTcB and 
QTcF interval between treatment groups across all post‐baseline values. 
 
Ophthalmology: Descriptive statistics will be presented for ophthalmology slit lamp examination data (age 
related  eye  disease  study  2  [AREDS2]  lens  opacity  classification  and  grading)  and  listed  by  Subject. 
Categorical  data  for  lens  opacity  will  be  summarized  in  a  frequency  table  for  the  left  and  right  eye, 
respectively.  
 
Other  safety  variables:  Laboratory  Parameters,  Physical  Examination,  Vital  signs  (see  Appendix  3), 
Concomitant medication.  Descriptive summary statistics will be presented. The incidence of liver related 
laboratory abnormalities will be explored. 
 
Survival Follow Up status per contact will be summarized descriptively. This analysis will be included as an 
Addendum to the final CSR. 


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8.5.3.  Pharmacokinetics: 
For each analyte (per visit), the PK plasma concentrations and parameters 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  median  concentration‐versus‐time  graphs  will  be  provided  (with  error  bars  as 
appropriate).  
8.5.4. Pharmacokinetics‐Pharmacodynamics (PK‐PD):   
 
Pearson correlation coefficients will be reported for the correlation analysis of all relevant PK‐PD and 
exploratory PK‐PD endpoints. 
 
Descriptive summary statistics for TMIC will be presented. 
8.6. 
Exploratory Endpoint Analysis 
8.6.1. Efficacy 
The exploratory efficacy endpoints and analyses are as follows: 
 
Sub‐analysis  of  the  primary  and  secondary  efficacy  endpoints  of  the  MDR‐TB  pyrazinamide  resistant 
subjects compared to the MDR‐TB sensitive subjects.  
 
Sub‐analysis of the primary and secondary efficacy endpoints of the H or R mono‐resistant subjects will be 
evaluated as separate sub‐groups. 
8.7. 
General Mycobacteriology 
Descriptive summary statistics for the mycobacterial characteristics will be presented. 
9. RECORDS MANAGEMENT 
9.1. 
Data Collection 
All CRF/eCRF pages will be completed for each Subject who receives any amount of IMP.  For screening failure 
Subjects a screening failure CRF/eCRF will be completed.  For Subjects who are prematurely withdrawn, the 
visits up to withdrawal plus the withdrawal and applicable follow‐up visits need to be completed. 
9.2. 
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, 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 (IEC/IRB) 
review and regulatory inspections providing authorized persons direct access to source documents. 
9.3. 
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. 
 
9.4. 
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 


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5 years after the last approval of a marketing application and until there are no pending or contemplated 
marketing  applications  or  at  least  5  years  have  elapsed  since  the  formal  discontinuation  of  clinical 
development of the IMP.   
The Sponsor will make financial provisions for the Investigator to deposit the documents at an external site 
for safekeeping for as long as required by regulations and the Sponsor.  
10. QUALITY CONTROL AND ASSURANCE 
10.1. Site Procedures 
The Investigator undertakes to perform the clinical trial in accordance with this protocol, International GCP, 
and  the  ethical  principles  that  have  their  origin  in  the  Declaration  of  Helsinki,  and  applicable  regulatory 
requirements. 
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 study.  Subject compliance will be monitored throughout the study. 
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  study.  However  the  Investigator 
maintains responsibility for the study and will supervise the Sub‐Investigators. Written IEC/IRB approval will 
be obtained prior to involvement in the study. 
The Investigator will ensure that all site personnel are adequately trained in GCP, the protocol, IB and all study 
procedures and requirements.  
10.2. 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. A risk based monitoring approach will be followed. 
The purpose of monitoring is to verify that the rights and well‐being of human Subjects 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 for the purpose of monitoring various aspects 
of the study.  Visits will take place usually within a predetermined interval, but this may vary during the course 
of the study.  The Investigator and site staff will allow the study 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),  Subject  records  and  laboratory  raw  data,  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. 
10.3. 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 


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quality of data with regard to accuracy, adequacy and consistency, and to assure that studies are in accordance 
with the guidelines.  Having the highest quality data from studies 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 study.  The audit will involve the 
review  of  all  study‐related  documentation  required  by  GCP  to  be  maintained  by  each  site;  drug  storage, 
dispensing  and  return;  all  study‐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.  
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.  
11. ETHICS AND REGULATORY 
11.1. 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.  
11.2. Independent Ethics Committee/Institutional Review Board (IEC/IRB) Review 
The Investigator's/institution’s written application to the IRB/IEC will include the approved protocol, written 
informed consent, any written information to be provided to the Subject or any modification thereof, plus any 
other  study  related  documents  required  for  review.    The  protocol  and  all  these  required  study  related 
documents will be reviewed by the sites’ respective IEC/IRB.  The study will not start until the IEC/IRB has 
approved all the relevant documents.  As part of the Investigator's/institution’s written application to the 
IRB/IEC,  the  Investigator/institution  should  provide  the  IRB/IEC  with  a  current  copy  of  the  Investigator's 
Brochure. If the Investigator's Brochure is updated during the trial, the investigator/institution should supply 
a copy of the updated Investigator’s Brochure to the IRB/IEC. During the trial the Investigator/institution 
should provide to the IRB/IEC all documents subject to review.  
The  IEC/IRB  shall  be  constituted  and  shall  operate  in  accordance  with  International  GCP  and  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 the IRB/IEC.  The records should be filed in the Investigator’s Study 
File, and copies will be sent to the Sponsor. 
11.3. 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. 
11.4. Informed Consent 
Written informed consent will be obtained from all Subjects (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 Subject 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 Subject being considered for 
inclusion in this trial is given a full explanation of the protocol.  This shall be documented on a written informed 
consent form that shall be approved by the same IEC/IRB responsible for approval of this protocol.  Each 


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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.  
Once  the  appropriate  essential  information  has  been  provided  to  the  Subject  and  fully  explained  by  the 
Investigators  (or  qualified  designees)  and  it  is  felt  that  the  Subject  understands  the  implications  of 
participating, the IEC/IRB approved written informed consent form will be signed and dated by both the 
Subject and the person obtaining consent (Investigators or designees), and by any other parties required by 
the IEC/IRB. 
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 Subject.  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 Subject’s medical 
record. 
The monitor will inspect the original completed consent form(s) for all Subjects. 
11.5. Confidentiality 
All site staff, the Sponsor, and any Sponsor representatives will preserve the confidentiality of all Subjects 
taking part in the study, in accordance with International GCP, applicable local legislation/regulations.  Subject 
to the requirement for source data verification by the study personnel by reference to the Subject’s notes, 
confidentiality of all Subject identities will be maintained.  Only Subject study number and initials will be used 
on the CRF and in all study correspondence, as permitted.  No material bearing a Subject’s name will be kept 
on file by the Sponsor. The written informed consent will contain a clause granting permission for review of 
the Subjects’ source data. 
12. PUBLICATION POLICY 
The definition of publication for this purpose is any public presentation of the data emerging from this study.  
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 IEC/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 study in 
the form of a joint publication(s) between Sponsor and Investigator(s), including site clinical and laboratory 
Investigators, as appropriate. 
13. PROTOCOL AMENDMENT POLICY 
Any change to the protocol will be effected by means of a protocol amendment.  Any changes which affect 
Subject safety or welfare will be submitted to the IEC/IRB and Regulatory Authorities prior to implementation.  
The Investigator, IEC/IRB, and Sponsor must agree on all amendments.  No amendment will be implemented 
until approved by the relevant Authorities and/or IEC/IRB and signed by all required parties.  Exceptions to 
this are when the Investigator considers that the Subject’s safety is compromised.  
Protocol amendments detailing minor administrative changes should be submitted by the Investigator to the 
IEC/IRB and Regulatory Authorities, either for notification purposes or approval as appropriate.  
14. FINANCIAL ASPECTS, INSURANCE AND INDEMNITY 
The study Sponsor and funder 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 Subjects currently on such therapies, and improve treatment of latent 
infection. 


Global Alliance for TB Drug Development 
Protocol Number: NC‐005‐(J‐M‐Pa‐Z) 
Working Protocol Version: 1.1 (Final) 
Protocol Date: 19 September 2014 
 
 
 
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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 Subjects will not receive any incentives for their involvement in the study.  The Sponsor has made provision 
to reimburse the Subjects for out‐of‐pocket expenses such as travelling to and from the study site and other 
miscellaneous costs as a result of their study 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. 


Global Alliance for TB Drug Development 
Protocol Number: NC‐005‐(J‐M‐Pa‐Z) 
Working Protocol Version: 1.1 (Final) 
Protocol Date: 19 September 2014 
 
  
TMP02‐B V1.0  
 
   
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15. REFERENCES  
1. Maggi  N,  Pasqualucci  CR,  Ballotta  R,  Sensai  P.    Rifampicin:  A  new  orally  active  rifamycins.  
Chemotherapy 1966; 11 (5): 285‐92. 
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): 939‐49. 
3. Dietze R, Teixeira L, Rocha LMC, et al.  Safety and bactericidal activity of rifalazil in patients with 
pulmonary tuberculosis.  Antimicrob Agents Chemother 2001; 47 (7): 1972‐6. 
4. Donald PR, Sirgel FA, Venter A, et al.  Early bactericidal activity of antituberculosis agents. Expert 
Rev Anti‐infect Ther 2003; 1 (1): 141‐55. 
5. Johnson  JL,  Hadad  DJ,  Boom  WH,  et  al.    Early  and  extended  early  bactericidal  activity  of 
levofloxacin, gatifloxacin and moxifloxacin in pulmonary tuberculosis.  Int J Tuberc Lung Dis 2006; 
10 (6): 1‐8. 
6. Rustomjee R, Diacon AH, Allen J, et al.  Early bactericidal activity and pharmacokinetics of the 
diarylquinoline TMC207 in treatment of pulmonary tuberculosis.  Antimicrob Agents Chemother 
2008 Aug; 52(8): 2831‐5.  Epub 2008 May 27. 
7. Donald PR, Diacon AH.   The early  bactericidal activity of anti‐tuberculosis drugs: a literature 
review.  Tuberculosis 2008; 88 Suppl 1: S75‐S83. 
8. Brindle RJ, Nunn PP, Githui W, Allen BW, Gathua S and Waiyake P. Quantitative bacillary response 
to treatment in HIV‐associated pulmonary tuberculosis. Am Rev Respir Dis 1993; 147:958‐961. 
9. Rustomjee R, Lienhardt C, Kanyok T, Davies GR, Levin J, Mthiyane T, Reddy C, Sturm AW, Sirgel 
FA, Allen J, Coleman DJ, Fourie B, Mitchison DA; Gatifloxacin for TB (OFLOTUB) study team. A 
Phase II study of the sterilising activities of ofloxacin, gatifloxacin and moxifloxacin in pulmonary 
tuberculosis. Int J Tuberc Lung Dis. 2008 Feb; 12(2):128‐38. 
10. Davies  GR,  Brindle  R,  Khoo  SH  and  Aarons  A.  Use  of  Nonlinear  Mixed‐Effects  Analysis  for 
Improved  Precision  of  Early  Pharmacodynamic  Measures  in  Tuberculosis  Treatment.]  LJ. 
Antimicrob Agents Chemother. 2006 September; 50(9): 3154–3156.  
11. Package Insert, SirturoTM, Janssen Therapeutics, February 2012. 
12. TMC207 Investigator’s Brochure, Janssen Research and Development, Edition 7, 18 September 
2012.  
13. TMC207 Addendum 1 to Investigator’s Brochure Edition 7, 3 July 2013. 
14. Koul A, Dendouga N, Vergauwen K, et al.  Diarylquinolines target subunit c of mycobacterial ATP 
synthase.  Nat Chem Biol 2007; 3: 323‐4. 
15. Andries K, Verhasselt P, Guillemont J, et al.  A diarylquinoline drug active on the ATP synthase of 
Mycobacterium turberculosis.  Science 2005; 307: 223‐7. 
16. Huitric  E,  Verhasselt  P,  Andries  K,  Hoffner  SE.    In  vitro  antimycobacterial  spectrum  of  a 
diarylquinoline ATP synthase inhibitor.  Antimicrob Agents Chemother 2007; 51: 4202‐4. 
17. Koul A, Vranckx L, Dendouga N, et al.  Diarylquinolines are bactericidal for dormant mycobacteria 
as a result of disturbed homeostasis.  J Biol Chem 2008; 283: 25273‐80. 
18. Mdluli K, Nuermberger, E. Pre‐Clinical Drug Combination Studies to Identify Novel Regimens for 
TB. In: Recent Advances in TB Drug Development symposium, 40th Union World Conference, 
International Union Against TB and Lung Disease, Cancun, Mexico, 2009. 
19. Mdluli K , Nuermberger E, Taylor K,  Williams N, Koen A, Khisimuzi E, Rokeya T, Si‐Yang L, Peloquin 
C, Dinesh C, Sterilizing activity of novel TMC207‐ and PA‐824‐containing regimens in a murine 
model of tuberculosis.  Antimicrobial Agents and Chemotherapy 2011; 55: 5485‐5492. 


Global Alliance for TB Drug Development 
Protocol Number: NC‐005‐(J‐M‐Pa‐Z) 
Working Protocol Version: 1.1 (Final) 
Protocol Date: 19 September 2014 
 
 
 
TMP02‐A V1.0 
 
 
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20. Rustomjee R, Diacon AH, Allen J, et al.  Early bactericidal activity and pharmacokinetics of the 
diarylquinoline TMC207 in treatment of pulmonary tuberculosis.  Antimicrob Agents Chemother 
2008 Aug; 52(8): 2831‐5.  Epub 2008 May 27. 
21. Diacon AH, Dawson R, Von Groote‐Bidlingmaier F, Symons G, Venter A, Donald PR, Conradie A, 
Erondu N, Ginsberg AM, Egizi E, Winter H, Becker P, Mendel CM, Randomized dose‐ranging study 
of  the  14‐day  early  bactericidal  activity  of  bedaquiline  (TMC207)  in  patients  with  sputum 
microscopy  smear‐positive  pulmonary  tuberculosis.  Antimicrob  Agents  Chemother.  2013 
May;57(5):2199‐203. doi: 10.1128/AAC.02243‐12. Epub 2013 Mar. 
22. Diacon AH, Dawson R, von Groote‐Bidlingmaier F, Symons G, Venter A, Donald PR, van Niekerk 
C, Everitt D, Winter H, Becker P, Mendel CM, Spigelman MK. 14‐day bactericidal activity of PA‐
824, bedaquiline, pyrazinamide, and moxifloxacin combinations: a randomised trial. Lancet. 2012 
Sep 15;380(9846):986‐93. doi: 10.1016/S0140‐6736(12)61080‐0. Epub 2012 Jul 23. 
23. Investigator’s Brochure, Global Alliance for TB Drug Development, PA‐824, Version 15, 31 January 
2013. 
24. Stover, C. K., P. Warrener, D. R. VanDevanter, et al. 2000. A small‐molecule nitroimidazopyran 
drug candidate for the treatment of tuberculosis. Nature 405:962–966. 
25. Anne J. Lenaerts, Veronica Gruppo, Karen S. Marietta, Christine M. Johnson, Diane K. Driscoll, 
Nicholas M. Tompkins, Jerry D. Rose, Robert C. Reynolds, and Ian M. Orme. 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 June; 49(6): 2294–2301. 
26. Baohong PI, Lounis N, Maslo C, Truffot‐Pernot C, Bonnafous P, Grosset J.  In vitro and in vivo 
activities 
of 
moxifloxacin 
and 
clinafloxacin 
against 
Mycobacterium 
tuberculosis. 
Antimicrob.Agents Chemother. 1998; 42(8):2066‐9. 
27. Miyazaki E, Miyazaki M, Chen JM, Chaisson RE, Bishai WR. Moxifloxacin (BAY12‐8039), a new 8‐
methoxyquinolone, is active in a mouse model of tuberculosis. Antimicrob. Agents Chemother. 
1999; 43(1):85‐9. 
28. Nuermberger EL, Yoshimatsu T, Tyagi S, O'Brien RJ, Vernon AN, Chaisson RE et al. Moxifloxacin‐
containing  regimen  greatly  reduces  time  to  culture  conversion  in  murine  tuberculosis. 
Am.J.Respir.Crit.Care Med. 2003; 169:421‐6. 
29. O'Brien RJ. Scientific blueprint for tuberculosis drug development. Tuberculosis 2001; 81(S1):19‐
45. 
30. Gosling RD, Uiso LO, Sam NE, Bongard E, Kanduma EG, Nyindo M et al. The bactericidal activity 
of moxifloxacin in patients with pulmonary tuberculosis. Am J Respir Crit Care Med 2003; 168 
(11):1342‐5. 
31. Pletz MWR, De Roux A, Roth A et al.  Early Bactericidal Activity of Moxifloxacin in Treatment of 
Pulmonary  Tuberculosis:  a  Prospective,  Randomized  Study.    Antimicrob.  Agents  Chemother 
2004; 48 (3); 780‐2. 
32. Burman W, Goldberg S, Johnson JL, et al.  Moxifloxacin versus ethambutol in the first 2 months 
of treatment for pulmonary tuberculosis.  Am J Respir Crit Care Med 2006; 174: 331‐38. 
33. Rustomjee R, Lienhardt C, Kanyok T et al.  Gatifloxacin for TB (OFLOTUB) study team. A phase II 
study  of  the  sterilizing  activities  of  ofloxacin,  gatifloxacin  and  moxifloxacin  in  pulmonary 
tuberculosis.  Int J Tuberc Lung Dis 2008; 12:128‐38. 
34. Conde MB, Efron A, Loredo C et al.  Moxifloxacin versus ethambutol in the initial treatment of 
tuberculosis: a double‐blind, randomized, controlled phase II trial.  Lancet 2009; 373: 1183‐89. 


Global Alliance for TB Drug Development 
Protocol Number: NC‐005‐(J‐M‐Pa‐Z) 
Working Protocol Version: 1.1 (Final) 
Protocol Date: 19 September 2014 
 
 
 
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35. Dorman  SE,  Johnson  JL,  Goldberg  S,  et  al.    Substitution  of  Moxifloxacin  for  Isoniazid  during 
Intensive Phase Treatment of Pulmonary Tuberculosis.  Am J Respir Crit Care Med 2009; 180: 
273‐80. 
36. Investigator’s Brochure, Bayer HealthCare AG, moxifloxacin, Version 14, 01 Oct2011. 
37. Package Insert, Moxifloxacin, Macleods Pharmaceuticals Ltd, 01/2014, Version 0.1. 
38. Zhang Y and Mitchison D.  The curious characteristics of pyrazinamide: a review.  Int J Tuberc 
Lung Dis; 7 (1): 6‐21. 
39. Rokeya  Tasneen,  Sandeep  Tyagi,  Kathy  Williams,  Jacques  Grosset,  and  Eric  Nuermberger 
Enhanced Bactericidal Activity of Rifampin and/or Pyrazinamide When Combined with PA‐824 in 
a Murine Model of Tuberculosis.  Antimicrob Agents Chemother 2008 Oct; 52(10): 3664–8. 
40. Package Insert, Rifampicin/Isoniazid/Pyrazinamide/Ethambutol, Macleods Pharmaceuticals Ltd., 
September 2011. 
41. Botha FJH, Sirgel FA, Parkin DP, van de Wall BW, Donald PR, Mitchison DA.  Early bactericidal 
activity  of  ethambutol,  pyrazinamide  and  the  fixed  combination  of  isoniazid,  rifampicin  and 
pyrazinamide (RIFATER) in patients with pulmonary tuberculosis.  South African Medical J 1996; 
86: 155‐158. 
42. Package Insert, Pyrazinamide, Macleods Pharmaceuticals Ltd, November 2012.  
43. GlaxoSmithKline.  Study  Report.  Technical  Report  no.  2011N119717_01.  Model‐based 
assessment of the feasibility of a 1500 mg fixed dose regimen of pyrazinamide and its impact on 
systemic drug exposure and liver safety in patients with tuberculosis. 2011. 
44. Oxford Textbook of Palliative Medicine, Oxford University Press.  1993; 109. 
 
 


Global Alliance for TB Drug Development 
Protocol Number: NC‐005‐(J‐M‐Pa‐Z) 
Working Protocol Version: 1.1 (Final) 
Protocol Date: 19 September 2014 
 
  
TMP02‐B V1.0  
 
   
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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 
exact figure/100/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. 
 
 


Global Alliance for TB Drug Development 
Protocol Number: NC‐005‐(J‐M‐Pa‐Z) 
Working Protocol Version: 1.1 (Final) 
Protocol Date: 19 September 2014 
 
 
 
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APPENDIX 2 DIVISION OF MICROBIOLOGY AND INFECTIOUS DISEASES (DMID) ADULT 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 AIDS, NCI’s Common Toxicity Criteria (CTC), 
and World Health Organization (WHO)) have been adapted for use by the Division of Microbiology and 
Infectious Diseases (DMID) and modified to better meet the needs of patients 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. 
 


Global Alliance for TB Drug Development 
Protocol Number: NC‐005‐(J‐M‐Pa‐Z) 
Working Protocol Version: 1.1 (Final) 
Protocol Date: 19 September 2014 
 
 
 
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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 %
 
 


Global Alliance for TB Drug Development 
Protocol Number: NC‐005‐(J‐M‐Pa‐Z) 
Working Protocol Version: 1.1 (Final) 
Protocol Date: 19 September 2014 
 
 
 
TMP02‐A V1.0 
 
 
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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 
(nonfasting  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 
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 
 


Global Alliance for TB Drug Development 
Protocol Number: NC‐005‐(J‐M‐Pa‐Z) 
Working Protocol Version: 1.1 (Final) 
Protocol Date: 19 September 2014 
 
 
 
TMP02‐A V1.0 
 
 
Page 104 of 112  Confidential 
 
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 
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 
 
 
 


Global Alliance for TB Drug Development 
Protocol Number: NC‐005‐(J‐M‐Pa‐Z) 
Working Protocol Version: 1.1 (Final) 
Protocol Date: 19 September 2014 
 
 
 
TMP02‐A V1.0 
 
 
Page 105 of 112  Confidential 
 
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 
 
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 
 
 


Global Alliance for TB Drug Development 
Protocol Number: NC‐005‐(J‐M‐Pa‐Z) 
Working Protocol Version: 1.1 (Final) 
Protocol Date: 19 September 2014 
 
 
 
TMP02‐A V1.0 
 
 
Page 106 of 112  Confidential 
 
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 
 
 


Global Alliance for TB Drug Development 
Protocol Number: NC‐005‐(J‐M‐Pa‐Z) 
Working Protocol Version: 1.1 (Final) 
Protocol Date: 19 September 2014 
 
 
 
TMP02‐A V1.0 
 
 
Page 107 of 112  Confidential 
 
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 
 
 


Global Alliance for TB Drug Development 
Protocol Number: NC‐005‐(J‐M‐Pa‐Z) 
Working Protocol Version: 1.1 (Final) 
Protocol Date: 19 September 2014 
 
 
 
TMP02‐A V1.0 
 
 
Page 108 of 112  Confidential 
 
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
 
Rash at Injection Site 
< 15mm  
15‐30 mm
>30mm
 
Pruritus 
slight itching at 
injection site 
moderate itching at 
injection extremity 
itching over entire 
body 
 
 
 


Global Alliance for TB Drug Development 
Protocol Number: NC‐005‐(J‐M‐Pa‐Z) 
Working Protocol Version: 1.1 (Final) 
Protocol Date: 19 September 2014 
 
 
 
TMP02‐A V1.0 
 
 
Page 109 of 112  Confidential 
 
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 
 
 
 
 


Global Alliance for TB Drug Development 
Protocol Number: NC‐005‐(J‐M‐Pa‐Z) 
Working Protocol Version: 1.1 (Final) 
Protocol Date: 19 September 2014 
 
 
 
TMP02‐A V1.0 
 
 
Page 110 of 112  Confidential 
 
APPENDIX 3 CARDIOVASCULAR SAFETY 
ECG 
All important abnormalities from the ECG readings will be reported. 
The  percentage  of  patients  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 
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 


Global Alliance for TB Drug Development 
Protocol Number: NC‐005‐(J‐M‐Pa‐Z) 
Working Protocol Version: 1.1 (Final) 
Protocol Date: 19 September 2014 
 
 
 
TMP02‐A V1.0 
 
 
Page 111 of 112  Confidential 
 
APPENDIX 4 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. 
 
 


Global Alliance for TB Drug Development 
Protocol Number: NC‐005‐(J‐M‐Pa‐Z) 
Working Protocol Version: 1.1 (Final) 
Protocol Date: 19 September 2014 
 
 
 
TMP02‐A V1.0 
 
 
Page 112 of 112  Confidential 
 
APPENDIX 5 TUBERCULOSIS SYMPTOM PROFILE (Version 3) 
 
The questionnaire asks about symptoms that patients with tuberculosis may or may not experience. 
Please read each symptom carefully to the patient and provide them time to think about their experience 
during the past 7 days before you mark their response below. Tick () only one box for each symptom. 
 
If they did not experience the symptoms during the past 7 days, please tick () “None” for that 
symptom. 
 
If they did experience the symptom during the last 7 days, please tick () whether the intensity of the 
symptom they experienced was “mild”, “moderate”, or “severe”. 
 
TB Symptom 
Rate the patient’s experience of each symptom during the past 7 days 
Feeling feverish 
□ None 
□ Mild 
□ Moderate 
□ Severe 
Feeling chills 
□ None 
□ Mild 
□ Moderate 
□ Severe 
Excessive sweating 
□ None 
□ Mild 
□ Moderate 
□ Severe 
Shortness of breath 
□ None 
□ Mild 
□ Moderate 
□ Severe 
Chest pain 
□ None 
□ Mild 
□ Moderate 
□ Severe 
Feeling unwell 
□ None 
□ Mild 
□ Moderate 
□ Severe 
Tiredness/weakness 
□ None 
□ Mild 
□ Moderate 
□ Severe 
Cough 
□ None 
□ Mild 
□ Moderate 
□ Severe 
Coughing up mucus 
□ None 
□ Mild 
□ Moderate 
□ Severe 
Coughing up blood 
□ None 
□ Mild 
□ Moderate 
□ Severe 
 
During the past 7 days, how would the patient rate the quality of their appetite? 
 
 
 
□ Good  
□ Fair   
 
□ Poor 
Approved, Issued date: 09‐Apr‐2012: adopted by Global Alliance for TB Drug Development 
 
Completed by: ______________________________ 
Date completed: _______________ 
 

SAP_001.pdf: 
 
 
 
NC-005-(J-M-PA-Z) 
Page 1 of 72 
 
Document: 
20161214 NC-005-(J-M-PA-Z) SAP V2.0.docx 
Author: 
Divan Burger and Lucia Mans 
Version Number: 2.0 
Version Date: 
14DEC2016 
Template No: CS_TP_BS016 – Revision 3 
Reference: CS_WI_BS005
Effective Date: 01MAY2012 
 
STATISTICAL ANALYSIS PLAN 
NC-005-(J-M-PA-Z) 
 
A PHASE 2 OPEN-LABEL PARTIALLY RANDOMIZED TRIAL TO 
EVALUATE THE EFFICACY, SAFETY AND TOLERABILITY OF 
COMBINATIONS OF BEDAQUILINE, MOXIFLOXACIN, PA-824 AND 
PYRAZINAMIDE DURING 8 WEEKS OF TREATMENT IN ADULT 
SUBJECTS WITH NEWLY DIAGNOSED DRUG-SENSITIVE OR MULTI 
DRUG-RESISTANT, SMEAR-POSITIVE PULMONARY TUBERCULOSIS 
 
AUTHOR: DIVAN BURGER AND LUCIA MANS 
 
VERSION NUMBER AND DATE: VERSION 2.0, 
14DEC2016 


 
 
 
NC-005-(J-M-PA-Z) 
Page 2 of 72 
 
Document: 
20161214 NC-005-(J-M-PA-Z) SAP V2.0.docx 
Author: 
Divan Burger and Lucia Mans 
Version Number: 2.0 
Version Date: 
14DEC2016 
Template No: CS_TP_BS016 – Revision 3 
Reference: CS_WI_BS005
Effective Date: 01MAY2012 
 
Statistical Analysis Plan (SAP) Signature Page 
 
Name 
Signature 
Date 
Author: 
Divan Burger, PhD 
 
 
Position: 
Senior Biostatistician 
Company: 
Quintiles, South Africa 
 
 
Name 
Signature 
Date 
Author: 
Lucia Mans, BSc (Hons) 
 
 
Position: 
Biostatistician 1 
Company: 
Quintiles, South Africa 
The signatures below indicate review and approval of the proposed analysis and presentation of data as planned for protocol 
NC-005-(J-M-PA-Z) Version 1.0, dated 31 January 2014, including final protocol amendment 01, dated 19 September 2014 
(incorporated into the working protocol Version 1.1, dated 19 September 2014). 
This version of the statistical analysis plan (SAP) was approved by the undersigned. 
 
Name 
Signature 
Date 
Approved By: 
Robert Schall, PhD 
 
 
Position: 
Senior Director, Biostatistics 
Company: 
Quintiles, South Africa 
 
Approved By: 
Carl Mendel 
 
 
Position: 
Study Physician 
Company: 
Global Alliance for TB Drug Development 
 
Approved By: 
Almari Conradie, MPh 
 
 
Position: 
Global Clinical Project Manager 


 
 
 
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Company: 
Global Alliance for TB Drug Development 


 
 
 
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Version Number: 2.0 
Version Date: 
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Reference: CS_WI_BS005
Effective Date: 01MAY2012 
 
Modification History 
Unique 
Identifier for 
this Version 
Date of 
Document 
Version 
Authors 
Significant Changes from Previous Authorized Version 
1.0 
22FEB2016 
Divan Burger & 
Lucia Mans 
Not applicable. 
2.0 
14DEC2016 
Divan Burger & 
Lucia Mans 
 
All wording related to “topline” updated to “snapshot”. 
 
Section 1 (Introduction) – Phrase added to state that the pharmacokinetic 
(PK) analysis will be described in a separate statistical analysis plan (SAP). 
 
Section 4.3 (Final Analysis) – Paragraph added to state the minimum 
inhibitory concentration (MIC) data will form part of an appendix to the 
“final analysis”. 
 
Section 6.3 (End of Treatment) – Definition for end of treatment 
measurement added. 
 
Section 6.4 (End of Study) – Definition for end of study measurement added. 
 
Section 6.5 (Treatment-Emergent Incidences) – Definition of treatment-
emergent updated to include measurement up to and including the Day 70 
Follow-up visit. Also, definition of post-treatment incidences during the Day 
70-140 Follow-up period updated to start after the Day 70 Follow-up 
measurement. 
 
Section 6.10 (Software Version) – R Version 3.0.2 or higher added as 
software used. Removed software used for PK analysis as this is now part of 
the separate PK SAP. 
 
Section 9 (Disposition and Withdrawals) – Removed the paragraph on the 
randomization and visit dates listings, as these will not be presented 
separately anymore. Also, paragraph on inclusion and exclusion criteria was 
removed as this will not be presented in a data listing anymore. Text was 
added to indicate that protocol deviations during study conduct will be 
displayed. Updated text for derivations for detail on day 140 follow-up. 
 
Section 10 (Demographics and Other Baseline Characteristics) – Derivation 
for tuberculosis (TB) duration updated to be presented in days. 
 
Section 
11 
(Medical 
and 
Treatment 
History 
[Excluding 
Human 
Immunodeficiency Virus {HIV}, Tuberculosis {TB} and Ophthalmology 


 
 
 
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Unique 
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Document 
Version 
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Significant Changes from Previous Authorized Version 
History]) – Data listing will be presented for all patients screened, not just all 
patients randomized/assigned to study drug. 
 
Section 12 (Concomitant Medications and Procedures) – Definition for 
concomitant medications added. 
 
Section 15 (Efficacy Analyses) - Cultures collected 60 days after the first 
study drug administration will be excluded from the statistical analysis of 
efficacy data. 
 
Section 15.1.3 (Primary Efficacy Analysis) - For the calculation of the 
precision matrix of the Wishart distribution, the linear mixed effects 
regression model (incorporating censoring) will be fitted using the “lmec” 
library of the R project. 
 
Section 15.2 (Secondary Efficacy Variables) - Additional “proportions” 
analyses of liquid and solid media sputum culture conversion have been 
included for coached spot sputum samples. 
 
Section 15.2 (Secondary Efficacy Variables) – Removed inferences on v50j. 
 
Section 15.1.3 (Primary Efficacy Analysis) - Minor typographical corrections 
to the specification of truncated normal prior distributions have been made. 
 
Section 7.3 (Examination of Subgroups) - Additional subgroup analyses of 
bactericidal activity by laboratory have been included. 
 
Section 15.2.3 (Secondary, Exploratory and Sensitivity Efficacy Analyses) - 
The analyses of log(TTP) and log(CFU) count collected from coached spot 
sputum samples will include the sensitvity analyses (specification of the 
Student t distribution). 
 
Section 15.2.3 (Secondary, Exploratory and Sensitivity Efficacy Analyses) - 
Inferences on the differences of Kaplan-Meier estimates at the end of the 
treatment period (Day 56) have been included. 
 
Section 15.2.3 (Secondary, Exploratory and Sensitivity Efficacy Analyses) - 
As a sensitivity analysis for time to sputum culture conversion of overnight 
sputum samples, the coached spot sputum samples will be used if results of 
the overnight sputum samples are not available. 
 
Section 15.2.3 (Secondary, Exploratory and Sensitivity Efficacy Analyses) – 


 
 
 
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Unique 
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Significant Changes from Previous Authorized Version 
Kaplan-Meier analysis: Patients’ time to sputum culture conversion or 
censoring on or after Day 53 will be considered as events which occurred on 
Day 56. 
 
Section 15.2.3 (Secondary, Exploratory and Sensitivity Efficacy Analyses) - 
Patients’ time to sputum culture conversion or censoring on or after Day 53 
will be considered as events which occurred on Day 56. 
 
Section 15.2.3 (Secondary, Exploratory and Sensitivity Efficacy Analyses) - 
Kappa coefficients applicable to the “agreement” analysis will no longer be 
“weighted”. 
 
Section 15.3 (Tuberculosis Symptoms and Weight) – Updated text to indicate 
that a shift table and stacked bar chart will be displayed for tuberculosis 
symptoms. Replaced box-and-whisker plot for weight with a mean weight 
over time line plot. 
 
Section 17.2 (Adverse Events [AEs]) – Updated definitions of treatment-
emergent adverse events and post-treatment adverse events during the Day 
70-140/Follow-up period. All Standardized MedDRA query tables removed.  
 
Section 17.3 (Deaths) – Section added to describe the analysis of deaths 
(table and listing). All further sections were renumbered to make place for the 
deaths section. 
 
Section 17.4 (Laboratory Tests) – Text on worst case for laboratory 
classifications removed, as worst case tables will not be displayed. Text was 
added to indicate that a stacked bar chart for classifications according to 
laboratory reference ranges will be displayed. Liver enzyme profile plots for 
patients who died and patients with serious TEAEs removed. 
 
Section 17.7 (Physical Examination) – Analysis text on physical examination 
removed. 
 
Section 17.8 (Ophthalmological Examination) – Analysis text updated to 
indicate that decreases and increases from baseline will be displayed for the 
near and distance visual acuity test. A slit lamp grading of > 0.0 will be 
displayed in a data listing. 
 
Updated signature page from Stephen Murray to Carl Mendel. 


 
 
 
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Table of Contents 
Page: 
Statistical Analysis Plan (SAP) Signature Page ................................................................................2 
Modification History ............................................................................................................................4 
Table of Contents .................................................................................................................................7 
1 
Introduction ...............................................................................................................................10 
2 
Study Objectives........................................................................................................................10 
3 
Study Design ..............................................................................................................................11 
3.1 
General Description ..................................................................................................................... 11 
3.2 
Schedule of Events ........................................................................................................................ 13 
3.3 
Changes to Analysis from Protocol ............................................................................................. 13 
4 
Planned Analyses ......................................................................................................................13 
4.1 
Data Safety and Monitoring Committee (DSMC) Analysis ...................................................... 14 
4.2 
Snapshot Analysis ......................................................................................................................... 14 
4.3 
Final Analysis ................................................................................................................................ 15 
4.4 
Survival Follow-Up Analysis ....................................................................................................... 15 
5 
Analysis Populations .................................................................................................................16 
5.1 
All Patients Screened .................................................................................................................... 16 
5.2 
All Patients Randomized/Assigned to Study Drug .................................................................... 17 
5.3 
Safety Analysis Population .......................................................................................................... 17 
5.4 
Modified Intention-to-Treat (mITT) Analysis Population ....................................................... 18 
5.5 
Multi-Drug Resistant Tuberculosis (MDR-TB) Exploratory Analysis Population ................ 18 
6 
General Considerations ............................................................................................................18 
6.1 
Reference Start Date and Study Day .......................................................................................... 18 
6.2 
Baseline .......................................................................................................................................... 19 
6.3 
End of Treatment ......................................................................................................................... 19 
6.4 
End of Study ................................................................................................................................. 19 
6.5 
Treatment-Emergent Incidences ................................................................................................. 20 
6.6 
Retests, Unscheduled Visits and Early Termination Data ........................................................ 20 
6.7 
Windowing Conventions .............................................................................................................. 21 
6.8 
Statistical Tests ............................................................................................................................. 21 
6.9 
Common Calculations .................................................................................................................. 21 
6.10 Software Version .......................................................................................................................... 21 
7 
Statistical Considerations .........................................................................................................22 
7.1 
Multicenter Studies ...................................................................................................................... 22 
7.2 
Missing Data ................................................................................................................................. 22 
7.3 
Examination of Subgroups .......................................................................................................... 22 
8 
Output Presentations ................................................................................................................22 
9 
Disposition and Withdrawals ...................................................................................................23 


 
 
 
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9.1 
Derivations .................................................................................................................................... 23 
9.2 
Analysis ......................................................................................................................................... 23 
10 
Demographic and Other Baseline Characteristics .................................................................24 
10.1 Derivations .................................................................................................................................... 24 
10.2 Analysis ......................................................................................................................................... 25 
11 
Medical and Treatment History (Excluding Human Immunodeficiency Virus [HIV], 
Tuberculosis [TB] and Ophthalmology History) ...................................................................27 
11.1 Derivations .................................................................................................................................... 27 
11.2 Analysis ......................................................................................................................................... 27 
12 
Concomitant Medications and Procedures .............................................................................27 
12.1 Derivations .................................................................................................................................... 27 
12.2 Analysis ......................................................................................................................................... 28 
13 
Study Drug Exposure ...............................................................................................................28 
13.1 Derivations .................................................................................................................................... 28 
13.2 Analysis ......................................................................................................................................... 29 
14 
Study Drug Compliance ...........................................................................................................29 
14.1 Derivations .................................................................................................................................... 29 
14.2 Analysis ......................................................................................................................................... 30 
15 
Efficacy Analysis .......................................................................................................................30 
15.1 Primary Efficacy Variable ........................................................................................................... 30 
15.1.1 Derivations 
30 
15.1.2 Efficacy Endpoints 
32 
15.1.3 Primary Efficacy Analysis 
33 
15.1.4 Secondary Efficacy Analyses 
37 
15.1.5 Exploratory Efficacy Analyses 
38 
15.1.6 Sensitivity Efficacy Analyses 
39 
15.2 Secondary Efficacy Variables ...................................................................................................... 40 
15.2.1 Derivations 
40 
15.2.1.1 
CFU Count in Solid Media: “7H11S” Overnight Sputum Samples ...................................................................... 40 
15.2.1.2 
TTP in Liquid Media: Coached Spot Sputum Samples .......................................................................................... 43 
15.2.1.3 
CFU Count in Solid Media: “7H11S+C” Overnight Sputum Samples ................................................................. 43 
15.2.1.4 
CFU Count in Solid Media: “7H11S” Coached Spot Sputum Samples ................................................................ 43 
15.2.1.5 
CFU Count in Solid Media: “7H11S+C” Coached Spot Sputum Samples ........................................................... 43 
15.2.2 Efficacy Endpoints 
44 
15.2.2.1 
Rate of Change in CFU Count: “7H11S” Overnight Sputum Samples ................................................................. 44 
15.2.2.2 
Rate of Change in TTP: Coached Spot Sputum Samples....................................................................................... 44 
15.2.2.3 
Rate of Change in CFU Count: “7H11S+C” Overnight Sputum Samples............................................................ 45 
15.2.2.4 
Rate of Change in CFU Count: “7H11S” Coached Sputum Samples ................................................................... 45 
15.2.2.5 
Rate of Change in CFU Count: “7H11S+C” Coached Sputum Samples.............................................................. 45 
15.2.2.6 
Time to Liquid Media Sputum Culture Conversion ............................................................................................... 46 
15.2.2.7 
Proportion of Patients with Liquid Media Sputum Culture Conversion ................................................................ 46 
15.2.2.8 
Time to Solid Media Sputum Culture Conversion ................................................................................................. 46 
15.2.2.9 
Proportion of Patients with Solid Media Sputum Culture Conversion .................................................................. 47 
15.2.2.10 Correlation and Agreement Between Overnight and Coached Spot Sputum Samples ........................................... 47 
15.2.3 Secondary, Exploratory and Sensitivity Efficacy Analyses 
48 
15.3 Tuberculosis Symptoms and Weight .......................................................................................... 51 
15.3.1 Derivations 
52 


 
 
 
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15.3.2 Analysis 
52 
16 
Mycobacteriologic Characteristics ..........................................................................................52 
16.1 Derivations .................................................................................................................................... 52 
16.2 Analysis ......................................................................................................................................... 53 
17 
Safety Outcomes ........................................................................................................................53 
17.1 Survival Follow-Up....................................................................................................................... 53 
17.2 Adverse Events (AEs) ................................................................................................................... 53 
17.2.1 Derivations 
53 
17.2.2 Analysis 
55 
17.3 Deaths ............................................................................................................................................ 56 
17.3.1 Derivations 
56 
17.3.2 Analysis 
56 
17.4 Laboratory Tests .......................................................................................................................... 56 
17.4.1 Derivations 
56 
17.4.2 Analysis 
57 
17.5 Electrocardiogram (ECG) Parameters ....................................................................................... 58 
17.5.1 Derivations 
58 
17.5.2 Analysis 
59 
17.6 Vital Signs ..................................................................................................................................... 60 
17.6.1 Derivations 
60 
17.6.2 Analysis 
60 
17.7 Physical Examination ................................................................................................................... 61 
17.7.1 Derivations 
61 
17.7.2 Analysis 
61 
17.8 Ophthalmological Examination .................................................................................................. 61 
17.8.1 Derivations 
61 
17.8.2 Analysis 
61 
17.9 Other Assessments ........................................................................................................................ 62 
18 
List of References ......................................................................................................................62 
Appendix 1: Rationale for Correction Factors ...............................................................................63 
Appendix 2: Programming Conventions for Tables, Data Listings and Figures (TLFs) ............65 
Paper Size, Orientation and Margins ................................................................................................... 65 
Fonts 65 
Header Information ............................................................................................................................... 66 
Table and Data Listing Table, Listing and Figure (TLF) Conventions ............................................ 67 
Figure Output Conventions ................................................................................................................... 69 
Dates and Times ..................................................................................................................................... 69 
Spelling Format ...................................................................................................................................... 69 
Presentation of Treatment Groups ....................................................................................................... 69 
Presentation of Visits ............................................................................................................................. 69 
Appendix 3: Partial Adverse Event (AE) Date Conventions .........................................................71 
Algorithm for Treatment-Emergent Adverse Events (TEAEs) ......................................................... 71 
 


 
 
 
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1 
Introduction 
This document describes the rules and conventions to be used in the presentation and analysis of 
efficacy, safety and mycobacteriology characterization data for protocol NC-005-(J-M-Pa-Z). It 
describes the data to be summarized and analyzed, including specifics of the statistical analyses to 
be performed. 
This statistical analysis plan (SAP) is based on Working Protocol Version 1.1, dated 
19 September 2014. 
The pharmacokinetic (PK) analysis and analysis on MIC data of this study will be described in a 
separate SAP. 
2 
Study Objectives 
The primary objective of this study is to evaluate the bactericidal activity, safety, and tolerability of 
bedaquiline, PA-824 and pyrazinamide in drug-sensitive (DS) tuberculosis (TB) and bedaquiline, 
moxifloxacin, PA-824 and pyrazinamide in multi-drug resistant (MDR) TB (MDR-TB).  
Secondary objectives include evaluating the bactericidal activity, safety and tolerability of 
bedaquiline dosed using two different schemes (400 mg daily for two weeks followed by 200 mg 
three times a week [loading dose/t.i.w] and 200 mg daily [200 mg]). Additional key secondary 
objectives are to evaluate the population PK characteristics of bedaquiline, moxifloxacin, PA-824 
and pyrazinamide when administered as a part of 3- and 4-drug regimens in adults with TB, and 
investigation of the methodology of sputum sampling by comparing colony forming unit (CFU) 
count and time to positivity (TTP) in liquid culture (MGIT), quantified from both overnight and 
coached spot sputum samples. 
The study endpoints are listed in Section 4.2 of the protocol. 


 
 
 
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3 
Study Design 
3.1 
General Description 
This is a Phase 2, multi-center, open-label, partially randomized study conducted in four parallel 
treatment groups. The study will be performed at multiple sites globally. 
Drug-Sensitive (DS) Tuberculosis (TB) (DS-TB): 
A total of 180 eligible patients who meet all of the inclusion criteria and none of the exclusion 
criteria, aged between 18 and 75 years (inclusive), with newly diagnosed, smear-positive DS 
pulmonary TB will be randomized to one of three treatment groups: 
 J(loading dose/t.i.w.)PaZ: Bedaquiline 400 mg once daily from Day 1 up to Day 14, 200 mg three 
times per week from Day 15 up to Day 56; plus PA‐824 200 mg once daily from Day 1 up to 
Day 56; plus pyrazinamide 1500 mg once daily from Day 1 to Day 56. 
 J(200 mg)PaZ: Bedaquiline 200 mg once daily from Day 1 up to Day 56; plus PA‐824 200 mg 
once daily from Day 1 up to Day 56; plus pyrazinamide 1500 mg once daily from Day 1 to 
Day 56. 
 HRZE: Isoniazid 75 mg, rifampicin 150 mg, pyrazinamide 400 mg and ethambutol 275 mg 
from Day 1 up to Day 56. 
The HRZE treatment group is included as a control for the DS treatment groups. Additionally, it is 
included as a control for the quantitative mycobateriology. 


 
 
 
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Multi-Drug Resistant (MDR) Tuberculosis (TB) (MDR-TB): 
Up to 60 eligible patients who meet all of the inclusion criteria and none of the exclusion criteria, 
aged between 18 and 75 years (inclusive), with newly diagnosed, smear-positive MDR pulmonary 
TB will be assigned to the following treatment group: J(200 mg)MPaZMDR: Bedaquiline 200 mg once 
daily from Day 1 up to Day 56; plus moxifloxacin 400 mg once daily from Day 1 up to Day 56; plus 
PA‐824 200 mg once daily from Day 1 up to Day 56; plus pyrazinamide 1500 mg once daily from 
Day 1 to Day 56. 
The number of patients to be randomized/assigned to each treatment group is presented below. 
Treatment Groups 
 
Treatment Group 
Patient Population 
Number of Patients 
1. 
J(loading dose/t.i.w.)PaZ 
DS-TB 
60 
2. 
J(200 mg)PaZ 
DS-TB 
60 
3. 
HRZE 
DS-TB 
60 
4. 
J(200 mg)MPaZMDR 
MDR-TB 
Up to 60 
DS: Drug-sensitive. MDR: Multi-drug resistant. TB: Tuberculosis. 
A schematic of study design is presented below. 
Fifteen (15) patients from each of the treatment groups will be included in a PK sub-study, for 
whom intense-sampling will be performed on Day 14 and Day 56. 
 
 


 
 
 
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Study Schematic 
 
3.2 
Schedule of Events 
The schedule of events can be found in Section 1.2 of the protocol. 
3.3 
Changes to Analysis from Protocol 
There are no changes to analyses from the protocol. 
4 
Planned Analyses 
The following analyses will be performed for this study: 
 Data Safety and Monitoring Committee (DSMC) analysis. 
 Snapshot analysis. 
 Final analysis. 
 Survival follow-up analysis. 


 
 
 
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4.1 
Data Safety and Monitoring Committee (DSMC) Analysis 
A DSMC analysis will be performed by Quintiles Biostatistics after 10 MDR patients have 
completed 2 weeks of treatment. 
A DSMC analysis will be performed by Quintiles Biostatistics once 33% of the patients have 
completed the 8-week treatment period.  
The DSMC analyses will be described in the DSMC charter and separate output templates. 
4.2 
Snapshot Analysis  
A snapshot analysis, based on the analysis of a subset of efficacy, safety (including 
electrocardiogram [ECG]), pncA sequencing and mycobacteriology characterization endpoints, will 
be performed after the last DS-TB patient has completed the 8-week treatment period and 
Day 70/Follow-up, and the safety (including ECG), TTP and CFU are available. Adverse events 
(AEs) and serious adverse events (SAE) will also be analyzed for the snapshot analysis. 
The database snapshot will occur after the last DS-TB patient has completed the 8-week treatment 
period and Day 70/Follow-up. The aforementioned data (excluding ophthalmology, drug 
susceptibility, minimum inhibitory concentration [MIC] data, and final analysis AEs, SAEs) will be 
soft locked for the database snapshot. The ophthalmology, drug susceptibility data and final analysis 
AEs, SAEs and concomitant medications, will only be available at the time of final analysis 
database lock, and will therefore not form part for the snapshot analysis. 
The snapshot analysis as described in this SAP, using table, data listing and figure (TLF) shells (to 
be outlined in a separate output templates document), will be performed by Quintiles Biostatistics 
following database snapshot. 


 
 
 
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4.3 
Final Analysis 
The final analysis as described in this SAP, using TLF shells (to be outlined in a separate output 
templates document), will be performed by Quintiles Biostatistics following final analysis database 
lock of data for all patients (DS-TB and MDR-TB). The ophthalmology, drug susceptibility data and 
final analysis AEs, SAEs and concomitant medications, will be completed by the time of final 
analysis database lock, and will therefore only be included in the final analysis.  
Final analysis database lock will occur after completion of the Day 140 follow-up visit, or 12 weeks 
following last study drug administration (and the CFU and TTP data are available), and after the 
ophthalmology, drug susceptibility data and final analysis AEs, SAEs and concomitant medications 
are available. 
PK and MIC data will only be available after final analysis database lock and will therefore form 
part of an appendix to the final analysis. 
Data associated with the survival follow-up analysis (survival follow-up data, AEs, SAEs and 
concomitant medications) will not be included in the final analysis. 
4.4 
Survival Follow-Up Analysis  
The survival follow-up analysis (which will include survival follow-up data, AEs, drug-related 
SAEs and concomitant medications [associated with drug-related SAEs only]) will be included as an 
addendum to the clinical study report (CSR) of the final analysis. Relevant sections of the database 
will accordingly be reopened to include survival follow-up data, AEs, SAEs and concomitant 
medications. The database will accordingly be relocked afterwards. 


 
 
 
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5 
Analysis Populations 
Agreement and authorization of patients included/excluded from each analysis population (for both 
the snapshot and final analysis) will be reached (data review meeting) prior to the database snapshot 
and final analysis database lock, respectively. The criteria defining the various analysis populations 
will be outlined in a separate data review plan. 
Pyrazinamide resistant patients will be excluded from the general efficacy analyses (applicable to 
both DS-TB and MDR-TB patients), except from the exploratory analyses associated with the 
comparison according to pyrazinamide resistant versus sensitive status in MDR-TB patients. 
Note:  Patients’ pyrazinamide susceptibility status at baseline, applicable to the snapshot analysis, 
will be determined using pncA sequencing data only. For the final analysis, both pncA 
sequencing and MGIT data will be used to determine the latter. That is, pncA sequencing 
will be used as the primary determinant, but, should the pncA sequencing data be missing at 
the time of the final analysis, the MGIT data will be used to determine the latter instead.  
For the purpose of analyses based on each of the analysis populations, patients will be classified 
according to actual study drug received, regardless of randomized/assigned study drug.  
Note:  Statistical analyses will not necessarily be performed for all of the below analysis 
populations. Analyses populations applicable to a certain analysis will be mentioned 
explicitly within the particular analysis sections of this document. 
5.1 
All Patients Screened 
This analysis population will include all patients who provided written informed consent for this 
study. 


 
 
 
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Screening failures (i.e. patients not randomized/assigned to study drug) will be included in this 
analysis population. 
The main purpose of this analysis population is to list disposition data of all patients enrolled in the 
study. 
5.2 
All Patients Randomized/Assigned to Study Drug 
This analysis population will include all patients screened that were randomized to study drug (for 
the DS patient population) or assigned to study drug (for the MDR patient population). 
The main purpose of this analysis population is to limit data listings to all patients 
randomized/assigned to study drug (thus excluding those patients who are [1] either screening 
failures or [2] “passed” screening but were not randomized/assigned to study drug). 
5.3 
Safety Analysis Population 
This analysis population will include all patients who were randomized to study drug (for the DS 
patient population) or assigned to study drug (for the MDR patient population) and received at least 
one administration of study drug.  
If there is any doubt whether a patient was treated or not, the patient will be assumed treated for the 
purposes of this analysis.  
The main purpose of this analysis population is to summarize safety data for patients who were, 
during the course of the study, exposed to study drug. 


 
 
 
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5.4 
Modified Intention-to-Treat (mITT) Analysis Population 
This analysis population will contain all patients included in the Safety analysis population for 
whom valid corresponding efficacy data are available. Pyrazinamide resistant patients will be 
excluded from this analysis population (applicable to both DS-TB and MDR-TB patients). 
The main purpose of this analysis population is to summarize efficacy data for patients based on the 
intention-to-treat principle, however modified by excluding those patients for whom no valid 
corresponding data are available, and also excluding those patients who are resistant to 
pyrazinamide. 
5.5 
Multi-Drug 
Resistant 
Tuberculosis 
(MDR-TB) 
Exploratory 
Analysis 
Population 
This analysis population will contain all MDR-TB patients included in the Safety analysis 
population for whom valid corresponding efficacy data are available. Pyrazinamide resistant patients 
will be considered for this analysis population (provided that their pyrazinamide susceptibility status 
at baseline is available). 
The main purpose of this analysis population is to compare efficacy data between pyrazinamide 
sensitive versus pyrazinamide resistant MDR-TB patients. 
6 
General Considerations 
6.1 
Reference Start Date and Study Day 
Study day will be calculated from the reference start date which will be used to present start/stop 
day of assessments and events.  


 
 
 
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The reference start date is defined as the date of first study drug administration: 
 If the date of assessment/event is on or after the reference date then:  
o Study day = (Date of assessment/event – Reference date) + 1. 
 If the date of assessment/event is prior to the reference date then:  
o Study day = (Date of assessment/event – Reference date). 
In the case where the assessment/event date is partial or missing, for which no imputation rules 
apply, study day, and any corresponding durations will be presented as missing in the data listings. 
6.2 
Baseline 
Baseline is defined as the last available observation (scheduled or unscheduled) before the first study 
drug administration. 
For analysis purposes, a separate baseline visit will be presented for each patient, where applicable. 
6.3 
End of Treatment Period 
For the purpose of defining treatment-emergent events the end of treatment visit is defined as the 
last available observation (scheduled or unscheduled) made after the first study drug administration 
up to and including the Day 70 Follow-up visit (or up to and including 14 days after last study drug 
administration for patients not having the Day 70 Follow-up visit). 
6.4 
End of Study 
The end of study visit is defined as the last available observation (scheduled or unscheduled) made 
after the first study drug administration. 
 


 
 
 
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6.5 
Treatment-Emergent Incidences  
A treatment-emergent incidence is defined as any event (scheduled or unscheduled) which started 
after the first study drug administration up to and including the Day 70 Follow-up visit (or up to and 
including 14 days after last study drug administration for patients not having the Day 70 Follow-up 
visit). 
A post-treatment incidence during the Day 70-140/Follow-up period is defined as any event 
(scheduled or unscheduled) which started after the Day 70 follow-up visit up to the last visit, early 
study withdrawal or last contact associated with the Day 140/Follow-up period, as indicated on the 
‘Disposition’ eCRF page, whichever occurs last. 
Events recorded during the survival follow-up period will be reported separately. 
6.6 
Retests, Unscheduled Visits and Early Termination Data 
In general, data recorded at the scheduled visit will be presented for by-visit summaries. 
Unscheduled measurements will not be included in by-visit summaries. Exception: The last 
available unscheduled laboratory assessment corresponding to screening assessments will be used 
for the Day -9 to Day -3 visit of all analyses. Unscheduled visits will be sorted in a chronological 
order, and the associated scheduled visit number will accordingly be provided in the data listings 
(e.g. Visit number X.Y for the Yth unscheduled visit number associated with the Xth scheduled visit 
number). 
In the case of a retest, the last available laboratory assessment will be used for all analyses, 
including identification of markedly abnormal laboratory assessments, regardless of whether the 
laboratory assessment for that particular scheduled visit is available or not. 
In the case of a retest, the last available assessment will be used for all analyses. 


 
 
 
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Data listings will include scheduled, unscheduled and retest data. 
6.7 
Windowing Conventions  
No visit windowing (i.e. remapping of visits based on visit windows, except for unscheduled visits 
associated with the Day -9 to Day -3 visit) will be performed for this study. The assigned scheduled 
visit will be used for by-visit summaries. 
6.8 
Statistical Tests 
The default significance level is set at 5%. All confidence intervals (CIs) (95%) and statistical tests 
will be two-sided, unless otherwise specified. 
No multiplicity adjustments will be done for this study. 
6.9 
Common Calculations 
For quantitative measurements, change from baseline will be calculated as: (Value at Visit X – 
Baseline value). 
For numerical values > 0 where the logarithmic transformation is required, the logarithm value will 
be calculated as: log10(Value). 
6.10 
Software Version 
All analyses will be conducted using SAS® Version 9.4, OpenBUGS Version 3.1.2 (or higher) and 
R Version 3.0.2 (or higher). 


 
 
 
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7 
Statistical Considerations 
7.1 
Multicenter Studies 
This study will be conducted by multiple investigators at multiple sites internationally. 
Randomization to treatment groups is not stratified by country/site, and therefore, all analyses will 
be unstratified. However, subgroup analyses will be included by site (see Section 7.3). 
7.2 
Missing Data 
Missing data will not be imputed for this study, unless otherwise specified.  
7.3 
Examination of Subgroups 
A subset of patients from each treatment group will be included in a PK sub-study. 
Subgroup analyses by site, laboratory, human immunodeficiency virus (HIV) status and absence or 
presence of cavities, will be performed for key efficacy analyses (see Section 15.1.5). 
The CFU and TTP data will be analyzed for patients assigned to J(200 mg)MPaZMDR according to their 
pyrazinamide susceptibility status at baseline (sensitive versus resistant). In addition, the analysis 
will be repeated for patients assigned to HRZE who are mono-resistant to isoniazid according to 
their susceptibility status at baseline. 
8 
Output Presentations 
Appendix 2 contains conventions for presentation of data in TLFs. 
Summary tables will be presented by treatment group, unless otherwise specified. 


 
 
 
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The shells to be provided in the separate output templates document will describe the format and 
content for presentation of TLFs, for the snapshot, final and survival follow-up analyses. The TLFs 
not to be provided for the snapshot analysis will be marked with an asterisk (*). 
All percentages (%) calculated for a specific summary are calculated using the total number of 
patients included in the relevant analysis population with data, as the denominator, unless otherwise 
specified. 
By default, descriptive statistics will include the number of patients (n), mean, standard deviation 
(SD), minimum, median and maximum for quantitative measurements. 
9 
Disposition and Withdrawals 
9.1 
Derivations 
Disposition events of the Day 140 Follow-up period will take into account the last status of the 
patient up until Day 140. This will include the status of patients who withdrew consent before Day 
140, patients who were not required to attend the Day 140 visit (received less than 15 days of 
treatment), patients who withdrew from treatment but continued into follow up, or patients that died 
before the Day 140 visit. 
9.2 
Analysis 
Patient disposition and withdrawals up to Day 140 (obtained from the electronic case report form 
[eCRF] “Subject Disposition Up to D140” panel) will be summarized and presented in data listings 
for all patients screened. 


 
 
 
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Patient disposition and withdrawals for the Survival Follow-Up period (obtained from the electronic 
case report form [eCRF] “Subject Disposition Survival FU” panel) will be summarized and 
presented in data listings for all patients screened for the survival follow-up analysis. 
The number of patients included in the relevant analysis populations, as well as the number of 
patients excluded with reasons for exclusion from the relevant analysis populations and protocol 
violations/deviations, will be summarized for patients randomized/assigned to study drug. Major 
protocol deviations during study conduct will be presented in data listings for all patients 
randomized/assigned to study drug. 
10 
Demographic and Other Baseline Characteristics 
10.1 
Derivations 
Age (Years) and body mass index (BMI) (kg/m2) will be calculated as follows: 
Age (Years) = Floor of ([Date of informed consent – Date of birth]/365.25). 
BMI (kg/m2) = Weight (kg)/([Height {cm}/100]2). 
Human immunodeficiency virus (HIV) duration (Years) will be calculated as follows: 
HIV duration (Years) = Floor of ([Date of first administration of study drug – Date of HIV 
diagnosis]/365.25). 
Tuberculosis (TB) duration (Days) will be calculated as follows: 
TB duration (Days) = Floor of (Date of first administration of study drug – Date of TB 
diagnosis). 


 
 
 
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If the date of birth, HIV or TB diagnosis is partial, then the date of birth, HIV or TB diagnosis will 
be imputed as follows:  
 If the day of birth, HIV or TB diagnosis is missing, then the 15th day of the month will be used 
as the day of birth, HIV or TB diagnosis. 
 If the month of birth, HIV or TB diagnosis is missing, then 02JUL will be used as the day and 
month of birth, HIV or TB diagnosis (i.e. the 183rd day of the year). 
The imputed date of birth, HIV or TB diagnosis will not be presented in the data listings and will 
only be used for the calculation of age (Years), HIV duration (Years) and TB duration (Days).  
10.2 
Analysis 
Demographic data and other baseline characteristics will be summarized for the Safety and mITT 
analysis populations, and presented in data listings for all patients screened. Summary tables will 
only be displayed if at least 10 percent of patients fall within the specific analysis population. 
The following demographic and other baseline characteristics will be summarized and presented in 
data listings: 
 Age (Years). 
 Gender. 
 Race. 
 Site. 
 HIV status: 
o Negative. 
o Positive. 
 HIV duration (Years). 


 
 
 
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 Antiretrovirals (ARVs). 
 TB type. 
 TB duration (Days). 
 Karnofsky performance score (%). 
 Ophthalmology history: 
o Personal history of vision or eye disorders. 
o Immediate family history of cataracts. 
o Personal history of prior eye surgery. 
o Eye trauma (right and left eye). 
 Height (cm). 
 Weight (kg). 
 BMI (kg/m2). 
 Chest X-ray: 
o Normal. 
o Abnormal. 
o Cavities: 
 No cavities. 
 Unilateral. 
 Bilateral. 
Tuberculosis (TB) and HIV history, and TB symptoms, will be presented in data listings. 


 
 
 
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11 
Medical and Treatment History (Excluding Human Immunodeficiency 
Virus [HIV], Tuberculosis [TB] and Ophthalmology History) 
11.1 
Derivations 
Medical history (excluding HIV, TB and ophthalmology history) will be coded using Medical 
Dictionary for Regulatory Activities (MedDRA) central coding dictionary, Version 17.1. 
Uncoded medical history events will be presented as “uncoded”. 
11.2 
Analysis 
Medical history (excluding HIV, TB and ophthalmology history) will be summarized by MedDRA 
System Organ Class (SOC) and Preferred Term (PT) for the Safety analysis population and 
presented in data listings for all patients screened. 
12 
Concomitant Medications and Procedures 
12.1 
Derivations 
Concomitant medications will be coded using World Health Organization-Drug Dictionary 
(WHO-DD) 01JUN2014_CLASSIC, whereas procedures will be coded using MedDRA central 
coding dictionary, Version 17.1. Preferred Anatomical Therapeutic Chemical (ATC) coding will be 
applied to medications for this study. 
Uncoded concomitant medications and procedures will be presented as “uncoded”. 


 
 
 
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12.2 
Analysis 
Concomitant medications will be summarized by WHO-DD ATC Level 4, whereas procedures will 
be summarized by MedDRA SOC and PT for the Safety analysis population, and presented in data 
listings for all patients screened. Concomitant medications are defined as medications which started 
30 days prior to the first study drug administration or during the study up to the Day 70 Follow-up 
visit. 
Concomitant medications which started during the survival follow-up period will be listed 
separately. 
13 
Study Drug Exposure 
13.1 
Derivations 
The date of first study drug administration will be derived as the first dosing date from the 
investigational medicinal product (IMP) administration eCRF page. The date of last study drug 
administration will be obtained from “Date of Last Dose of IMP” from the patient disposition eCRF 
page. 
Interruptions, compliance, and dose changes will not be taken into account for the purpose of 
calculating the duration of exposure.  
Duration of exposure (days) = (Date of last study drug administration – Date of first study drug 
administration) + 1.  


 
 
 
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13.2 
Analysis 
Exposure to study drug will be summarized for the Safety and mITT analysis populations, and 
presented in data listings for all patients randomized/assigned to study drug. 
14 
Study Drug Compliance  
14.1 
Derivations 
The number of doses missed will be obtained from the missed doses eCRF page.  
The expected number of doses taken will be calculated as the duration of exposure, as a patient is 
dosed daily. 
The actual number of doses taken will be calculated as the difference between the expected number 
of doses taken and the number of doses missed. 
Overall compliance to study drug will be calculated as follows: Compliance to study drug (%) = 100 
× (Actual number of doses taken/Expected number of doses taken). 
Compliance to study drug will be categorized as follows: 
 < 80%. 
 ≥ 80%. 
The following example is given for illustrative purposes: 
Example: A patient in the HRZE treatment group for 7 days on treatment is expected to have 7 
doses. From the eCRF it is noted that he missed 2 doses in total (which may have been at different 
visits). Compliance to study drug for this patient is then calculated as 71.43% ([5/7] × 100).  


 
 
 
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14.2 
Analysis 
Compliance to study drug (i.e. not by visit interval, but over the whole of the treatment period) will 
be summarized for the Safety and mITT analysis populations, and presented in data listings for all 
patients randomized/assigned to study drug. 
15 
Efficacy Analysis 
Three types of media, namely liquid media and 7H11S and 7H11S+C solid media, will be used to 
grow cultures collected from overnight and coached spot sputum samples. Cultures collected after 
Day 60 (relative to first study drug administration) will be excluded from the statistical analysis of 
efficacy data. 
15.1 
Primary Efficacy Variable 
15.1.1 
Derivations 
TTP in Liquid Media: Overnight Sputum Samples 
The primary efficacy variable is log(TTP) over time (derived from TTP results in liquid media) 
collected from overnight sputum samples. The logarithm of the TTP result per timepoint will be 
calculated as follows: 
log(TTP) = log(TTP/hours) = log10(TTP result). 
log(TTP) collected before the first study drug administration (Day -2 and Day -1) will be used as 
log(TTP) at Day 0. 


 
 
 
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In addition, the TTP result can be categorized as follows: 
Terminology: TTP Results 
Terminology for TB Culture 
Description 
Contaminated: “MTC present with contamination” 
or “positive for Mycobacterium tuberculosis 
complex and contaminated” or “contaminated” or 
“positive for AFB growth and contaminated” 
Sputum culture reported as positive; a positive 
result from a blood agar test suggests that 
contamination is present. A Ziehl-Neelsen 
smear is subsequently performed to determine 
whether AFB is present, showing that the 
culture was positive for TB, regardless of the 
sample’s contamination status. The numeric 
TTP result associated with this terminology is 
indicated as “no result” or “-”. 
“No result” or NA” 
No processing done, or other problems 
associated with the calculation of TTP. The 
numeric TTP result associated with this 
terminology is indicated as “no result” or “-”. 
Negative: “MTC negative” or “negative for 
Mycobacterium tuberculosis complex” 
After 42 days incubation, no growth is 
reported in the tube. The numeric TTP result 
associated with this terminology is indicated 
as “no result” or “-”. 
Unable to produce 
If indicated that “patient was unable to 
produce sputum”. The numeric TTP result 
associated with this terminology is indicated 
as “no result” or “-”. 


 
 
 
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Terminology for TB Culture 
Description 
Positive: 
“MTC 
present” 
or 
“positive 
for 
Mycobacterium tuberculosis” or “positive for AFB 
growth” 
Positive MGIT culture and negative blood 
agar suggest that a true positive culture, with 
no influence from contaminants, is present. 
The numeric TTP result associated with this 
terminology is indicated in days or hours. 
AFB: Acid-fast bacilli; MGIT: Mycobacterial growth indicator tube; NA: Not applicable; TB: Tuberculosis; TTP: Time 
to positivity. 
Numeric TTP results (associated with “positive” results) reported as “> 1008 hours” will be 
considered as “negative” results. 
The following rules and conventions will apply for the handling of the aforementioned categories: 
 Contaminated/Unable to produce: The TTP results associated with “contaminated” or “unable 
to produce” samples will be set to missing. 
 No result or not applicable (NA): The TTP results will be set to missing in the case of “no 
result” or NA. Specifically, log(TTP) of patients who withdrew early from the study will not be 
imputed, and will therefore be treated as missing. 
 Negative: The TTP results associated with “negative” sample results will be right-censored 
at 600 hours or the maximum observed TTP in the study, whichever is greatest. 
15.1.2 
Efficacy Endpoints 
Rate of Change in TTP: Overnight Sputum Samples 
The primary efficacy endpoint is the rate of change in log(TTP) collected from overnight sputum 
samples, over 8 weeks of treatment, i.e. the bactericidal activity of log(TTP) over Day 0 to Day 56 
(or BATTP[0-56]). 


 
 
 
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For a given patient, BATTP(𝑡1 −𝑡2) from Day 𝑡1 to Day 𝑡2 is expressed as follows: 
BATTP(𝑡1 −𝑡2) = 100 ∙(10
[𝑓̂(𝑡2)−𝑓̂(𝑡1)
𝑡2−𝑡1
] −1) 
(15.1) 
where 𝑓̂(𝑡1) and 𝑓̂(𝑡2) represent the model-fitted log(TTP) at Day 𝑡1 and Day 𝑡2, respectively, as 
calculated by the regression of observed log(TTP) over time. Here, BATTP(t1 −t2) represents the 
daily percentage change in TTP from Day 𝑡1 to Day 𝑡2. 
Secondary efficacy endpoints (based on the primary efficacy variable) include BATTP(0-2) and 
BATTP(14-56) collected from overnight sputum samples over 8 weeks of treatment. 
15.1.3 
Primary Efficacy Analysis 
Regression Analyses: 
The following Bayesian non-linear mixed effects (NLME) regression model (Burger, D.A. and 
Schall, R., 2015) will be fitted to log(TTP) collected from overnight sputum samples, observed from 
Day 0 to Day 56, of all patients jointly included in the mITT analysis population: 
𝑦𝑖𝑗𝑘= 𝛼𝑖𝑗+ 𝛽1𝑖𝑗𝑡𝑖𝑗𝑘+ 𝛽2𝑖𝑗𝛾𝑗log (
exp[
𝑡𝑖𝑗𝑘−𝜅𝑗
𝛾𝑗
]+exp[−
𝑡𝑖𝑗𝑘−𝜅𝑗
𝛾𝑗
]
exp[
𝜅𝑗
𝛾𝑗]+exp[−
𝜅𝑗
𝛾𝑗]
) + 𝑒𝑖𝑗𝑘  
(15.2) 
where 𝛼𝑖𝑗= 𝛼𝑗+ 𝑢0𝑖𝑗, 𝛽1𝑖𝑗= 𝛽1𝑗+ 𝑢1𝑖𝑗 and 𝛽2𝑖𝑗= 𝛽2𝑗+ 𝑢2𝑖𝑗, 𝑦𝑖𝑗𝑘 represents log(TTP) for patient 
𝑖= 1, … , 𝑁𝑗 in treatment group 𝑗= 1, … , 𝐽 at timepoint 𝑘= 1, … , 𝐾𝑖𝑗 and 𝑡𝑖𝑗𝑘 is the corresponding 
time. 𝑢0𝑖𝑗, 𝑢1𝑖𝑗 and 𝑢2𝑖𝑗 denote random coefficients for patient 𝑖 assigned to treatment 𝑗 and 𝑒𝑖𝑗𝑘 is 
the random error term at time 𝑡𝑖𝑗𝑘 of patient 𝑖 assigned to treatment group 𝑗. 


 
 
 
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The random coefficients 𝛼𝑖𝑗, 𝜆1𝑖𝑗= (𝛽1𝑖𝑗−𝛽2𝑖𝑗) and 𝜆2𝑖𝑗= (𝛽1𝑖𝑗+ 𝛽2𝑖𝑗) can be interpreted as the 
intercept and rate (or slope) parameters during the initial and terminal phase of the treatment period, 
respectively. 
For the prevention of numerical overflow, the regression model will be fitted with the times (sample 
days) 𝑡𝑖𝑗𝑘 expressed in weeks. 
Let 𝝁𝒊𝒋 denote the vector of random coefficients (𝛼𝑖𝑗, 𝛽1𝑖𝑗, 𝛽2𝑖𝑗)
′, which is assumed to be 
independent and identically distributed (i.i.d.) as follows: 
𝝁𝒊𝒋 ~ 𝑁3(𝝁𝒋, Ω𝝁𝒋) 
(15.3) 
where 𝝁𝒋= (𝛼𝑗, 𝛽1𝑗, 𝛽2𝑗)
′ and Ω𝝁𝒋= [
𝜎𝛼𝑗
2
𝐶𝑜𝑣𝑗(𝛼𝑖𝑗, 𝛽1𝑖𝑗)
𝐶𝑜𝑣𝑗(𝛼𝑖𝑗, 𝛽2𝑖𝑗)
𝐶𝑜𝑣𝑗(𝛼𝑖𝑗, 𝛽1𝑖𝑗)
𝜎𝛽1𝑗
2
𝐶𝑜𝑣𝑗(𝛽1𝑖𝑗, 𝛽2𝑖𝑗)
𝐶𝑜𝑣𝑗(𝛼𝑖𝑗, 𝛽2𝑖𝑗)
𝐶𝑜𝑣𝑗(𝛽1𝑖𝑗, 𝛽2𝑖𝑗)
𝜎𝛽2𝑗
2
]. 
In order to complete the Bayesian specification of the regression model, proper prior distributions 
will be assigned to all unknown parameters. The values of the hyper parameters will be chosen in 
such a way to assure vagueness with regard to prior belief on the parameters. 
The prior distributions for 𝝁𝒋 and Ω𝝁𝒋 will be assumed to follow a multivariate normal and Wishart 
distribution, respectively, namely: 
𝝁𝒋 ~ 𝑁(𝟎, 104 × 𝑰𝟑) 
(15.4) 
Ω𝝁𝒋
−𝟏 ~ 𝑊(3, 3 × 𝑹𝒋) 
(15.5) 
where 𝟎= (0, 0, 0)′ and 𝑰𝟑 denotes a 3 × 3 identity matrix, and 𝑹𝒋 represent 3 × 3 inverse scale 
matrices. 


 
 
 
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Here, 𝑹𝒋 will be derived by fitting the model as a linear mixed effects regression model under 
the assumption that the node and smoothness parameters are fixed at 𝜅𝑝=
(11+3)
2×7 = 1 and 𝛾𝑝=
(2+0.05)
2
= 1.025, respectively. Accordingly, the estimates for Ω𝝁𝒋 will be calculated using the 
methodology by Vaida and Liu (2009), to serve as 𝑹𝒋. The linear mixed effects regression model 
(incorporating censoring) will be fitted using the “lmec” library of the R project. 
The parameters 𝜅𝑗, 𝛾𝑗 and 𝜎𝜅𝑗
2  are assumed to follow uniform distributions, namely: 
𝜅𝑗 ~ 𝑈(3
7 , 11
7 ) 
(15.6) 
𝛾𝑗 ~ 𝑈(0.05,2) 
(15.7) 
Here, 𝛾𝑗 govern the “smoothness” or “speed” of the transition from one rate (or slope) to another, 
whereas 𝜅𝑗 can be viewed as the nodes at which the regression functions transition from one rate (or 
slope) to another. 
Finally, the parameters 𝜎𝑒𝑗
2  are assumed to follow an inverse gamma distribution, namely: 
𝜎𝑒𝑗
2  ~ 𝐼𝐺(10−4, 10−4) 
(15.8) 
With the regression model described above, the node parameters 𝜅𝑗 are restricted to the range 
3
7 to 
11
7  
weeks. The “smoothness” parameters 𝛾𝑗 are restricted to the range 0.05 to 2. The level at which a 
given log(TTP) is censored will be taken into account (therefore treating the log[TTP] result as 
censored). Adjustment to the regression model will be made should the data not be optimally fitted 
using the specified bounds of the node parameter. 


 
 
 
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The Markov Chain Monte Carlo (MCMC) Gibbs sampling algorithm will be used to draw samples 
from the joint posterior distribution of the preceding regression model parameters. The MCMC 
Gibbs sampler is an algorithm based on drawing from the full conditional posterior distributions of 
each regression model parameter, conditional on the latest values of the remaining parameters in the 
regression model. Samples drawn from the full conditional posterior distributions have been shown 
to approximate samples from that of each regression model parameter’s unconditional joint posterior 
distribution once convergence has been reached. The OpenBUGS software will be used to carry out 
the MCMC Gibbs sampling procedure. 
Given that the regression model is quite complex (as it incorporates a large number of regression 
parameters) good starting values should be used to expedite convergence of the MCMC algorithm. 
The corresponding regression model's individual (per patient) parameter estimates, obtained from 
the SAS® procedure PROC NLMIXED, can be used as starting values for the regression model's 
random coefficients. The first Q observations need to be omitted from the T simulated observations, 
as the first Q observations may be invalid due to poor convergence during the initial stage 
(simulation “burn-in”). Graphical convergence diagnostics, such as iteration and autocorrelation 
plots, will be used to monitor convergence of the regression model's posterior samples. The 
posterior samples may be thinned to reduce the autocorrelation amongst posterior samples. For 
additional validation of the convergence of posterior samples, multiple chains of posterior samples, 
each with different sets of starting values, may be simulated. 
Posterior estimates and corresponding 95% Bayesian credibility intervals (BCIs) for the mean 
BATTP(0-56), including pairwise comparisons, will be presented accordingly in summary tables and 
figures for the mITT analysis population. 


 
 
 
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15.1.4 
Secondary Efficacy Analyses 
Regression Analyses: 
log(TTP) over time will be summarized descriptively for each collection visit for the mITT analysis 
population. Here, censored log(TTP) will be imputed with the level at which they are censored. The 
actual TTP results will be presented in data listings for all patients randomized/assigned to study 
drug. 
From the analysis described in Section 15.1.3, posterior estimates and corresponding 95% BCIs for 
the mean BATTP(0-2) and BATTP(14-56), including pairwise comparisons, will be presented 
accordingly in summary tables and figures for the mITT analysis population. Similarly, the 
aforementioned will be presented for the mean regression parameters and future regression slopes 
𝛽2𝑓𝑗= 𝛽2𝑗+ 𝑢2𝑓𝑗 (where the subscript 𝑓 stands for “future”) in summary tables for the mITT 
analysis population. The individual (per patient) BATTP(0-56), BATTP(0-2) and BATTP(14-56) 
estimates will be summarized by descriptive statistics and presented in figures and data listings 
(including individual regression model parameters) for the mITT analysis population. Data listings 
and plots of the observed and model-fitted log(TTP) over time will be presented accordingly for all 
patients randomized/assigned to study drug, and the mITT analysis population, respectively. These 
data of patients who are resistant to pyrazinamide and mono-resistant to isoniazid (according to their 
susceptibility status at baseline) will be flagged in data listings. The level at which log(TTP) is 
censored will be indicated in the relevant data listings and figures. The posterior estimate and 
corresponding 95% BCI of the mean log(TTP) for each sample day will be presented by treatment 
group on an individual (per patient) basis (summary tables; separate graphs per treatment group) for 
the mITT analysis population. The posterior estimate of the mean log(TTP) for each sample day will 
be presented by treatment group on an overall basis (combined graph for all treatment groups) for 
the mITT analysis population. 


 
 
 
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In order to establish whether patients with higher bacterial load at Day 0 (i.e. 𝛼𝑖𝑗) are associated 
with higher initial and terminal rates of decline in log(TTP) (i.e. 𝜆1𝑖𝑗 and 𝜆2𝑖𝑗, respectively) and 
similarly, to establish whether higher rates of decline during the initial phase (i.e. 𝜆1𝑖𝑗) are 
associated with higher terminal rates of decline (i.e. 𝜆2𝑖𝑗), or vice versa. That is, posterior samples of 
correlation coefficients between random intercepts and slopes, i.e. 𝜌𝛼𝑗𝜆1𝑗, 𝜌𝛼𝑗𝜆2𝑗and 𝜌𝜆1𝑗𝜆2𝑗, can be 
obtained, and will be presented in summary tables for the mITT analysis population, e.g.: 
𝜌𝛼𝑗𝜆1𝑗=
𝐶𝑜𝑣𝑗(𝛼𝑖𝑗, 𝜆1𝑖𝑗)
√𝑉𝑎𝑟𝑗(𝛼𝑖𝑗)𝑉𝑎𝑟𝑗(𝜆1𝑖𝑗)
=
𝐶𝑜𝑣𝑗(𝛼𝑖𝑗, 𝛽1𝑖𝑗) −𝐶𝑜𝑣𝑗(𝛼𝑖𝑗, 𝛽2𝑖𝑗)
√𝜎𝛼𝑗
2 (𝜎𝛽1𝑗
2
+ 𝜎𝛽2𝑗
2 −2𝐶𝑜𝑣𝑗[𝛽1𝑖𝑗, 𝛽2𝑖𝑗])
 
(15.9) 
𝜌𝛼𝑗𝜆2𝑗=
𝐶𝑜𝑣𝑗(𝛼𝑖𝑗, 𝜆2𝑖𝑗)
√𝑉𝑎𝑟𝑗(𝛼𝑖𝑗)𝑉𝑎𝑟𝑗(𝜆2𝑖𝑗)
=
𝐶𝑜𝑣𝑗(𝛼𝑖𝑗, 𝛽1𝑖𝑗) + 𝐶𝑜𝑣𝑗(𝛼𝑖𝑗, 𝛽2𝑖𝑗)
√𝜎𝛼𝑗
2 (𝜎𝛽1𝑗
2
+ 𝜎𝛽2𝑗
2 + 2𝐶𝑜𝑣𝑗[𝛽1𝑖𝑗, 𝛽2𝑖𝑗])
 
(15.10) 
𝜌𝜆1𝑗𝜆2𝑗=
𝐶𝑜𝑣𝑗(𝜆1𝑖𝑗, 𝜆2𝑖𝑗)
√𝑉𝑎𝑟𝑗(𝜆1𝑖𝑗)𝑉𝑎𝑟𝑗(𝜆2𝑖𝑗)
=
𝜎𝛽1𝑗
2
−𝜎𝛽2𝑗
2
√(𝜎𝛽1𝑗
2
+ 𝜎𝛽2𝑗
2
−2𝐶𝑜𝑣𝑗[𝛽1𝑖𝑗, 𝛽2𝑖𝑗]) (𝜎𝛽1𝑗
2
+ 𝜎𝛽2𝑗
2
+ 2𝐶𝑜𝑣𝑗[𝛽1𝑖𝑗, 𝛽2𝑖𝑗])
 
(15.11) 
15.1.5 
Exploratory Efficacy Analyses 
Regression Analyses: 
The regression model in Section 15.1.3 will be fitted using interaction terms for site, laboratory, 
HIV status (see Section 10), presence or absence of cavities (see Section 10) and treatment group for 
the mITT analysis population. For each interaction term, separately for site and treatment group, and 
HIV status and treatment group, posterior estimates and corresponding 95% BCIs for the mean 
BATTP(0-56) will be presented accordingly in summary tables for the mITT analysis population. 


 
 
 
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The regression model in Section 15.1.3 and Section 15.1.4 will be fitted by comparing patients 
according to their pyrazinamide susceptibility status at baseline (sensitive versus resistant) for the 
MDR-TB exploratory analysis population. This analysis may be performed for DS-TB patients on 
an ad-hoc basis if sample size warrants. 
The regression analyses described in Section 15.1.3 and Section 15.1.4 will be repeated for patients 
assigned to HRZE included in the mITT analysis population who are mono-resistant to isoniazid 
according to their susceptibility status at baseline if sample size warrants. 
15.1.6 
Sensitivity Efficacy Analyses 
Regression Analyses: 
The regression model in Section 15.1.3 can incorporate the assumption that the residual errors and 
random intercept and slope parameters follow i.i.d. (multivariate) Student t distributions, 
respectively, i.e.: 
𝑒𝑖𝑗𝑘 ~ 𝑇(0, 𝜎𝑒𝑗
2 , 𝑣𝑗) 
(15.12) 
𝝁𝒊𝒋 ~ 𝑇3(𝝁𝒋, Ω𝝁𝒋, 𝑤𝑗) 
(15.13) 
where 𝜎𝑒𝑗
2 ~𝐼𝐺(10−4, 10−4) and Ω𝝁𝒋
−𝟏 ~ 𝑊(3, 3 × 𝑹𝒋) are scale parameters and matrices, 
respectively, and 𝑣𝑗 and 𝑤𝑗 represent the corresponding degrees of freedom. 
The parameters 𝑣𝑗 and 𝑤𝑗 are assumed to follow uniform distributions, namely: 
𝑣𝑗 ~ 𝑈(2,100) 
(15.14) 
𝑤𝑗 ~ 𝑈(2, 100) 
(15.15) 


 
 
 
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The specification of the Student t distribution for both random coefficients (intercepts and slopes) 
and residual errors may provide a more robust modeling approach for outliers in any of the latter 
components of the given model. The analyses described in Section 15.1.3 and Section 15.1.4, 
excluding the correlation analysis between random coefficients, will be repeated for the mITT 
analysis population using the regression model which incorporates the specification of the Student t 
distribution. 
15.2 
Secondary Efficacy Variables 
15.2.1 
Derivations 
15.2.1.1 CFU Count in Solid Media: “7H11S” Overnight Sputum Samples 
Secondary efficacy variables include log(CFU) count over time, derived from CFU counts per mL 
collected from “7H11S” overnight sputum samples. log(CFU) counts will be calculated as follows:  
log(CFU) = log(CFU/mL) = log10(Mean of four CFU plate counts × factor × 10dilution) 
In the above formula, the “factor” compensates for the dilution of the specimens during the culture 
process, converting the result back to the actual CFU count per milliliter. The factor will 
respectively be set to 20 and 11 for samples associated with equal and 10% Sputasol volumes. The 
CFU calculations/determinations will be done for both types of media separately. 
The four CFU plate counts associated with a given sputum sample will consist of two CFU counts 
from two different plates. 
All log(CFU) counts collected before the first study drug administration (Day -2 and Day -1) will be 
used as the log(CFU) counts at Day 0. 


 
 
 
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Furthermore, results from the four CFU plate counts will be categorized as follows: 
Terminology: CFU Counts 
Terminology for TB Culture 
Description 
“Contaminated” or “CU” (contaminated and unreadable) 
Plate overgrown with contaminants 
(CFU counts therefore not available). 
“No result” or “NA” 
No 
processing 
done, 
or 
other 
problems 
associated 
with 
the 
calculation of CFU counts. 
“CR (contaminated but readable)/“n” or CR/“TNTC” 
Plate overgrown with contaminants 
but CFU counts readable. 
Zero (“0”) 
No growth on the plate. 
TNTC (≥ 200 colonies) 
Too numerous to count. 
Unable to produce 
If indicated that “patient was unable 
to produce sputum”. 
Numerical value 
The CFU count equivalent to the 
number of colonies recorded as a 
numerical value. A numerical value 
will also be recorded for “CR/n” 
where “n” will be the number of 
colonies. 
CFU: Colony forming unit; NA: Not applicable. 
For a given sputum sample, if “0” is reported for one of the two plates, and a result other than “0” is 
reported for the other plate, then the average of zero (“0”) and of the (non-zero) count for the second 
plate will be used for the calculation of log(CFU) count. 


 
 
 
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Similarly, for a given sputum sample, if “TNTC (≥ 200 colonies)” is reported for one of the two 
plates, and a result other than “TNTC” is reported for the other plate, then the average of a count 
of 200 (“TNTC [≥ 200 colonies]”) and of the (non-zero) count for the second plate will be used for 
the calculation of log(CFU) count. 
If the CFU counts for one of the two plates are reported as “contaminated” or “no result”, and a 
result other than “contaminated” or “no result” is reported for the other plate, then the CFU counts 
of the second plate will be used for the calculation of log(CFU) count. 
The following rules and conventions will apply for the handling of the aforementioned categories: 
 Contaminated or CU (contaminated and unreadable): The CFU counts associated with 
contaminated or “contaminated and unreadable” samples will be set to missing. 
 No result (unable to produce/sample leaked/sample not collected) or NA: The CFU counts 
will be set to missing in the case of “no result” or “NA”. Specifically, all missing log(CFU) 
counts due to early withdrawal from the study (see Section 9) will not be imputed, and will 
therefore be treated as missing. 
 CR/“n” (Contaminated but readable) or CR/TNTC: For CFU counts associated with 
“contaminated but readable” or “CR/TNTC”, the CFU count recorded in the “n” value of the 
field will be considered for analysis. log(CFU) count associated with a result of “TNTC (≥ 200 
colonies)” (only applicable when the four CFU plate counts are reported as “TNTC [≥ 200 
colonies]”) will be right-censored at a value of 200. 
 “0”: For the purpose of log-transformation, log(CFU) count associated with a result of “0” (only 
applicable when the four CFU plate counts are reported as “0”) will be left-censored at a value 
of 1.  


 
 
 
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Rationale:  The smallest possible CFU count above zero is 1 for counts from the one plate and 
zero for counts from the other plate with zero dilution, leading to a calculated 
log(CFU) count of: 
log(CFU) count = log([0 + 0 + 1 + 1]/4 × 20 × 100) = log(10) = 1. 
 TNTC (≥ 200 colonies): log(CFU) count associated with a result of “TNTC (≥ 200 colonies)” 
(only applicable when the four CFU plate counts are reported as “TNTC [≥ 200 colonies]”) will 
be right-censored at a value of 200. 
Other secondary efficacy variables include: 
15.2.1.2 TTP in Liquid Media: Coached Spot Sputum Samples 
log(TTP) over time, derived from TTP results collected from coached spot sputum samples. 
15.2.1.3 CFU Count in Solid Media: “7H11S+C” Overnight Sputum Samples 
log(CFU) counts over time, derived from CFU counts per mL collected from “7H11S+C” overnight 
sputum samples. 
15.2.1.4 CFU Count in Solid Media: “7H11S” Coached Spot Sputum Samples 
log(CFU) counts over time, derived from CFU counts per mL collected from “7H11S” coached spot 
sputum samples. 
15.2.1.5 CFU Count in Solid Media: “7H11S+C” Coached Spot Sputum Samples 
log(CFU) counts over time, derived from CFU counts per mL collected from “7H11S+C” coached 
spot sputum samples. 


 
 
 
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Note:  log(TTP) and log(CFU) count collected from coached spot sputum samples will be 
calculated similarly to those collected from overnight sputum samples. 
15.2.2 
Efficacy Endpoints 
15.2.2.1 Rate of Change in CFU Count: “7H11S” Overnight Sputum Samples 
Secondary efficacy endpoints include the rate of change in log(CFU) count collected from “7H11S” 
overnight sputum samples, over 8 weeks of treatment, i.e. the bactericidal activity of log(CFU) 
count over Day 0 to Day 56 (or BACFU[0-56]). 
For a given patient, BACFU(𝑡1 −𝑡2) from Day 𝑡1 to Day 𝑡2 is expressed as follows: 
BACFU(𝑡1 −𝑡2) = −
𝑓̂(𝑡2)−𝑓̂(𝑡1)
𝑡2−𝑡1
  
(15.16) 
where 𝑓̂(𝑡1) and 𝑓̂(𝑡2) represent the model-fitted log(CFU) count at Day 𝑡1 and Day 𝑡2, 
respectively, as calculated by the regression of the observed log(CFU) count over time. 
Other secondary efficacy endpoints (based on the secondary efficacy variables) include BACFU(0-2) 
and BACFU(14-56) collected from “7H11S” overnight sputum samples over 8 weeks of treatment. 
15.2.2.2 Rate of Change in TTP: Coached Spot Sputum Samples 
Endpoints associated with the rate of change in TTP over 56 days of treatment, collected from 
coached spot sputum samples, are analogous to those collected from overnight sputum samples. 


 
 
 
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15.2.2.3 Rate of Change in CFU Count: “7H11S+C” Overnight Sputum Samples 
Endpoints associated with the rate of change in CFU count over 56 days of treatment, collected from 
“7H11S+C” overnight sputum samples, are analogous to those collected from “7H11S” overnight 
sputum samples. 
15.2.2.4 Rate of Change in CFU Count: “7H11S” Coached Sputum Samples 
Endpoints associated with the rate of change in CFU count over 56 days of treatment, collected from 
“7H11S” coached spot sputum samples, are analogous to those collected from “7H11S” overnight 
sputum samples.. 
15.2.2.5 Rate of Change in CFU Count: “7H11S+C” Coached Sputum Samples 
Endpoints associated with the rate of change in CFU count over 56 days of treatment, collected from 
“7H11S+C” coached spot sputum samples, are analogous to those collected from “7H11S” 
overnight sputum samples. 


 
 
 
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15.2.2.6 Time to Liquid Media Sputum Culture Conversion 
Other secondary efficacy endpoints include the time to sputum culture conversion, derived from 
results in liquid media, collected from sputum samples over 8 weeks of treatment. For sputum 
samples collected before Day 56, the time (study day) to liquid media sputum culture conversion is 
defined as the time (study day) of the first of two consecutive available sputum samples (thus 
excluding “contaminated”, “no result”, “unable to produce” or missing) reported as “negative”. For 
sputum samples collected on Day 56, the time (study day) to liquid media sputum culture 
conversion is defined as the time (study day) of the last available (Day 56) sputum sample reported 
as “negative”. The time to liquid media sputum culture conversion will be determined separately 
from overnight and coached spot sputum samples, and also based on both overnight and coached 
spot sputum samples combined.  
15.2.2.7 Proportion of Patients with Liquid Media Sputum Culture Conversion 
Other secondary efficacy endpoints include the proportion of patients with liquid media sputum 
culture conversion at Day 28, Day 42 and Day 56, collected from overnight and coached spot 
sputum samples over 8 weeks of treatment. 
15.2.2.8 Time to Solid Media Sputum Culture Conversion 
Other secondary efficacy endpoints include the time to sputum culture conversion, derived from 
results in solid media, collected from “7H11S” sputum samples over 8 weeks of treatment. The time 
to solid media sputum culture conversion will be determined separately from overnight and coached 
spot sputum samples, and also based on both overnight and coached spot sputum samples combined. 


 
 
 
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15.2.2.9 Proportion of Patients with Solid Media Sputum Culture Conversion 
Other secondary efficacy endpoints include the proportion of patients with solid media sputum 
culture conversion at Day 28, Day 42 and Day 56, collected from “7H11S” overnight and coached 
spot sputum samples over 8 weeks of treatment. 
15.2.2.10 Correlation and Agreement Between Overnight and Coached Spot Sputum Samples 
Other secondary efficacy endpoints include the following: 
 The correlation of log(TTP) between overnight and coached spot sputum samples. 
 The correlation of log(CFU) count between overnight and coached spot sputum samples, 
separately for both types of media (7H11S” and “7H11S+C”). 
 The agreement of liquid media sputum culture conversion between overnight and coached spot 
sputum samples. 
 The agreement of solid media sputum culture conversion between overnight and coached spot 
sputum samples, separately for both types of media (7H11S” and “7H11S+C”). 
 The agreement of solid media sputum culture conversion between “7H11S” overnight and 
“7H11S+C” overnight sputum samples. 


 
 
 
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15.2.3 
Secondary, Exploratory and Sensitivity Efficacy Analyses 
Regression Analyses 
For the analysis of log(CFU) count collected from “7H11S” and “7H11S+C” overnight and 
“7H11S” and “7H11S+C” coached spot sputum samples, those described for the primary efficacy 
variable (see Section 15.1) will be repeated using the same regression model in Section 15.1, 
however incorporating a slight modification in the sign of the slope parameters 𝛽1 and 𝛽2: 
𝑦𝑖𝑗𝑘= 𝛼𝑖𝑗−𝛽1𝑖𝑗𝑡𝑖𝑗𝑘−𝛽2𝑖𝑗𝛾𝑗log (
exp[
𝑡𝑖𝑗𝑘−𝜅𝑗
𝛾𝑗
]+exp[−
𝑡𝑖𝑗𝑘−𝜅𝑗
𝛾𝑗
]
exp[
𝜅𝑗
𝛾𝑗]+exp[−
𝜅𝑗
𝛾𝑗]
) + 𝑒𝑖𝑗𝑘  
(15.17) 
where 𝑦𝑖𝑗𝑘 represents the log(CFU) count for patient 𝑖= 1, … , 𝑁𝑗 in treatment group 𝑗= 1, … , 𝐽 at 
timepoint 𝑘= 1, … , 𝐾𝑖𝑗. The parameters of the regression model are analogous to those described in 
Section 15.1. 
log(TTP) collected from coached spot sputum samples will be analyzed similarly to the analysis 
described in Section 15.1. 
The analyses of log(TTP) and log(CFU) count collected from coached spot sputum samples, and 
those applicable to the “7H11S+C” media, will not include the exploratory analyses described in 
Section 15.1. 
The analyses of log(TTP) and log(CFU) count collected from coached spot sputum samples will 
include the sensitvity analyses described in Section 15.1, and will be performed for the mITT 
analysis population. 


 
 
 
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Time to Liquid Media Sputum Culture Conversion 
The time to liquid media sputum culture conversion will be analyzed using Kaplan-Meier “survival” 
analysis, and will be depicted in figures. The log-rank test will be used for the comparison of the 
median time to liquid media sputum culture conversion. In addition, the corresponding hazard ratios 
for time to liquid media sputum culture conversion will be reported. Patients will be censored at the 
last available valid sample day should no sample be collected at Day 56.  
As a sensitivity analysis, the coached spot sputum samples will be used if results of the overnight 
sputum samples are not available. 
Patients’ time to sputum culture conversion or censoring on or after Day 53 up to and including Day 
60 will be considered as events which occurred on Day 56. 
The identity transformation will be applied to obtain the 95% CIs for the “survival” function and 
quartiles of the “survival” times. The differences, including 95% CIs, of the probability of time to 
liquid media sputum culture conversion between treatment groups will be presented. The 95% CIs 
will be calculated as follows: 
(𝐾𝑀𝑖
̂  − 𝐾𝑀𝑗
̂ ) ± 𝑍(1−𝛼
2) × √𝑆𝐸𝑖2
̂  + 𝑆𝐸𝑗2
̂   
where 𝐾𝑀𝑖
̂  and 𝐾𝑀𝑗
̂  are respectively the estimated probabilities of the 𝑖th and 𝑗th treatment group, 
and 𝑆𝐸𝑖
̂  and 𝑆𝐸𝑗
̂  are the associated estimates of the standard errors (SEs). 𝑍(𝑥) is the 𝑥th quantile of 
the standard normal distribution. Here, 𝛼= 0.05. 
The “survival” analysis will be performed for the mITT and MDR-TB exploratory analysis 
populations. 


 
 
 
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Proportion of Patients with Liquid Media Sputum Culture Conversion 
The proportion of patients with liquid media sputum culture conversion per visit will be compared 
pairwise between treatment groups using a Chi-Square test with treatment group as row variable and 
liquid media sputum culture conversion status (i.e. with versus without liquid media sputum culture 
conversion) as column variable. In addition, the corresponding odds ratios for patients with liquid 
media sputum culture conversion per visit will be reported. The analysis will be performed for the 
mITT analysis population. 
Time to Solid Media Sputum Culture Conversion 
The time to solid media sputum culture will be analyzed similarly to the analysis of time to liquid 
media sputum culture conversion. The analysis will be performed for the mITT and MDR-TB 
exploratory analysis populations.  
Proportion of Patients with Solid Media Sputum Culture Conversion 
The proportion of patients with solid media sputum culture conversion will be analyzed similarly to 
the analysis of the proportion of patients with liquid media sputum culture conversion. The analysis 
will be performed for the mITT analysis population. 
Correlation Between Overnight and Coached Spot Sputum Samples: 
Pearson correlation coefficients of the following will be calculated and presented in summary tables 
for the mITT analysis population: 
 log(TTP) quantified from overnight sputum samples versus log(TTP) quantified from coached 
spot sputum samples. 


 
 
 
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 log(CFU) count quantified from overnight sputum samples versus log(CFU) count quantified 
from coached spot sputum samples (separately for both types of media). 
The correlation analysis will be adjusted for patient. That is, patients will be “partialled out” of the 
analysis. 
Agreement Between Overnight and Coached Spot Sputum Samples: 
Kappa coefficients stratified by patient of the following will be calculated and presented in summary 
tables for the mITT analysis population: 
 Liquid media sputum culture conversion readouts from overnight sputum samples versus those 
from coached spot sputum samples. 
 Solid media sputum culture conversion readouts from overnight sputum samples versus those 
from coached spot sputum samples (separately for both types of media). 
Agreement Between Charcoal Treated and Non-Charcoal Treated Overnight Sputum Samples: 
Kappa coefficients stratified by patient of the following will be calculated and presented in summary 
tables for the mITT analysis population: 
 Solid media sputum culture conversion readouts from “7H11S” overnight sputum samples 
versus those from “7H11S+C” overnight sputum samples. 
15.3 
Tuberculosis Symptoms and Weight 
All summaries for TB symptoms and weight will be performed for the mITT analysis population, 
unless otherwise specified. Data listings for the aforementioned will be based on all patients 
randomized/assigned to study drug. Displays of TB symptoms will only occur for patients with TB 
symptoms available. 


 
 
 
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15.3.1 
Derivations 
Not applicable. 
15.3.2 
Analysis 
A shift in TB symptoms from baseline to end of treatment will be displayed, where TB symptoms 
are classified “None”, “Mild”, “Moderate” or “Severe”.  
TB symptoms will also be presented by means of a stacked bar chart over all scheduled visits. 
Mean weight (kg) over time will be presented in a figure. 
16 
Mycobacteriologic Characteristics 
16.1 
Derivations 
Mycobacteriologic assessments, beyond the scope of mycobacterial growth indicator tube (MGIT) 
and solid media data, include: 
 Sputum smear results. 
 Confirmation of Mycobacterium TB. 
 Molecular drug susceptibility. 
 Streptomycin, isoniazid, rifampicin and ethambutol (SIRE) drug susceptibility, also for 
fluoroquinolone and pyrazinamide. 
 pncA. 


 
 
 
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16.2 
Analysis 
Summaries of mycobacteriologic characteristics will be performed for the Safety analysis 
population. Data listings for the aforementioned will be based on all patients randomized/assigned to 
study drug. 
17 
Safety Outcomes 
All summaries for safety will be performed for the Safety analysis population, unless otherwise 
specified. Data listings for the aforementioned will be based on all patients randomized/assigned to 
study drug. 
17.1 
Survival Follow-Up 
Survival follow-up data, including overall survival follow-up, will be summarized descriptively 
using frequencies and percentages (n and %) (qualitative) by visit. 
17.2 
Adverse Events (AEs) 
17.2.1 
Derivations 
Adverse events (AEs) will be coded using MedDRA central coding dictionary, Version 17.1. 
Uncoded AEs will be presented as “uncoded”. 
A treatment-emergent adverse event (TEAE) is defined any AE which started or worsened on or 
after the first study drug administration up to and including the Day 70 Follow-up visit (or up to and 
including 14 days after last study drug administration for patients not having the Day 70 Follow-up 
visit). 


 
 
 
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A post-treatment AE is defined as any AE which started or worsened after the Day 70 Follow-up 
visit up to the last visit, early study withdrawal or last contact associated with the Day 140/Follow-
up period, as indicated on the ‘Disposition’ eCRF page, whichever occurs last. 
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 by the worst case assigned, i.e. a TEAE.  
Appendix 3 contains conventions for the calculation of TEAEs. 
Treatment-Emergent Adverse Events (TEAEs) Leading to Death 
Treatment-emergent adverse events (TEAEs) leading to death are defined as TEAEs for which 
outcome is indicated as “fatal”. 
Serious Treatment-Emergent Adverse Events (TEAEs) 
Serious TEAEs are defined as TEAEs for which serious is indicated as “yes”. 
Treatment-Emergent Adverse Events (TEAEs) Leading to Early Withdrawal from Study 
Treatment-emergent adverse events (TEAEs) leading to early withdrawal from the study are defined 
as TEAEs for which study discontinuation is indicated as “yes”. 
Treatment-Emergent Adverse Events (TEAEs) Leading to Discontinuation of Study Drug 
Treatment-emergent adverse events (TEAEs) leading to discontinuation of study drug are defined as 
TEAEs for which action taken with study drug is indicated as “IMP stopped”. 


 
 
 
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Drug-Related Treatment-Emergent Adverse Events (TEAEs) 
Drug-related TEAEs are defined as TEAEs for which relationship to study drug is indicated as 
“possible”, “probable”, “certain” or missing. 
Treatment-Emergent Adverse Events (TEAEs) by Severity 
Severity is categorized as “grade I (mild)”, “grade II (moderate)”, “grade III (severe)”, “grade IV 
(potentially life-threatening)”. 
Liver-Related Adverse Events 
Liver-related adverse events are defined as any events with a high level group term of “HEPATIC 
AND BILIARY NEOPLASMS BENIGN”, “HEPATIC AND HEPATOBILIARY DISORDERS”, 
“HEPATOBILIARY 
DISORDERS 
CONGENITAL”, 
“HEPATOBILIARY 
NEOPLASMS 
MALIGNANT 
AND 
UNSPECIFIED”, 
“HEPATOBILIARY 
INVESTIGATIONS” 
or 
“HEPATOBILIARY THERAPEUTIC PROCEDURES”. 
17.2.2 
Analysis 
An overall summary, including the incidence of TEAEs (applicable to each observation period; only 
deaths and SAEs are applicable to “AEs during the survival follow-up period”) by SOC and PT, will 
be presented for some of the categories described.  
The incidence of drug-related TEAEs by SOC, PT and severity will be presented. 
Post-treatment AEs will be presented overall. Incidences of post-treatment AEs will be presented for 
serious AEs and AEs leading to early withdrawal from the study. 


 
 
 
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A data listing with all AEs (including coding details), all AEs for patients who died and serious 
adverse events (SAEs) will be presented. 
17.3 
Deaths 
17.3.1 
Derivations 
Deaths will be presented as captured on the Subject Disposition eCRF page.  
17.3.2 
Analysis 
The number of deaths, as well as the causes of deaths will be summarized for all patients 
randomized/assigned to study drug and will be presented by treatment group. Deaths, date of death, 
cause of death, adverse events leading to death and the adverse event’s relationship to study drug 
will be presented in data listings for patients randomized/assigned to study drug. 
17.4 
Laboratory Tests 
17.4.1 
Derivations 
A list of laboratory tests (hematology, clinical chemistry, urinalysis, serum endocrinology and other 
laboratory tests) to be included in the analysis is presented in Section 6.3 of the protocol.  
Quantitative laboratory measurements reported as “< X”, i.e. BLQ, or “> X”, i.e. above the upper 
limit of quantification (ULQ), will be converted to X for the purpose of quantitative summaries, but 
will be presented as recorded, i.e. as “< X” or “> X” in the data listings. 


 
 
 
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Quantitative laboratory measurements will be categorized in accordance with the relevant laboratory 
reference ranges as follows: 
 Low: Below the lower limit of the laboratory reference range.  
 Normal: Within the laboratory reference range (upper and lower limit included). 
 High: Above the upper limit of the laboratory reference range. 
In addition, quantitative liver enzyme (alanine aminotransferase [ALT], aspartate aminotransferase 
[AST], alkaline phosphatase and total bilirubin) laboratory measurements will be characterized in 
accordance with the predefined markedly abnormal criteria as presented below: 
 Result > 3 × Upper limit of normal (ULN).  
 Result > 10 × ULN.  
 1.1 × ULN ≤ Measurement < 2 × ULN (Grade 1). 
 2 × ULN ≤ Measurement < 3 × ULN (Grade 2).  
 3 × ULN ≤ Measurement ≤ 8 × ULN (Grade 3).  
 Measurement > 8 × ULN (Grade 4).  
17.4.2 
Analysis 
Summaries of hematology, clinical chemistry, urinalysis and serum endocrinology laboratory tests, 
by visit, will include the following: 
 Actual and change from baseline in laboratory measurements (quantitative). 
Quantitative (“low”, “normal” and “high” classifications according to laboratory reference ranges) 
will be summarized in a shift table (from baseline) to end of treatment, and presented in a stacked 
bar chart. 


 
 
 
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Other laboratory results (apart from hematology, clinical chemistry, urinalysis and serum 
endocrinology laboratory tests) will be listed. 
Treatment-emergent incidences and post-treatment incidences during the Day 70 or 140 Follow-up 
period for liver enzyme abnormalities, will be summarized. 
Total bilirubin versus ALT (normalized values) will be presented in figures (eDISH plot). Here, 2 
times the ULN for total bilirubin, and 3 times the ULN for ALT will be provided accordingly (using 
horizontal and vertical lines). The most extreme treatment-emergent measurement for the 
aforementioned laboratory tests will be presented. The figure will be displayed on the logarithmic 
scale and will be repeated for total bilirubin versus AST (normalized values). 
Liver enzyme profile plots will be provided for the following: 
 Patients with eDISH abnormalities. (Based on Possible Hy’s Law criteria). 
 Patients with treatment-emergent Grade 3 or Grade 4 AST or ALT measurements. 
An abnormality possibly meeting Hy’s Law criteria is defined as an event where a patient has an 
AST or ALT result ≥ 3 x ULN and a total bilirubin result ≥ 2 x ULN. 
Patients with ALT or AST > 3, 5, 8 or × ULN will be provided in data listings. 
17.5 
Electrocardiogram (ECG) Parameters 
17.5.1 
Derivations 
The mean of the three observed values obtained from triplicate readings per visit will be used for 
analysis purposes. 


 
 
 
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The actual QT, QTcB and QTcF intervals will be classified as follows: 
 QT/QTcB/QTcF interval < 450 msec. 
 450 msec ≤ QT/QTcB/QTcF interval < 480 msec. 
 480 msec ≤ QT/QTcB/QTcF interval < 500 msec.  
 QT/QTcB/QTcF interval ≥ 500 msec. 
The change from baseline in QT, QTcB and QTcF intervals will be classified as follows: 
 > 0 and < 30 msec increase from baseline. 
 ≥ 30 msec and < 60 msec increase from baseline. 
 ≥ 60 msec increase from baseline. 
17.5.2 
Analysis 
Electrocardiogram (ECG) will be summarized for the Safety analysis population (tables and 
figures), and presented in data listings for all patients randomized/assigned to study drug. 
Summaries of ECG measurements, by visit and timepoint (where applicable), will include the 
following: 
 Actual and change from baseline in ECG measurements (quantitative). 
 Frequencies and percentages (n and %) (qualitative). 
 Tukey honestly significant difference (HSD) analysis of the change from baseline in QTcB and 
QTcF interval between treatment groups. 
The mean QTcB and QTcF interval will be presented in summary tables and figures by visit and 
timepoint. 


 
 
 
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Quantitative ECG measurements will be summarized in shift tables (from baseline) by visit. 
Treatment-emergent incidences of the aforementioned QT, QTcB and QTcF interval classifications 
will be summarized. 
17.6 
Vital Signs 
17.6.1 
Derivations 
Vital signs will be characterized in accordance with the predefined markedly abnormal criteria as 
presented below: 
Abnormality Code 
Vital Sign 
Heart Rate 
DBP 
SBP 
Respiratory 
Rate 
Abnormally low 
≤ 50 bpm 
≤ 50 mmHg 
≤ 90 mmHg 
< 12 bpm 
Grade 1 or mild 
 
> 90 mmHg to  
< 100 mmHg 
> 140 mmHg to 
< 160 mmHg 
≥ 17 bpm to 
≤ 20 bpm 
Grade 2 or moderate 
 
≥ 100 mmHg to 
< 110 mmHg 
≥ 160 mmHg to 
< 180 mmHg 
≥ 21 bpm to 
≤ 25 bpm 
Grade 3 or severe 
 
≥ 110 mmHg 
≥ 180 mmHg 
> 25 bpm 
Abnormally high 
≥ 120 bpm 
 
 
 
bpm: Beats per minute, DBP: Diastolic blood pressure, SBP: Systolic blood pressure. 
17.6.2 
Analysis 
Summaries of vital signs, including BMI (kg/m2), by visit, will include the actual and percent 
change from baseline in vital signs. 


 
 
 
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Treatment-emergent incidences of markedly abnormal vital signs will be summarized. 
Vital signs will be presented in data listings. 
17.7 
Physical Examination 
17.7.1 
Derivations 
Not applicable. 
17.7.2 
Analysis 
Not applicable. 
17.8 
Ophthalmological Examination 
17.8.1 
Derivations 
The following ophthalmological examination results will be reported for this study: 
 Visual acuity. 
 Slit lamp examination. 
17.8.2 
Analysis 
Qualitative analysis will be performed on visual acuity test data (frequencies and percentages).  
Decreases (and increases) of 1, 2 and more than 2 lines from baseline to Day 140 Follow-up will be 
presented per eye for the visual acuity near test. 
Decreases (and increases) of 1, 2 and more than 2 categories from baseline to Day 140 Follow-up 
will be presented per eye for the visual acuity distance test. 


 
 
 
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For lens opacities, an Age Related Eye Disease Study 2 (AREDS2) grading of > 0.0 will be listed 
for all patients randomized/assigned to study drug. 
17.9 
Other Assessments 
The following assessments will only be presented in data listings for all patients 
randomized/assigned to study drug: 
 Sample collection information. 
  
18 
List of References 
Burger, D.A. and Schall, R. (2015). A Bayesian nonlinear mixed-effects regression model for the 
characterization of early bactericidal activity of tuberculosis drugs. Journal of Biopharmaceutical 
Statistics 25(6), 1247–1271. 
Hahn, G.J. and Meeker, W.Q. (1991). Statistical Intervals: A Guide for Practitioners, New York: 
John Wiley & Sons. 
Food & Drug Administration (February 27, 1987). Supplementary suggestions for preparing an 
integrated summary of safety information in an original NDA submission and for organizing 
information in Periodic Safety Updates. 
Vaida, F. and Liu, L. (2009). Fast implementation for normal mixed effects models with censored 
response. Journal of Computational and Graphical Statistics 18(4), 797–817. 
 


 
 
 
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Appendix 1: Rationale for Correction Factors 
Most modern drugs are low-clearance drugs, since low clearance often (although not always) 
equates to long half-life and therefore once daily dosing. For low-clearance drugs, the biological 
activity in vivo is driven by the unbound (free) drug concentration. 
In static in vitro systems, the setting by definition is low clearance and the free drug concentration 
will determine the biological response. If the free drug concentration in the in vitro system is 
different from that in vivo, a correction factor needs to be applied to extrapolate the in vitro results 
to the in vivo situation. 
In the case of measuring MICs for Mycobacterium TB, protein in the medium is required. The most 
common protein used is bovine serum albumin (BSA) at a final concentration of 5 g/L, which is 
approximately one-eighth the concentration found in plasma. For a drug which is highly albumin-
bound in plasma, 5 g/L BSA can still result in a very high degree of protein binding. In such a case, 
the measured MIC is not the intrinsic MIC of free drug. Therefore, extrapolating from the in vitro 
MIC to the MIC in plasma cannot be done just by multiplying the measured MIC by a correction 
factor based on the free fraction of drug in plasma. The correction factor needs to be adjusted for the 
free fraction in the in vitro assay as well. 
Measuring MICs in whole serum is not done due to technical limitations. So, how do we decide on 
the appropriate correction factor to extrapolate in vitro findings to the in vivo situation? 
This is easiest in the case of highly (> 99%) protein bound drugs where the free fraction is 
approximately linearly related to the amount of protein. That is, an in vitro system with one-eighth 
the amount of relevant protein as in plasma has an 8-fold higher free fraction of that drug than does 
plasma. In such a case, a measured in vitro MIC needs to be multiplied by a factor of 8 to obtain the 
predicted MIC in plasma. 


 
 
 
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For other drugs the calculation can be performed as follows. For an “unsaturable” drug, or a drug far 
from saturation like albumin, the mass action equation reduces to B = nKF, where B is the 
concentration of bound drug, n is the number of binding sites, K is the equilibrium association 
constant, and F is the concentration of free drug. The ratio B/F = nK and is directly proportional to 
the number of binding sites. Let us set B + F = 1 (or 100%).  
Thus, for the case of PA-824, which is a low clearance drug that is 85% bound to albumin in human 
plasma (which contains 40 g/L albumin), B/F in plasma = 85/15 = 5.67. B/F in the medium in which 
the MIC data are generated, containing 5 g/L albumin, is 8-fold lower, or 0.71. If B/F = 0.71 and 
B + F = 1 (setting the total B + F to 100%), then solving algebraically F = 0.58. That is, in the 
medium in which the MIC data are generated, PA-824 is 58% free, or approximately 4-fold its free 
fraction in plasma. Therefore, a factor of 4 should be applied to the MIC in plasma, that is, an MIC 
measured in the usual assay should be multiplied by four to ascertain the MIC in plasma. This in fact 
was confirmed experimentally, with a 4.2-fold shift in MIC observed as the albumin concentration 
in the MIC assay medium was increased from 5 g/L to 40 g/L. 
For the case of bedaquiline, which is greater than 99% protein bound in plasma, we use our (above) 
factor of 8. That is, the MIC in plasma is considered 8 times the MIC measured in the in vitro assay. 
For the case of moxifloxacin, which is 30-50% bound in human plasma, correcting for protein 
binding is not considered necessary, as the correction factor would be within the error of the MIC 
assay. 
 


 
 
 
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Appendix 2: Programming Conventions for Tables, Data Listings and Figures 
(TLFs) 
Paper Size, Orientation and Margins 
The margin, page size and line size specifications as stipulated below will be used for the 
presentation of all TLFs: 
 
Landscape 
Portrait 
Margins (Inches): 
Top  
Bottom 
Left 
Right 
 
1.25 
1 
1 
1 
 
1 
1 
1.25 
1 
Header (Inches) 
0.5 
0.5 
Footer (Inches) 
0.5 
0.5 
SAS® specifications: 
PAGESIZE 
LINE SIZE 
 
46 
134 
 
67 
93 
Fonts 
The font type ‘Courier New’ should be used as default for tables and data listings, with a font size 
of 8. The font color should be black. No bolding, underlining and italics are permitted. 


 
 
 
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Version Number: 2.0 
Version Date: 
14DEC2016 
Template No: CS_TP_BS016 – Revision 3 
Reference: CS_WI_BS005
Effective Date: 01MAY2012 
 
Header Information 
Headers should be defined as follows: 
 The header should be placed at the top of the page (same place on each page). 
 The sponsor name should appear in row 1, left-aligned. 
 The word “J-M-Pa-Z” should appear in row 1, right-aligned. 
 The protocol number should appear in row 2, left-aligned. 
 The page identification in the format Page X of Y (where Y is the total number of pages for the 
TLF) should appear in row 2, right-aligned. 
 The TLF identification number should appear in row 3, centered. 
 The TLF title should start in row 4, centered. 
 The TLF population should appear in row 5, centered. The population should be spelled out in 
full, e.g. Safety Analysis Population in preference to Safety analysis population. 
 Row 6 should be a continuous row of underscores (‘_’) (the number of underscores should equal 
the line size). 
 Row 7 should be a blank line. 
 Mixed case should be used for titles. 
 The column headings should be underlined with a row of underscores (‘_’). 
 Column headings spanning more than one column should be underlined and have underscores on 
either side of the title and should be centered. 
 Column headings should be in mixed case. 
 In general, the analysis population count should appear in the column header in the form 
“(N=XXX)”. 


 
 
 
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Effective Date: 01MAY2012 
 
Table, Listing and Figure (TLF) Conventions 
General: 
 The first row in the body of the table or data listing should be blank. 
 The left hand column should start in Column 1. No indenting or centering of the TLF should 
occur. 
 Rounding should be done with the SAS® function ROUND. 
 Numerical values in tables should be rounded, not truncated. 
 Numerical values should be decimal point aligned. 
 Text values should be left aligned. 
 The first letter of a text entry should be capitalized. 
 The study drug should appear first in tables with treatment group as columns. 
 All variables contained on the eCRF (which have data present) should appear in the data listings, 
along with all derived data appearing in the corresponding tables. 
 The width of the TLF should match the line size. 
Univariate statistics: 
 Statistics should be presented in the same order across tables (i.e., n, mean, SD, minimum, 
median and maximum). 
 If the original data has N decimal places, then the summary statistics should have the following 
decimal places: 
o Minimum, maximum and CV (%): N. 
o Mean and median: N + 1. 
o SD: N + 2. 


 
 
 
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Version Date: 
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Template No: CS_TP_BS016 – Revision 3 
Reference: CS_WI_BS005
Effective Date: 01MAY2012 
 
Frequencies and percentages (n and %): 
 Percent values should be reported inside parentheses, with one space between the count and the 
left parenthesis of the percentage. Parentheses should be justified to accept a maximum of 100.0 
as a value and padded with blank space if the percent is less than 100.0. An example is given 
below: 
o 77 (100.0) 
o 50 (64.9) 
o 1 (2.7) 
CIs: 
 CIs should be presented with one additional decimal place as that of the raw data, and SDs and 
SEs with two additional decimal places as that of the raw data. 
 CIs should be justified so that parentheses displayed on consecutive lines of a table “line up”. 
P-values: 
P-values should be reported to four decimal places. 
Ratios: 
Ratios should be reported with one additional decimal place as that of the raw data. 
Missing values: 
A “0” should be used to indicate a zero frequency. 
A blank will be used to indicate missing data in data listings. 


 
 
 
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Version Date: 
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Effective Date: 01MAY2012 
 
Figure Output Conventions 
Figures should be provided in RTF files using the SAS® Output Delivery System (ODS). 
Dates and Times 
Depending on data available, dates and times will take the form ddMMMyyyy and hh:mm. 
Spelling Format 
The spelling format to be used is English US.  
Presentation of Treatment Groups 
For TLFs, treatment groups will be represented in the following order: 
Treatment Group 
TLF Abbreviation 
See Section 3.1 
J(loading dose/t.i.w.)PaZ 
See Section 3.1 
J(200 mg)PaZ 
See Section 3.1 
HRZE 
See Section 3.1 
J(200 mg)MPaZMDR 
Screening Failure 
Screening Failure 
Presentation of Visits 
For outputs, visits will be represented in the following order: 
Visit Name 
Day -9 to Day -3 
Day -2 


 
 
 
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Effective Date: 01MAY2012 
 
Visit Name 
Day -1 
Day 1 
Baseline 
Day 4 
Day 8 
Day 14 
Day 15 
Day 22 
Day 29 
Day 36 
Day 43 
Day 50 
Day 56 
Day 57 
Day 70/Follow-up 
Day 140/Follow-up 
Unscheduled (chronologically) 
Early Withdrawal 
Month 8 Follow-Up 
Month 14 Follow-Up 
Month 20 Follow-Up 
Month 26 Follow-Up 
Note: Overnight sputum sample collection started one day prior to the visit. 


 
 
 
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Appendix 3: Partial Adverse Event (AE) Date Conventions 
No AE date imputations will be done for this study. 
Algorithm for Treatment-Emergent Adverse Events (TEAEs) 
START DATE 
STOP 
DATE 
ACTION 
Known 
Known, 
partial or 
missing 
If Start date < Study drug start date, then not TEAE. 
If Start date ≥ Study drug start date, then TEAE. 
If Start date = Study drug start date and the variable 
“...prior to first dose of study medication” is equal to 
“no”, then TEAE. 
If Start date = Study drug start date and the variable 
“...prior to first dose of study medication” is equal to 
“yes”, then not TEAE. 
 
 
 
Partial, but known 
components show that it 
cannot be on or after 
study drug start date 
Known, 
partial or 
missing 
Not TEAE. 
 
 
 
Partial, could be on or 
after study drug start date 
Known 
If Stop date < Study drug start date, then not TEAE. 
If Stop date ≥ Study drug start date, then TEAE. 
Else assumed TEAE. 
Partial 
Assume stop date as latest possible date (i.e. last day of 
month if day unknown or 31st December if day and 


 
 
 
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START DATE 
STOP 
DATE 
ACTION 
month are unknown), then: 
If Stop date < Study drug start date, then not TEAE. 
If Stop date ≥ Study drug start date, then TEAE. 
Else assumed TEAE. 
Missing 
Assumed TEAE. 
 
 
 
Missing 
Known 
If Stop date < Study drug start date, then not TEAE. 
If Stop date ≥ Study drug start date, then TEAE. 
Else assumed TEAE. 
Partial 
Assume stop date as latest possible date (i.e. last day of 
month if day unknown or 31st December if day and 
month are unknown), then: 
If Stop date < Study drug start date, then not TEAE. 
If Stop date ≥ Study drug start date, then TEAE. 
Else assumed TEAE. 
Missing 
Assumed TEAE. 
 


 
 
 
 
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Version Date: 
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Template No: CS_TP_BS016 – Revision 3 
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Effective Date: 01MAY2012 
 
PK, PD AND PK/PD STATISTICAL ANALYSIS PLAN 
NC-005-(J-M-PA-Z) 
 
A PHASE 2 OPEN-LABEL PARTIALLY RANDOMIZED 
TRIAL TO EVALUATE THE EFFICACY, SAFETY AND 
TOLERABILITY OF COMBINATIONS OF 
BEDAQUILINE, MOXIFLOXACIN, PA-824 AND 
PYRAZINAMIDE DURING 8 WEEKS OF TREATMENT IN 
ADULT SUBJECTS WITH NEWLY DIAGNOSED 
DRUG-SENSITIVE OR MULTI DRUG-RESISTANT, 
SMEAR-POSITIVE PULMONARY TUBERCULOSIS 
 
AUTHOR: DIVAN BURGER AND LUCIA MANS 
 
VERSION NUMBER AND DATE: VERSION 2.0, 
25MAY2017 


 
 
 
 
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Version Date: 
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Effective Date: 01MAY2012 
 
PK, PD and PK/PD Statistical Analysis Plan (SAP) Signature Page 
 
Name 
Signature 
Date 
Author: 
Divan Burger, PhD 
 
 
Position: 
Senior Biostatistician 
Company: 
QuintilesIMS, South Africa 
 
 
Name 
Signature 
Date 
Author: 
Lucia Mans, BSc (Hons) 
 
 
Position: 
Biostatistician 1 
Company: 
QuintilesIMS, South Africa 
The signatures below indicate review and approval of the proposed PK analysis and presentation of data as planned for protocol NC-
005-(J-M-PA-Z) Version 1.0, dated 31 January 2014, including final protocol amendment 01, dated 19 September 2014 (incorporated 
into the working protocol Version 1.1, dated 19 September 2014). 
This version of the PK, PD and PK/PD statistical analysis plan (SAP) was approved by the undersigned. 
 
Name 
Signature 
Date 
Approved By: 
Robert Schall, PhD 
 
 
Position: 
Senior Director, Biostatistics 
Company: 
QuintilesIMS, South Africa 
 
Approved By: 
Almari Conradie, MPh 
 
 
Position: 
Global Clinical Project Manager 
Company: 
Global Alliance for TB Drug Development 
 
 
Approved By: 
Jerry Nedelman 
 
 
Position: 
Senior Director, Pharmacometrics 
Company: 
Global Alliance for TB Drug Development 


 
 
 
 
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Effective Date: 01MAY2012 
 
Modification History 
Unique 
Identifier for 
this Version 
Date of 
Document 
Version 
Author 
Significant Changes from Previous 
Authorized Version 
1.0 
08JUN2016 
Divan Burger & 
Lucia Mans 
Not applicable – First authorized version 


 
 
 
 
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Version Date: 
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Template No: CS_TP_BS016 – Revision 3 
Reference: CS_WI_BS005
Effective Date: 01MAY2012 
 
Unique 
Identifier for 
this Version 
Date of 
Document 
Version 
Author 
Significant Changes from Previous 
Authorized Version 
2.0 
25MAY2017 
Divan Burger & 
Lucia Mans 
 Updated the Quintiles logo to the 
QuintilesIMS logo. Also, updated 
“Quintiles” to “QuintilesIMS” 
throughout the document. 
 Removed Stephen Murray from 
the Signature Page, as he is no 
longer working at GATB. 
Replaced with Jerry Nedelman for 
Signature Page. 
 Section 5: Removed text referring 
to a data review plan, as the 
analysis populations were not 
outlined in such documentation, 
but rather discussed directly with 
GATB. Also, reference to a topline 
analysis removed as PK and PK-
PD analyses are performed as a 
final analysis only. 
 Section 5.6: Reference link 
removed from text, as this is not 
applicable any longer.  


 
 
 
 
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Effective Date: 01MAY2012 
 
Unique 
Identifier for 
this Version 
Date of 
Document 
Version 
Author 
Significant Changes from Previous 
Authorized Version 
2.0 
25MAY2017 
Divan Burger & 
Lucia Mans 
 Section 9.1: Indicated that 
between-treatment comparisons 
will also be performed of TMIC. 
 Section 9.1.1: Added clarification 
for trailing BLQ values set to zero.  
 Section 9.1.1: Added text to 
explain AUC(0-24) will not be 
calculated if both concentrations at 
predose and 24 h are missing. 
 Section 9.1.2: Updated geometric 
mean CV% to CV%, and added 
formula for this.  
 Section 9.1.2: Updated that 95% 
CIs of the geometric mean will be 
constructed using natural log 
transformation and then anti-
logged. 


 
 
 
 
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Effective Date: 01MAY2012 
 
Unique 
Identifier for 
this Version 
Date of 
Document 
Version 
Author 
Significant Changes from Previous 
Authorized Version 
2.0 
25MAY2017 
Divan Burger & 
Lucia Mans 
 Section 9.2.1: Updated formula for 
log-linear interpolation when PK 
concentrations are decreasing. 
Also, used “MIC” instead of “Ci” 
in formulae, as MIC is a constant 
over time. 
 
 


 
 
 
 
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Table of Contents 
Page: 
 
1 
Introduction .................................................................................................................................9 
2 
Study Objectives..........................................................................................................................9 
3 
Study Design ..............................................................................................................................10 
3.1 
General Description ..................................................................................................................... 10 
3.2 
Schedule of Events ........................................................................................................................ 12 
3.3 
Changes to Analysis from Protocol ............................................................................................. 12 
4 
Planned Analyses ......................................................................................................................12 
4.1 
Final Analysis ................................................................................................................................ 13 
5 
Analysis Populations .................................................................................................................13 
5.1 
All Patients Screened .................................................................................................................... 14 
5.2 
All Patients Randomized/Assigned to Study Drug .................................................................... 14 
5.3 
Safety Analysis Population .......................................................................................................... 14 
5.4 
Modified Intention-to-Treat (mITT) Analysis Population ....................................................... 14 
5.5 
Multi-Drug Resistant Tuberculosis (MDR-TB) Exploratory Analysis Population ................ 15 
5.6 
Pharmacokinetic (PK) Analysis Population ............................................................................... 15 
5.7 
Pharmacokinetic (PK)-Pharmacodynamic (PD) Analysis Population .................................... 16 
6 
General Considerations ............................................................................................................16 
6.1 
Software Version .......................................................................................................................... 16 
7 
Statistical Considerations .........................................................................................................16 
7.1 
Multicenter Studies ...................................................................................................................... 16 
7.2 
Missing Data ................................................................................................................................. 17 
7.3 
Examination of Subgroups .......................................................................................................... 17 
8 
Output Presentations ................................................................................................................17 
9 
Pharmacokinetics (PK) and Pharmacodynamics (PD) .........................................................17 
9.1 
Pharmacokinetics (PK) ................................................................................................................ 17 
9.1.1 
Derivations 
18 
9.1.2 
Analysis 
21 
9.2 
Intense Sampling Pharmacokinetics (PK)-Pharmacodynamics (PD) ...................................... 24 
9.2.1 
Derivations 
25 
9.2.2 
Analysis 
26 
10 
Pharmacokinetic (PK) Plasma Concentration-QT Prolongation .........................................27 
10.1 Derivations .................................................................................................................................... 27 
10.2 Analysis ......................................................................................................................................... 27 
Appendix 1: Rationale for Correction Factors ...............................................................................28 
Appendix 2: Programming Conventions for Tables, Data Listings and Figures (TLFs) ............30 
Paper Size, Orientation and Margins ................................................................................................... 30 


 
 
 
 
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Version Date: 
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Effective Date: 01MAY2012 
 
Header Information ............................................................................................................................... 31 
Table and Data Listing Table, Listing and Figure (TLF) Conventions ............................................ 32 
Figure Output Conventions ................................................................................................................... 34 
Dates and Times ..................................................................................................................................... 34 
Spelling Format ...................................................................................................................................... 34 
Presentation of Treatment Groups ....................................................................................................... 34 
Presentation of Visits ............................................................................................................................. 35 
 


 
 
 
 
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1 
Introduction 
This document describes the rules and conventions to be used in the presentation and analysis of  
pharmacokinetic (PK), pharmacodynamic (PD) and PK-PD data for protocol NC-005-(J-M-Pa-Z). It 
describes the data to be summarized and analyzed, including specifics of the statistical analyses to be 
performed. 
This PK statistical analysis plan (SAP) is based on Working Protocol Version 1.1, dated 
19 September 2014. 
2 
Study Objectives 
The primary objective of this study is to evaluate the bactericidal activity, safety, and tolerability of 
bedaquiline, PA-824 and pyrazinamide in drug-sensitive (DS) tuberculosis (TB) and bedaquiline, 
moxifloxacin, PA-824 and pyrazinamide in multi-drug resistant (MDR) TB (MDR-TB).  
Secondary objectives include evaluating the bactericidal activity, safety and tolerability of bedaquiline 
dosed using two different schemes (400 mg daily for 2 weeks followed by 200 mg three times a week 
[loading dose/t.i.w] and 200 mg daily [200 mg]). Additional key secondary objectives are to evaluate 
the population PK characteristics of bedaquiline, moxifloxacin, PA-824 and pyrazinamide when 
administered as a part of 3- and 4-drug regimens in adults with TB, and investigation of the 
methodology of sputum sampling by comparing colony forming unit (CFU) count and time to 
positivity (TTP) in liquid culture (MGIT), quantified from both overnight and coached spot sputum 
samples. 
The study endpoints are listed in Section 4.2 of the protocol. 


 
 
 
 
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3 
Study Design 
3.1 
General Description 
This is a Phase 2, multi-center, open-label, partially randomized study conducted in four parallel 
treatment groups. The study will be performed at multiple sites globally. 
Drug-Sensitive (DS) Tuberculosis (TB) (DS-TB): 
A total of 180 eligible patients who meet all of the inclusion criteria and none of the exclusion criteria, 
aged between 18 and 75 years (inclusive), with newly diagnosed, smear-positive DS pulmonary TB 
will be randomized to one of three treatment groups: 
 J(loading dose/t.i.w.)PaZ: Bedaquiline 400 mg once daily from Day 1 up to Day 14, 200 mg three times 
per week from Day 15 up to Day 56; plus PA‐824 200 mg once daily from Day 1 up to Day 56; 
plus pyrazinamide 1500 mg once daily from Day 1 to Day 56. 
 J(200 mg)PaZ: Bedaquiline 200 mg once daily from Day 1 up to Day 56; plus PA‐824 200 mg once 
daily from Day 1 up to Day 56; plus pyrazinamide 1500 mg once daily from Day 1 to Day 56. 
 HRZE: Isoniazid 75 mg, rifampicin 150 mg, pyrazinamide 400 mg and ethambutol 275 mg from 
Day 1 up to Day 56. 
The HRZE treatment group is included as a control for the DS treatment groups. Additionally, it is 
included as a control for the quantitative mycobateriology. 


 
 
 
 
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Multi-Drug Resistant (MDR) Tuberculosis (TB) (MDR-TB): 
Up to 60 eligible patients who meet all of the inclusion criteria and none of the exclusion criteria, aged 
between 18 and 75 years (inclusive), with newly diagnosed, smear-positive MDR pulmonary TB will 
be assigned to the following treatment group: J(200 mg)MPaZMDR: Bedaquiline 200 mg once daily from 
Day 1 up to Day 56; plus moxifloxacin 400 mg once daily from Day 1 up to Day 56; plus PA‐824 
200 mg once daily from Day 1 up to Day 56; plus pyrazinamide 1500 mg once daily from Day 1 to 
Day 56. 
The number of patients to be randomized/assigned to each treatment group is presented below. 
Treatment Groups 
 
Treatment Group 
Patient Population 
Number of Patients 
1. 
J(loading dose/t.i.w.)PaZ 
DS-TB 
60 
2. 
J(200 mg)PaZ 
DS-TB 
60 
3. 
HRZE 
DS-TB 
60 
4. 
J(200 mg)MPaZMDR 
MDR-TB 
Up to 60 
DS: Drug-sensitive. MDR: Multi-drug resistant. TB: Tuberculosis. 
A schematic of study design is presented below. 
Fifteen (15) patients from each of the treatment groups will be included in a PK sub-study, for whom 
intense-sampling will be performed on Day 14 and Day 56. 
 
 


 
 
 
 
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Study Schematic 
 
3.2 
Schedule of Events 
The schedule of events can be found in Section 1.2 of the protocol. 
3.3 
Changes to Analysis from Protocol 
In the multiple-dose Day 14 and Day 56 PK analyses, linear up/log down trapezoidal summation is 
the preferred method for calculating areas under the curve.  This method will be used for deriving the 
total exposure parameters, instead of the linear trapezoidal rule described in the protocol. 
4 
Planned Analyses 
The following PK analyses will be performed for this study: 
 Final analysis. 
 


 
 
 
 
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4.1 
Final Analysis 
The final analysis as described in the main SAP handling safety and efficicy, using TLF shells (to be 
outlined in a separate output templates document), will be performed by QuintilesIMS Biostatistics 
following final analysis database lock of data for all patients (DS-TB and MDR-TB).  
The final PK, PD and PK/PD analyses and associated figures will be the responsibility of the clinical 
pharmacokineticist at QuintilesIMS.  The final PK, PD and PK/PD summaries and data listings as 
well as the statistical analyses of the PK, PD and PK/PD variables will be the responsibility of the 
study biostatistician at QuintilesIMS.   
5 
Analysis Populations 
Agreement and authorization of patients included/excluded from each analysis population will be 
reached prior to the final analysis database lock.  
For the purpose of analyses based on each of the analysis populations, patients will be classified 
according to actual study drug received, regardless of randomized/assigned study drug.  
Note:  Statistical analyses will not necessarily be performed for all of the below analysis populations. 
Analyses populations applicable to a certain analysis will be mentioned explicitly within the 
particular “analysis” sections of this document. 
The number of patients included in the relevant analysis populations, as well as the number of patients 
excluded with reasons for exclusion from the relevant analysis populations, will be summarized for 
patients randomized/assigned to study drug. 


 
 
 
 
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5.1 
All Patients Screened 
A full description of the all patients screened analysis population can be found in the main SAP 
handling safety and efficacy. 
 
5.2 
All Patients Randomized/Assigned to Study Drug 
A full description of the all patients randomized/assigned to study drug analysis population can be 
found in the main SAP handling safety and efficacy. 
 
5.3 
Safety Analysis Population 
This analysis population will include all patients who were randomized to study drug (for the DS 
patient population) or assigned to study drug (for the MDR patient population) and received at least 
one administration of study drug.  
If there is any doubt whether a patient was treated or not, the patient will be assumed treated for the 
purposes of this analysis.  
The main purpose of this analysis population is to summarize safety data for patients who were, during 
the course of the study, exposed to study drug. 
5.4 
Modified Intention-to-Treat (mITT) Analysis Population 
A full description of the mITT analysis population can be found in the main SAP handling safety and 
efficacy. 
 


 
 
 
 
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5.5 
Multi-Drug 
Resistant 
Tuberculosis 
(MDR-TB) 
Exploratory 
Analysis 
Population 
A full description of the MDR-TB analysis population can be found in the main SAP handling safety 
and efficacy. 
 
5.6 
Pharmacokinetic (PK) Analysis Population 
The PK population will consist of all patients who receive the Test Product (J dosing regimens) or 
Control Product (HRZE regimen) and have at least 1 measured concentration for any corresponding 
analytes (J, J metabolite M2, Pa, Z, or M) at a scheduled PK time point after the start of dosing regimen 
of the respective drug and had no protocol violations/deviations or events with potential to 
significantly affect the PK of the investigational product (examples include, but may not be limited 
to, vomiting following oral dosing occurring within the time frame of 2 times the median time of 
maximum concentration (tmax), or sample processing errors that lead to inaccurate bioanalytical 
results).  If any patients are found to be noncompliant with respect to dosing (eg, noncompliance on 
PK days or other study days, or have overall compliance <80% or have incomplete data), a decision 
will be made on a case-by-case basis as to their inclusion in the analysis, and subjected to the 
Sponsor’s approval.       
Patients in this population will be used for all applicable PK summaries. 
Pharmacokinetic parameters will be derived for patients in the PK population from the sub-group of 
each treatment who had serial PK samples collected. 


 
 
 
 
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5.7 
Pharmacokinetic (PK)-Pharmacodynamic (PD) Analysis Population 
This analysis population will contain all patients included in the PK analysis population for whom 
valid PD data are available, and who had no major protocol violations/deviations (defined as 
violations/deviations affecting the integrity of the PD data) as confirmed by the sponsor and data 
review meeting. 
The main purpose of this analysis population is to summarize PK-PD data for patients who have valid 
corresponding data available. 
6 
General Considerations 
Further general considerations can be found in the main SAP handling safety and efficacy. 
 
6.1 
Software Version 
All analyses will be conducted using SAS® Version 9.2 or higher and Phoenix® WinNonlin® 6.4 or 
higher (Certara L.P., Princeton, New Jersey), as applicable.  Graphics for PK data presentation may 
also be prepared with SigmaPlot® 12.5 or higher (Systat Software, Inc., San Jose, California); or 
Phoenix® WinNonlin® 6.4 or higher, or SAS® Version 9.2 or higher.   
7 
Statistical Considerations 
7.1 
Multicenter Studies 
This study will be conducted by multiple investigators at multiple sites internationally. Randomization 
to treatment groups is not stratified by country/site, and therefore, all analyses will be unstratified. 
However, subgroup analyses will be included by site (see Section 7.3). 


 
 
 
 
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7.2 
Missing Data 
Missing data will not be imputed for this study, unless otherwise specified.  
7.3 
Examination of Subgroups 
A subset of patients from each treatment group will be included in a PK sub-study. 
8 
Output Presentations 
Appendix 2 contains conventions for presentation of data in TLFs. 
Summary tables will be presented by treatment group, unless otherwise specified. 
The shells to be provided in the separate output templates document will describe the format and 
content for presentation of TLFs for the final analyses. 
All percentages (%) calculated for a specific summary are calculated using the total number of patients 
included in the relevant analysis population with data, as the denominator, unless otherwise specified. 
By default, descriptive statistics will include the number of patients (n), mean, standard deviation 
(SD), minimum, median and maximum for quantitative measurements. 
9 
Pharmacokinetics (PK) and Pharmacodynamics (PD) 
9.1 
Pharmacokinetics (PK) 
Sparse samples (predose on Days 1, 4, 8, 15, 22, 29, 36, 43, 50, and during the site visits on Days 57 
and 70) for all patients and serial samples up to 24 hours postdose on Day 14 and 56 for the PK 
sub-study patients were collected for the following analytes: 


 
 
 
 
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Pharmacokinetic Analyte(s) Per Treatment Group 
Treatment Group 
Analytes 
Patient Population 
J(loading dose/t.i.w.)PaZ 
J, J metabolite M2, Pa, Z 
DS-TB 
J(200 mg)PaZ 
J, J metabolite M2, Pa, Z 
DS-TB 
J(200 mg)MPaZ 
J, J metabolite M2, Pa, Z, M 
MDR-TB 
HRZE 
Z 
DS-TB 
DS: Drug-sensitive. J: Bedaquiline. M: Moxifloxacin. MDR: Multi-drug resistant. Pa: PA-824. TB: Tuberculosis.  
Z: Pyrazinamide. 
The relevant PK summaries will be presented for all patients in the PK population.  Multiple-dose PK 
parameters on Day 14 and Day 56 will be derived for bedaquiline, bedaquiline metabolite M2, 
moxifloxacin, PA-824, and pyrazinamide (depending on treatment group) for patients in the PK 
population from the sub-group of each treatment who had serial PK samples collected (Section 5.6). 
 
9.1.1 
Derivations 
Pharmacokinetic (PK) Plasma Concentrations 
Predose (or trough) PK plasma concentration samples of Day 15 and Day 57 collected from patients 
in the PK sub-study will also be used as the 24 hour post-dose PK plasma concentration sample of 
Day 14 and Day 56 in the respective concentration summaries and PK analyses. 
For the purpose of summarizing concentration data, below the limit of quantitation (BLQ) 
concentrations will be treated as zero for the computation of descriptive statistics.  Missing 
concentrations will be omitted from the calculation of descriptive statistics. 


 
 
 
 
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The following data handling conventions apply to the PK analyses for deriving the multiple-dose PK 
parameters on Day 14 and Day 56: 
 Predose samples that are BLQ will be assigned a numerical value of zero. 
 Postdose BLQ concentrations will be assigned a value of zero if they precede quantifiable 
samples in the initial portion of the profile.   
 A BLQ value that occurs between quantifiable data points, especially prior to Cmax, will be 
evaluated to determine if an assigned concentration of zero makes sense, or if reanalysis or 
exclusion of the data is warranted.  
 Following Cmax, BLQ values embedded between 2 quantifiable data points will be treated as 
missing. 
 Trailing BLQ values at the end of the collection interval (after the last quantifiable 
concentration) will be set to zero, and treated as missing when calculating AUC(0-t).   
 If consecutive BLQ concentrations are followed by quantifiable concentrations in the terminal 
portion of the concentration curve, these quantifiable values will be set to missing (blank data) 
and excluded from the PK analysis, unless otherwise warranted by the concentration-time 
profile. 
 For AUC(0-24) calculations: 
o For PK analyses of bedaquiline and bedaquiline metabolite M2 on Day 56 of the J(loading 
dose/t.i.w.)PaZ treatment, during the study timeframe of three times per week bedaquiline 
administration, missing predose and/or 24-h concentration will be kept as missing and 
AUC(0-24) will not be calculated. 


 
 
 
 
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o For all other analytes/study day/treatments, in which the respective drug is 
administered once daily, under the assumptions of linear PK and steady-state 
conditions, if predose concentration is missing, then the concentration shall be set to 
equal the concentration at 24 h (ie, end of the dosing interval).  Likewise, if 
concentration at 24 h is missing, the concentration shall be set to the predose value.  If 
both concentrations at predose and 24 h are missing, AUC(0-24) will not be calculated.    
Pharmacokinetic (PK) Parameters 
Pharmacokinetic parameters will be estimated by noncompartmental methods using actual elapsed 
time from dosing.   
Areas under the curve will be calculated by linear up/log down trapezoidal summation, and at least 3 
quantifiable postdose concentrations are required. 
The following multiple-dose PK parameters will be calculated for all analytes and treatments on 
Day 14 and Day 56; unless otherwise indicated:  
Cmax 
Observed maximum plasma concentration, obtained directly from the observed 
versus time concentration data 
tmax 
Time of Cmax 
AUC(0-24) 
Area under the PK plasma concentration time (t) curve from zero to 24 hours.  
As a general rule, AUCall shall be used as an estimate of AUC(0-24) if concentrations 
fall to BLQ at or before reaching 24 hours unless otherwise warranted by the data. 
AUCall is the area under the curve from zero (predose) to the time of the last 
observation (last quantifiable observation if no terminal BLQ values are present or 
first non-quantifiable observation if there are trailing BLQs). 


 
 
 
 
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AUC(0-t) 
Area under the PK plasma concentration time (t) curve from zero to time of last 
quantifiable analyte concentration. 
Cmax/D 
Dose-normalized Cmax 
AUC(0-24)/D 
Dose-normalized AUC(0-24). 
AUC(0-t)/D 
Dose-normalized AUC(0-t). 
Cmin 
Observed minimum plasma concentration, obtained directly from the observed 
versus time concentration data 
tmin 
Time of Cmin 
Cmin/D 
Dose-normalized Cmin 
 
The dose normalized exposure parameters (Cmax/D, Cmin/D, AUC(0-t)/D, and AUC(0-24)/D) will be 
derived for analytes that have the corresponding study drug dose varied across regimens, and include: 
bedaquiline, bedaquiline metabolite M2, and pyrazinamide. 
HRZE regimen (isoniazid 75 mg plus rifampicin 150 mg plus pyrazinamide 400 mg plus ethambutol 
275 mg per combination tablet) is administered on a weight-based dosing scheme, as follows: 30‐
37 kg: 2 tablets; 38‐54 kg: 3 tablets; 55‐70 kg: 4 tablets; and 71 kg and over: 5 tablets.  Pyrazinamide 
dose amount for calculating pyrazinamide dose-normalized PK parameters in the HRZE treatment on 
Day 14 and Day 56 will be derived as: 400 mg x number of combination tablets taken per 
administration specified in the protocol, based off weight measured on Day 1.  
9.1.2 
Analysis 
In general, PK data listings and summaries will be presented by treatment, study day, and schedule 
time if applicable.   


 
 
 
 
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Pharmacokinetic data (concentrations and PK parameters) will be summarized using descriptive 
statistics, including n (for available data), mean, SD, median, minimum, maximum, geometric mean, 
and CV% calculated as: 
, where s is the SD of the data on a log scale.   
For discrete variables (eg, tmax, and tmin), only n, minimum, median, and maximum will be reported.  
In addition, for concentration data, the 95% CIs for the geometric mean will be calculated. CIs will 
be constructed on a log scale and anti-logged for presentation. 
An n ≥3 will be required for calculations of descriptive statistics; except for minimum and maximum, 
where n ≥2 will be required.  If n <2, no descriptive statistics will be calculated; only n will be 
presented. 
All concentration data will be reported and analyzed with the same precision as the source data 
regardless of how many significant figures or decimals the data carry.  Derived PK parameters will be 
rounded for reporting purposes both in the summary tables and by-subject listings.  For the calculation 
of descriptive statistics and the statistical analysis, rounded values as presented in the data listings will 
be used.  For most derived PK parameters, 3 significant digits will be used as the standard rounding 
procedure, with the following exceptions: 
 Parameters directly derived from source data (eg, Cmax and Cmin) will be reported and analyzed 
with the same precision as the source data. 
 Parameters derived from actual sample collection times (eg, tmax and tmin) will be reported with 
the same precision as the actual elapsed sampling time which is presented as 2 decimals. 


 
 
 
 
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For the reporting of descriptive statistics, the mean, standard deviation and confidence intervals will 
be presented to one digit more precision than the source data.   The minimum, median, and maximum 
will be presented to the same precision as the source data.  Coefficient of variation will always be 
reported to 1 decimal place.  Ratios of means for pharmacokinetic parameters will be presented with 
two decimal places (as a percentage).  The p-values, if any, shall be reported to four decimal places 
or as <0.0001. 
In addition, subgroup analyses of the aforementioned will be included by gender. 
Pharmacokinetic (PK) Plasma Concentrations 
Listings of PK blood sample collection times, derived sampling time deviations, and plasma 
concentrations of each analyte will be provided.  For each analyte, trough (predose) plasma 
concentrations will be summarized by treatment and scheduled study day.  Serial PK concentrations 
on Day 14 and Day 56 will be summarized by treatment, scheduled study day, and scheduled times.   
For each analyte on Day 14 and Day 56, plots of the geometric mean (and corresponding 95% CIs) 
PK plasma concentrations over time (by study day) will be presented.   
In addition, plots of the mean and individual PK plasma trough concentrations versus study day and  
plots of the geometric mean (and corresponding 95% CIs) PK plasma trough concentrations versus 
study day will be presented.  Day 1 and Day 70 will be excluded from the trough graphical 
presentations.   
Individual overlaid plasma concentration-time profiles on Day 14 and Day 56, presented by patient 
number, will also be generated for each analyte. 
All concentration-time profile plots will be presented on linear and semi-logarithmic scales. 


 
 
 
 
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Pharmacokinetic (PK) Parameters 
The multiple-dose PK parameters on Day 14 on Day 56 will be summarized by treatments for each 
analyte.  
Scatter plots of individual and geometric mean Day 14 and Day 56 exposure parameters (Cmax, Cmin, 
AUC(0-t), and AUC(0-24)) and dose normalized exposure parameters (Cmax/D, Cmin/D, AUC(0-t)/D, and 
AUC(0-24)/D) versus treatments will be presented as appropriate for bedaquiline and bedaquiline 
metabolite M2.   
Additional graphical presentations of PK data may be added at the discretion of the PK scientist, if 
further illustration of the PK results is deemed appropriate. 
In order to compare the effects of the two J dosing schemes on bedaquiline exposure, the time over 
MIC (TMIC), Cmax, Cmin, Ctrough, and total exposures (AUC(0-t) and AUC(0-24)) of bedaquiline and 
bedaquiline metabolite M2 will be compared using PK sub‐study data from days 14 and 56. The 
primary comparisons will be performed for the J(loading dose/t.i.w.)PaZ versus J(200mg)PaZ DS‐TB arms.  
Secondary comparisons of these PK parameters and TMIC between the J(200mg)MPaZ MDR‐TB and 
J(200mg)PaZ DS‐TB arms will also be evaluated. On the logarithmic scale, TMIC and PK parameters 
will be analyzed pairwise using an analysis of variance (ANOVA) with treatment group as main effect. 
Point estimates and corresponding 95% CIs for the geometric mean will be presented. Point estimates 
and corresponding 95% CIs for the geometric mean ratios (between treatment groups) will also be 
presented accordingly. Point estimates and corresponding 95% CI for geometric mean ratios will be 
estimated after back exponentiation. 
 
9.2 
Intense Sampling Pharmacokinetics (PK)-Pharmacodynamics (PD) 
Intense sampling PK-PD will be summarized for all patients included in the PK sub-study. 


 
 
 
 
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9.2.1 
Derivations 
For each analyte (i.e. bedaquiline, bedaquiline metabolite M2, PA-824 and moxifloxacin, depending 
on treatment group), TMIC will be calculated as the percentage of time the PK plasma concentration 
is above MIC collected at Day -2. The PK and MIC data will be considered on an individual (per 
patient) basis. 
The TMIC calculations will be performed using the MICs with and without accounting for 
protein-binding shift. The required adjustment is as follows: 
Drug 
Multiplication Factor 
Bedaquiline 
8 
PA-824 
4 
Moxifloxacin 
1 
Pyrazinamide 
Not applicable 
For the TMIC calculations accounting for protein-binding shift, the MIC of the isolate from the 
individual study patient at Day -2 will be multiplied by these aforementioned multiplication factors. 
The rationale for correction factors to be used to calculate TMIC with protein shift is explained in 
Appendix 1. 
For the calculation of TMIC, the following will be taken into account: 
 The number of hours that the individual patient’s PK plasma concentration (separately for Day 14 
and Day 56) was above the individual patient’s predose MIC (Day -2) will be determined: 
o In situations where the PK plasma concentration crosses the threshold, interpolation will be 
used to determine the exact number of hours that the PK plasma concentration was above the 
threshold. 


 
 
 
 
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 Consequently the time above MIC will be expressed as a percentage (%) of the total hours over 
the relevant period. 
The PK plasma concentration profiles per patient will be used to estimate the time over the threshold 
using the method described above. 
An interpolated timepoint it  will be calculated using linear or log-linear interpolation as follows: 
 Linear interpolation is used when the PK plasma concentrations are increasing. 


















)
(
1
1
1
1
1
1
i
i
i
i
i
i
i
t
t
C
C
C
MIC
t
t
 
 Log-linear interpolation is used when the PK plasma concentrations are decreasing. 


















)
(
)
ln(
)
ln(
)
ln(
)
ln(
1
1
1
1
1
1
i
i
i
i
i
i
i
t
t
C
C
C
MIC
t
t
 
where 
1

i
C
 and 
1

i
C
 are the last available PK plasma concentrations before and after time it , i.e. 
1

it
 
and 
1

it
, respectively. 
9.2.2 
Analysis 
Summary tables and data listings for TMIC will be provided for the PK analysis population. 


 
 
 
 
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Pearson correlation coefficients of the following will be calculated and presented in summary tables 
and figures for the PK analysis population with valid efficacy data available: 
 The individual (per patient) estimates of BATTP(0-56), BATTP(14-56), BACFU(0-56) and BACFU(14-
56) as calculated from the joint Bayesian NLME regression model versus the following PK 
parameters (per analyte): 
o Cmax (Day 14 and Day 56). 
o AUC(0-24) (Day 14 and Day 56). 
o TMIC(0-24) (%) (Day 14 and Day 56). 
The correlation analysis is only applicable to overnight sputum samples; “7H11S” only (CFU count). 
10 
Pharmacokinetic (PK) Plasma Concentration-QT Prolongation 
10.1 
Derivations 
The relationship between predose PK plasma concentrations (for each analyte) versus the change from 
baseline in predose QT interval, QT interval corrected by Bazett’s method (QTcB) and QT interval 
corrected by Fridericia’s method (QTcF) (i.e. matched by timepoint) will be assessed. 
10.2 
Analysis 
Pearson correlations between PK trough concentrations (for each analyte) and change from baseline 
in predose QT, QTcB and QTcF intervals (matched by timepoint and visit) will be presented in tables 
and figures for the PK-PD analysis population. 
 
 
 


 
 
 
 
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25MAY2017 
Template No: CS_TP_BS016 – Revision 3 
Reference: CS_WI_BS005
Effective Date: 01MAY2012 
 
Appendix 1: Rationale for Correction Factors 
Most modern drugs are low-clearance drugs, since low clearance often (although not always) equates 
to long half-life and therefore once daily dosing. For low-clearance drugs, the biological activity in 
vivo is driven by the unbound (free) drug concentration. 
In static in vitro systems, the setting by definition is low clearance and the free drug concentration 
will determine the biological response. If the free drug concentration in the in vitro system is different 
from that in vivo, a correction factor needs to be applied to extrapolate the in vitro results to the in 
vivo situation. 
In the case of measuring MICs for Mycobacterium TB, protein in the medium is required. The most 
common protein used is bovine serum albumin (BSA) at a final concentration of 5 g/L, which is 
approximately one-eighth the concentration found in plasma. For a drug which is highly albumin-
bound in plasma, 5 g/L BSA can still result in a very high degree of protein binding. In such a case, 
the measured MIC is not the intrinsic MIC of free drug. Therefore, extrapolating from the in vitro 
MIC to the MIC in plasma cannot be done just by multiplying the measured MIC by a correction 
factor based on the free fraction of drug in plasma. The correction factor needs to be adjusted for the 
free fraction in the in vitro assay as well. 
Measuring MICs in whole serum is not done due to technical limitations. So, how do we decide on 
the appropriate correction factor to extrapolate in vitro findings to the in vivo situation? 
This is easiest in the case of highly (> 99%) protein bound drugs where the free fraction is 
approximately linearly related to the amount of protein. That is, an in vitro system with one-eighth the 
amount of relevant protein as in plasma has an 8-fold higher free fraction of that drug than does 
plasma. In such a case, a measured in vitro MIC needs to be multiplied by a factor of 8 to obtain the 
predicted MIC in plasma. 


 
 
 
 
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For other drugs the calculation can be performed as follows. For an “unsaturable” drug, or a drug far 
from saturation like albumin, the mass action equation reduces to B = nKF, where B is the 
concentration of bound drug, n is the number of binding sites, K is the equilibrium association 
constant, and F is the concentration of free drug. The ratio B/F = nK and is directly proportional to 
the number of binding sites. Let us set B + F = 1 (or 100%).  
Thus, for the case of PA-824, which is a low clearance drug that is 85% bound to albumin in human 
plasma (which contains 40 g/L albumin), B/F in plasma = 85/15 = 5.67. B/F in the medium in which 
the MIC data are generated, containing 5 g/L albumin, is 8-fold lower, or 0.71. If B/F = 0.71 and B + F 
= 1 (setting the total B + F to 100%), then solving algebraically F = 0.58. That is, in the medium in 
which the MIC data are generated, PA-824 is 58% free, or approximately 4-fold its free fraction in 
plasma. Therefore, a factor of 4 should be applied to the MIC in plasma, that is, an MIC measured in 
the usual assay should be multiplied by four to ascertain the MIC in plasma. This in fact was confirmed 
experimentally, with a 4.2-fold shift in MIC observed as the albumin concentration in the MIC assay 
medium was increased from 5 g/L to 40 g/L. 
For the case of bedaquiline, which is greater than 99% protein bound in plasma, we use our (above) 
factor of 8. That is, the MIC in plasma is considered 8 times the MIC measured in the in vitro assay. 
For the case of moxifloxacin, which is 30-50% bound in human plasma, correcting for protein binding 
is not considered necessary, as the correction factor would be within the error of the MIC assay. 


 
 
 
 
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Divan Burger and Lucia Mans 
Version Number: 2.0 
Version Date: 
25MAY2017 
Template No: CS_TP_BS016 – Revision 3 
Reference: CS_WI_BS005
Effective Date: 01MAY2012 
 
Appendix 2: Programming Conventions for Tables, Data Listings and Figures 
(TLFs) 
Paper Size, Orientation and Margins 
The margin, page size and line size specifications as stipulated below will be used for the presentation 
of all TLFs: 
 
Landscape 
Portrait 
Margins (Inches): 
Top  
Bottom 
Left 
Right 
 
1.25 
1 
1 
1 
 
1 
1 
1.25 
1 
Header (Inches) 
0.5 
0.5 
Footer (Inches) 
0.5 
0.5 
SAS® specifications: 
PAGESIZE 
LINE SIZE 
 
46 
134 
 
67 
93 
Fonts 
The font type ‘Courier New’ should be used as default for tables and data listings, with a font size 
of 8. The font color should be black. No bolding, underlining and italics are permitted. 


 
 
 
 
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Version Number: 2.0 
Version Date: 
25MAY2017 
Template No: CS_TP_BS016 – Revision 3 
Reference: CS_WI_BS005
Effective Date: 01MAY2012 
 
Header Information 
Headers should be defined as follows: 
 The header should be placed at the top of the page (same place on each page). 
 The sponsor name should appear in row 1, left-aligned. 
 The word “CONFIDENTIAL” should appear in row 1, right-aligned. 
 The protocol number should appear in row 2, left-aligned. 
 The page identification in the format Page X of Y (where Y is the total number of pages for the 
TLF) should appear in row 2, right-aligned. 
 The TLF identification number should appear in row 3, centered. 
 The TLF title should start in row 4, centered. 
 The TLF population should appear in row 5, centered. The population should be spelled out in 
full, e.g. Safety Analysis Population in preference to Safety analysis population. 
 Row 6 should be a continuous row of underscores (‘_’) (the number of underscores should equal 
the line size). 
 Row 7 should be a blank line. 
 Mixed case should be used for titles. 
 The column headings should be underlined with a row of underscores (‘_’). 
 Column headings spanning more than one column should be underlined and have underscores on 
either side of the title and should be centered. 
 Column headings should be in mixed case. 
 In general, the analysis population count should appear in the column header in the form 
“(N=XXX)”. 


 
 
 
 
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Template No: CS_TP_BS016 – Revision 3 
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Effective Date: 01MAY2012 
 
Table and Data Listing Table, Listing and Figure (TLF) Conventions 
General: 
 The first row in the body of the table or data listing should be blank. 
 The left hand column should start in Column 1. No indenting or centering of the TLF should occur. 
 Rounding should be done with the SAS® function ROUND. 
 Numerical values in tables should be rounded, not truncated. 
 Numerical values should be decimal point aligned. 
 Text values should be left aligned. 
 The first letter of a text entry should be capitalized. 
 The study drug should appear first in tables with treatment group as columns. 
 All variables contained on the eCRF (which have data present) should appear in the data listings, 
along with all derived data appearing in the corresponding tables. 
 The width of the TLF should match the line size. 
Univariate statistics: 
 Statistics should be presented in the same order across tables (i.e., n, mean, SD, minimum, median 
and maximum). 
 If the original data has N decimal places, then the summary statistics should have the following 
decimal places: 
o Minimum, maximum and CV (%): N. 
o Mean and median: N + 1. 
o SD: N + 2. 


 
 
 
 
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Version Number: 2.0 
Version Date: 
25MAY2017 
Template No: CS_TP_BS016 – Revision 3 
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Effective Date: 01MAY2012 
 
Frequencies and percentages (n and %): 
 Percent values should be reported inside parentheses, with one space between the count and the 
left parenthesis of the percentage. Parentheses should be justified to accept a maximum of 100.0 
as a value and padded with blank space if the percent is less than 100.0. An example is given 
below: 
o 77 (100.0) 
o 50 (64.9) 
o 0 (0.0) 
 Where counts are zero, percentages of 0.0 should appear in the table. 
CIs: 
 CIs should be presented with one additional decimal place as that of the raw data, and SDs and 
standard errors (SEs) with two additional decimal places as that of the raw data. 
 CIs should be justified so that parentheses displayed on consecutive lines of a table “line up”. 
P-values: 
P-values should be reported to four decimal places. 
Ratios: 
Ratios should be reported with one additional decimal place as that of the raw data. 
Spacing: 
Missing values: 
A “0” should be used to indicate a zero frequency. 


 
 
 
 
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Effective Date: 01MAY2012 
 
A blank will be used to indicate missing data in data listings. 
Figure Output Conventions 
Figures should be provided in RTF files using the SAS® Output Delivery System (ODS). 
Dates and Times 
Depending on data available, dates and times will take the form ddMMMyyyy and hh:mm. 
Spelling Format 
The spelling format to be used is English US.  
Presentation of Treatment Groups 
For TLFs, treatment groups will be represented in the following order: 
Treatment Group 
TLF Abbreviation 
See Section 3.1 of main SAP handling safety and efficacy 
J(loading dose/t.i.w.)PaZ 
See Section 3.1 of main SAP handling safety and efficacy 
J(200 mg)PaZ 
See Section 3.1 of main SAP handling safety and efficacy 
HRZE 
See Section 3.1 of main SAP handling safety and efficacy 
J(200 mg)MPaZMDR 
Screening Failure 
Screening Failure 


 
 
 
 
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Presentation of Visits 
For outputs, visits will be represented in the following order: 
Visit Name 
Day -9 to Day -3 
Day -2 
Day -1 
Day 1 
Baseline 
Day 4 
Day 8 
Day 14 
Day 15 
Day 22 
Day 29 
Day 36 
Day 43 
Day 50 
Day 56 
Day 57 
Day 70/Follow-up 
Day 140/Follow-up 
Unscheduled (chronologically) 


 
 
 
 
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Visit Name 
Early Withdrawal 
Month 8 Follow-Up 
Month 14 Follow-Up 
Month 20 Follow-Up 
Month 26 Follow-Up 
Note: Overnight sputum sample collection started one day prior to the visit.