Conditions: Tuberculosis, Pulmonary Tuberculosis, Multidrug-Resistant Tuberculosis, MDR Tuberculosis Drug-Resistant Tuberculosis
Keywords: tuberculosis TB DR-TB pretomanid (PA) PA-824 XDR TB Pa
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 26
Healthy volunteers: no

Brief summary:
Pretomanid is being used in an antimicrobial combination regimen(s) to treat patients with pulmonary tuberculosis (TB). The primary purpose of the Male Reproductive Safety - "BPaMZ/SEM"- clinical study is to evaluate the potential effect of pretomanid on human testicular function whilst being used in a 26 weeks antimicrobial combination regimen consisting of bedaquiline (B) plus pretomanid (Pa) plus moxifloxacin (M) and pyrazinamide (Z) (BPaMZ).

Detailed description:
The primary objective of this study is to assess the male reproductive safety of pretomanid in the regimen (BPaMZ) of bedaquiline 200mg (200mg daily for 8 weeks then 100 mg daily for 18 weeks), together with pretomanid 200 mg (1x daily) + moxifloxacin 400 mg (1x daily) + pyrazinamide 1500 mg (1 x daily) for 26 weeks in participants with drug-resistant pulmonary tuberculosis (DR-TB).

The secondary objective of the study is to evaluate the tuberculosis (TB) treatment efficacy, safety and tolerability after 26 weeks of active treatment for TB and follow up until 52 weeks after end of the above-described treatment regimen in participants with DR-TB.

Arms:
arm 1: Participants will receive bedaquiline 200 mg once daily for 8 weeks then 100 mg once daily for 18 weeks together with pretomanid 200 mg + moxifloxacin 400 mg + pyrazinamide 1500 mg once daily (BPaMZ) for 26 weeks.

Interventions: intervention 1: Pretomanid intervention 2: Bedaquiline intervention 3: moxifloxacin intervention 4: pyrazinamide
Intervention descriptions: intervention 1: pretomanid 200 mg (once daily) for 26 weeks (with meal) intervention 2: bedaquiline 200 mg (once daily) for 8 weeks (with meal), then bedaquiline 100mg (once daily) for 18 weeks (with meal) intervention 3: moxifloxacin 400 mg (once daily) for 26 weeks (with meal) intervention 4: pyrazinamide 1500 mg (once daily) for 26 weeks (with meal)

Protocol document:
Prot_000.pdf: 
 
 
CONFIDENTIAL  
Protocol Number:
Pa-824-CL-012 
Title:
An Open-Label Phase 2 Trial to Evaluate the Male 
Reproductive Safety of a 6-month Combination Treatment 
for Pulmonary Tuberculosis of Bedaquiline plus Pretomanid 
plus Moxifloxacin plus Pyrazinamide (BPaMZ) in Adult Male 
Participants with Drug Resistant (DR-TB) Pulmonary 
Tuberculosis
Drug(s)/Combination(s):
Bedaquiline tablets (B), pretomanid tablets (Pa), 
moxifloxacin tablets (M), pyrazinamide tablets (Z), 
Protocol Version/Date:
Version 4.0 / 07 APR 2022 
Protocol Name:
BPaMZ/SEM


TB Alliance
Protocol Number: Pa-824-CL-012 
Protocol Version: V4.0 07 Apr 2022
Protocol Name:    BPaMZ/SEM
TMP-C-SOP01-B V1.0 30-JAN-2019
CONFIDENTIAL
Page 2 of 79
PROTOCOL SIGNATURE PAGE
Protocol Title:  An Open-Label Phase 2 Trial to Evaluate the Male Reproductive Safety 
of a 6-month Combination Treatment for Pulmonary Tuberculosis of Bedaquiline plus 
Pretomanid plus Moxifloxacin plus Pyrazinamide (BPaMZ) in Adult Male Participants 
with Drug Resistant (DR-TB) Pulmonary Tuberculosis
Protocol Number:  Pa-824-CL-012
Protocol Date:        07-APR-2022
Protocol Name:      BPaMZ/SEM 
SPONSOR 
I agree to the terms of this trial protocol.
Paul Bruinenberg, MD 
Signature of Senior Medical Officer 
Printed Name
40 Wall Street, 24 FL
New York, NY, 10005
Phone: +1 646-616-8629/ +1 201-312-
0988  
email: Paul.Bruinenberg@tballiance.org
Date
LEAD INVESTIGATOR
I agree to the terms of this trial protocol. I will conduct the trial according to the procedures 
specified herein and in accordance to the principles of current Good Clinical Practice (cGCP) 
and local regulations.
Pauline Howell, MD
Signature 
Printed Name
Date


TB Alliance 
Protocol Number: Pa-824-CL-012 
Protocol Version: V4.0 07 APR 2022 
Protocol Name:   BPaMZ/SEM  
 
TMP-C-SOP01-B V1.0 30-JAN-2019 
CONFIDENTIAL
Page 3 of 79
 
PRINCIPAL INVESTIGATOR PROTOCOL SIGNATURE PAGE 
Protocol Title:  An Open-Label Phase 2 Trial to Evaluate the Male Reproductive Safety of a 
6-month Combination Treatment for Pulmonary Tuberculosis of Bedaquiline plus 
Pretomanid plus Moxifloxacin plus Pyrazinamide (BPaMZ) in Adult Male Participants with 
Drug Resistant (DR-TB) Pulmonary Tuberculosis  
Protocol Number:   Pa-824-CL-012  
 
Protocol Date:  V4.0 07 APR 2022 
 
Protocol Name:  BPaMZ /SEM  
 
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
 
 


TB Alliance 
Protocol Number: Pa-824-CL-012 
Protocol Version: V4.0 07 APR 2022 
Protocol Name:    BPaMZ/SEM 
 
TMP-C-SOP01-B V1.0 30-JAN-2019 
CONFIDENTIAL
Page 4 of 79
 
Table of Contents
a. 1 
Synopsis 
11 
1.1 
Synopsis Summary ..................................................................................................11 
1.1.1 
Synopsis Flow Chart and Procedures .......................................................15 
i. 
Screening Visit ..........................................................................................17 
ii. 
Day 1 (Baseline)........................................................................................17 
iii. 
Unscheduled Visits (due to unforeseen circumstances) ............................17 
iv. 
Follow-up Visits for Early Withdrawal Participants: ....................................17 
v. 
Visit Windows ............................................................................................17 
2 
Introduction and Rationale .................................................................................................21 
2.1 
Trial Rationale .........................................................................................................21 
2.2 
Drugs used in the TB Antimicrobial BPaMZ regimen ...............................................24 
2.2.1 
Pretomanid [5] ............................................................................................24 
2.2.2 
Information regarding other compounds used with in the BPaMZ ..............28 
2.3 
Overall Benefit/Risk Assessment .............................................................................31 
3 
Trial Objectives ..................................................................................................................32 
4 
Trial Endpoints ...................................................................................................................33 
4.1 
Primary Endpoint .....................................................................................................33 
4.2 
Secondary Endpoints ...............................................................................................33 
4.3 
Other Secondary Endpoints: ....................................................................................33 
5 
Trial Design ........................................................................................................................33 
5.1 
Summary of Trial Design .........................................................................................33 
5.2 
Treatment Plan: Schedule of Assessments..............................................................34 
6 
Trial Population ..................................................................................................................34 
6.1 
Inclusion Criteria ......................................................................................................34 
6.2 
Exclusion Criteria .....................................................................................................35 
Diagnostic and Laboratory Abnormalities ...........................................................37 
6.3 
Restrictions ..............................................................................................................38 
Discontinuation from Treatment/Trial ............................................................................39 
6.3.1 
Early Withdrawal .......................................................................................40 
6.3.2 
Unscheduled Visits ....................................................................................40 
6.3.3 
Lost-to-Follow-up ......................................................................................40
6.3.4 
Early Withdrawal due to TB .......................................................................40 


TB Alliance 
Protocol Number: Pa-824-CL-012 
Protocol Version: V4.0 07 APR 2022 
Protocol Name:    BPaMZ/SEM 
 
TMP-C-SOP01-B V1.0 30-JAN-2019 
CONFIDENTIAL
Page 5 of 79
 
6.4
Participant Progress Definitions...............................................................................41
6.5 
Trial Stopping Rules ................................................................................................42 
7 
Treatment ..........................................................................................................................42 
7.1 
IMP Administration ...................................................................................................42 
7.2 
Participant Compliance ............................................................................................42 
7.3 
Treatment Modification(s) ........................................................................................42 
7.4 
IMP Packaging and Labelling ..................................................................................43 
7.5 
Method of Treatment Assignment ............................................................................44 
7.6 
Blinding and Procedures for Breaking the Blind .......................................................44 
7.7 
Handling, Storage and Accountability ......................................................................44 
8 
Trial Variables and Procedures ..........................................................................................45 
8.1 
Demographic and Background Variables and Procedures .......................................45 
8.2 
Trial Variables and Procedures ................................................................................46 
8.2.1 
Semen Sample Test Parameters ..............................................................46 
8.2.2 
Laboratory Male Reproductive Hormone Blood Sample Test 
Parameters ...............................................................................................47 
8.2.3 
TB Efficacy Variables and Procedures ......................................................47 
8.3 
Safety and Tolerability Assessments .......................................................................48 
8.4 
PK Variables and Procedures ..................................................................................49 
8.5 
Mycobacteriology Characterization Variable and Procedures ..................................49 
9 
Adverse Events ..................................................................................................................50 
9.1 
Definitions ................................................................................................................50 
9.1.1 
Adverse Event (AE) ...................................................................................50 
9.1.2 
Serious Adverse Event (SAE) ...................................................................50 
9.1.3 
Attribution/Causality ..................................................................................50 
9.1.4 
Severity .....................................................................................................51 
9.2 
Reporting .................................................................................................................52 
9.2.1 
Follow up of Adverse Events .....................................................................53 
9.2.2 
Clinical Laboratory Adverse Events ...........................................................53 
9.2.3 
Disease under Study .................................................................................53 
9.2.4 
Overdose ..................................................................................................54 
9.2.5 
Drug Interaction.........................................................................................54
9.3 
Monitoring for Specific Toxicities ..............................................................................54 
9.3.1 
ALT, AST and Bilirubin ..............................................................................54 


TB Alliance 
Protocol Number: Pa-824-CL-012 
Protocol Version: V4.0 07 APR 2022 
Protocol Name:    BPaMZ/SEM 
 
TMP-C-SOP01-B V1.0 30-JAN-2019 
CONFIDENTIAL
Page 6 of 79
 
9.3.2
Lipase .......................................................................................................55
9.3.3 
Musculoskeletal System and Cardiac Muscle Myalgia ..............................55 
9.3.4 
Cardiac Rhythm Disturbances ...................................................................55 
9.4 
Safety Monitoring .....................................................................................................55 
10 Statistical Analysis .............................................................................................................56 
10.1 Analysis Population .................................................................................................56 
10.2 Sample Size ............................................................................................................57 
10.3 Interim Analyses ......................................................................................................57 
10.4 Primary and Secondary Endpoint Analysis ..............................................................57 
10.4.1 
Primary Endpoint Analysis ........................................................................57 
10.4.2 
Secondary Endpoints ................................................................................57 
10.4.3 
Other Secondary Endpoints ......................................................................57 
10.5 Safety and Tolerability Analysis ...............................................................................58 
10.6 Pharmacokinetics ....................................................................................................58 
10.7 Pharmacokinetics/Pharmacodynamics ....................................................................58 
11 Records Management ........................................................................................................58 
11.1 Data Collection ........................................................................................................58 
11.2 Source Documents ..................................................................................................59 
11.3 File Management at the Trial Centre ........................................................................59 
11.4 Records Retention at the Trial Centre ......................................................................59 
12 Quality Control and Assurance ...........................................................................................59 
12.1 Site Procedures .......................................................................................................59 
12.2 Monitoring ................................................................................................................60 
12.3 Protocol Deviations ..................................................................................................60 
12.4 Auditing  ..................................................................................................................60 
13 Ethics and Regulatory ........................................................................................................61 
13.1 Basic Principles .......................................................................................................61 
13.2 Independent Ethics Committee/Institutional Review Board (IEC/IRB) Review ..........61 
13.3 Regulatory Authorities .............................................................................................61 
13.4 Informed Consent ....................................................................................................61
13.5 Confidentiality ..........................................................................................................62 


TB Alliance 
Protocol Number: Pa-824-CL-012 
Protocol Version: V4.0 07 APR 2022 
Protocol Name:    BPaMZ/SEM 
 
TMP-C-SOP01-B V1.0 30-JAN-2019 
CONFIDENTIAL
Page 7 of 79
 
14
Publication Policy...............................................................................................................62
15 Protocol Amendment Policy ...............................................................................................63 
16 Sponsor, Financial Aspects, Insurance, and Indemnity ......................................................63 
17 References ........................................................................................................................64 
 
Appendices
Appendix 1: The IUATLD Scale ................................................................................................66 
Appendix 2: Division of Microbiology and Infectious Disease (DMID) Toxicity Table .................67 
Appendix 3: WHO Clinical Staging of HIV/AIDS for Adults and Adolescents .............................76 
Appendix 4: Cardiovascular Safety ...........................................................................................78 
Appendix 5: Paternity Questionnaire .........................................................................................79 
 


TB Alliance 
Protocol Number: Pa-824-CL-012 
Protocol Version: V4.0 07 APR 2022 
Protocol Name:    BPaMZ/SEM 
 
TMP-C-SOP01-B V1.0 30-JAN-2019 
CONFIDENTIAL
Page 8 of 79
 
Tables
Table 1: Products ......................................................................................................................34 
Table 2: Participant Progress Definitions...................................................................................41 
Table 3: Adverse Events Attribution/Causality Ratings ..............................................................51 
Table 4: Definitions for Adverse Event Severity Gradings .........................................................51 
 


TB Alliance 
Protocol Number: Pa-824-CL-012 
Protocol Version: V4.0 07 APR 2022 
Protocol Name:    BPaMZ/SEM 
 
TMP-C-SOP01-B V1.0 30-JAN-2019 
CONFIDENTIAL
Page 9 of 79
 
Abbreviations and Definition of Terms
AE 
Adverse Event 
AFB
Acid-Fast Bacillus  
AIDS
Acquired Immune Deficiency Syndrome
ALP
Alkaline Phosphatase
ALT 
Alanine aminotransferase
ART
AST
Anti-Retroviral Therapy
Aspartate aminotransferase
AUC
Area Under Concentration Time Curve 
AUC0-24
Area Under Concentration Time Curve 0 to 24 hours 
AUC0-inf
Area Under Concentration Time Curve extrapolated to infinity
AUC  
Area Under Concentration Time Curve during the dosing interval
B
BA
Bedaquiline 
Bacterial Activity 
BMI 
Body Mass Index 
BPaL 
BPaMZ 
C
Combination of Bedaquiline plus pretomanid plus Linezolid 
Combination of Bedaquiline plus pretomanid plus moxifloxacin plus pyrazinamide 
Clofazimine 
Cavg 
Average Plasma Concentration
CD4
Cluster of Differentiation 4
CFU 
Colony Forming Units
C(max), (min)
Plasma Concentration (maximum), (minimum)
CNS
Central Nervous System 
CO2
Carbon dioxide 
CPK 
Creatine Phosphokinase 
Ddn 
Deazaflavin-dependent nitro reductase 
DFID
Department for International Development
DGIS 
Netherlands Ministry of Foreign Affairs
DMID
Division of Microbiology and Infectious Disease
DR-TB 
Drug Resistant Tuberculosis
DS-TB
Drug Sensitive Tuberculosis
DSMC
Data Safety and Monitoring Committee 
E
Ethambutol
EBA
Early Bactericidal Activity 
EC 
Ethics Committee
ECG 
Electrocardiogram 
eCRF
electronic Case Report Form
ELISA 
Enzyme-linked immunosorbent assay 
EMS 
Early Morning Sputum
EOT 
End of Treatment
EWD
Early Withdrawal 
FSH
Follicle-stimulating hormone
GCP  
Good Clinical Practice
GGT 
Gamma Glutamyl Transferase
H
Isoniazid
HIV 
Human Immunodeficiency Virus
HR 
Isoniazid, Rifampicin 
HRZE
Isoniazid, Rifampicin, Pyrazinamide, Ethambutol 


TB Alliance 
Protocol Number: Pa-824-CL-012 
Protocol Version: V4.0 07 APR 2022 
Protocol Name:    BPaMZ/SEM 
 
TMP-C-SOP01-B V1.0 30-JAN-2019 
CONFIDENTIAL
Page 10 of 79
 
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee 
IMP 
Investigational Medicinal Product
IRB
Institutional Review Board
kg
kilogram
LFT
Liver Function Test
L 
Linezolid
LBBB
Left bundle branch block
LH
Luteinizing hormone 
LLN
LPLV 
Lower Limit of Normal
Last Patient Last Visit
LTFU 
Lost-to-Follow-up
M
Moxifloxacin
MDR-TB
Multi Drug Resistant Tuberculosis
mg/dl 
milligrams per deciliter
MGIT 
Mycobacterial Growth Inhibiting Tube
MRHD
Maximum recommended human dose
ms
millisecond 
Mtb
Mycobacterium tuberculosis 
N/A
Not Applicable 
NCS
Non-clinically Significant
NRTI
Nucleoside reverse transcriptase inhibitor
NTP
National TB Program
Pa 
Pretomanid 
Pa-824 
Pretomanid 
PD 
Pharmacodynamic 
PDE5
Phosphodiesterase type 5 inhibitor 
PK
Pharmacokinetic 
PT
Preferred Term
QD 
R
Once Daily 
Rifampicin 
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan 
TB
Tuberculosis
TdP 
Torsade de pointes 
TEAE
Treatment Emergent Adverse Events
TI/NR
Treatment intolerant/ nonresponse
TTP
Time to Positivity 
ULN
Upper Limit of Normal 
USAID 
United States Agency for International Development
 
WBC
micrograms per deciliter
White Blood Cell 
WHO 
World Health Organization
XDR-TB 
extensively Drug Resistant Tuberculosis 
Z
Pyrazinamide (tablets)


TB Alliance 
Protocol Number: Pa-824-CL-012 
Protocol Version: V4.0 07 APR 2022 
Protocol Name:    BPaMZ/SEM 
 
TMP-C-SOP01-B V1.0 30-JAN-2019 
CONFIDENTIAL
Page 11 of 79
 
1 
Synopsis
1.1
Synopsis Summary
Name of 
Sponsor/Company
Global Alliance for TB Drug Development
Name of Finished 
Products: 
Bedaquiline tablets (B), pretomanid tablets (Pa), moxifloxacin tablets (M), 
pyrazinamide tablets (Z) 
Protocol Number/Title:
An Open-Label Phase 2 Trial to Evaluate the Male Reproductive Safety of 
a 6-month Combination Treatment for Pulmonary Tuberculosis of 
Bedaquiline plus Pretomanid plus Moxifloxacin plus Pyrazinamide (BPaMZ) 
in Adult Male Participants with Drug Resistant (DR-TB) Pulmonary 
Tuberculosis
Treatment Indication:
Pulmonary Tuberculosis (TB)
Trial Objective(s):
Primary Objective:
To assess the male reproductive safety of pretomanid in the regimen 
(BPaMZ) of Bedaquiline 200mg (200mg daily for 8 weeks then 100 mg 
daily for 18 weeks), together with pretomanid 200 mg (1x daily) + 
moxifloxacin 400 mg (1x daily) + pyrazinamide 1500 mg (1x daily) for 26 
weeks in participants with Drug-resistant (DR) pulmonary TB. 
Secondary objective: 
To evaluate the TB treatment efficacy, safety and tolerability after 26 weeks 
of active treatment for TB and follow up for 52 weeks after end of the 
above-described treatment regimen in participants with Drug-resistant (DR) 
pulmonary TB. 
Patient population: 
DR-TB Defined as Mycobacterium tuberculosis that is sensitive to 
fluoroquinolones but   
1. Mono-resistant to rifampicin or isoniazid, OR  
2. Resistant to both rifampicin and isoniazid (MDR-TB) 
Trial Design:
Phase 2 single arm multi-center, open-label clinical trial in DR-TB 
participants.  
Participants will receive Bedaquiline 200 mg once daily for 8 weeks then 
100 mg once daily for 18 weeks; together with pretomanid 200 mg 
+ moxifloxacin 400 mg + pyrazinamide 1500 mg once daily (BPaMZ) for 26 
weeks.  
 
Participants will be followed for 52 weeks after end of treatment.  
Patient Population: 
A total of 20 evaluable male participants diagnosed with DR-TB who 
completed the trial is required. Twenty-five participants (25) will be enrolled 
in the trial assuming a 20% participant drop out of the trial.  
Replacing participants who drop out of the trial may be considered. 
Participants should be aged 18 years and over.    


TB Alliance 
Protocol Number: Pa-824-CL-012 
Protocol Version: V4.0 07 APR 2022 
Protocol Name:    BPaMZ/SEM 
 
TMP-C-SOP01-B V1.0 30-JAN-2019 
CONFIDENTIAL
Page 12 of 79
 
Name of 
Sponsor/Company 
Global Alliance for TB Drug Development
Name of Finished 
Products:
Bedaquiline tablets (B), pretomanid tablets (Pa), moxifloxacin tablets (M), 
pyrazinamide tablets (Z)
Test product, Dose 
and Mode of 
Administration: 
The Test Treatment Regimen (BPaMZ) consists of a combination of the 
following products and will be supplied as: 
Product
Tablet Strength
Abbreviation 
Bedaquiline
100 mg
(B)
Pretomanid
200 mg
(Pa)
Moxifloxacin
400 mg
(M)
Pyrazinamide
500 mg
(Z)
Instructions for Dosing of Test Regimen (BPaMZ): 
Treatment will be administered orally once daily, to be taken with a meal at 
approximately the same time each day with a full glass of water 
(approximately 240 ml), for 26 weeks in the following dosing scheme: 
Bedaquiline 200 mg once daily for 8 weeks then 100 mg once daily for 18 
weeks, together with pretomanid 200 mg + moxifloxacin 400 mg + 
pyrazinamide 1500 mg once daily for 26 weeks (total treatment duration 6 
months). 
Treatment Interruptions/Pauses 
Trial Regimen: 
The trial treatment regimen may require interruptions/pauses due to 
toxicities. All dose interruptions/pauses should be discussed with the 
Sponsor’s Medical Monitor prior to implementation unless an 
interruption/pause is required urgently for a safety concern.   
Action required for participants missing the following number of doses within 
the trial treatment regimen:  
 
Up to 7 consecutive doses: restart treatment, no extension of 
treatment required. 
 
 of IMP: restart IMP and 
extend the IMP treatment by the number of consecutive doses 
missed. In this scenario, >7 missed doses between Baseline (Day 1) 
through week 8 inclusive i.e., bedaquiline dose of 200mg BDQ, will 
need to be caught up before the participant can start week 9 
treatment visit.  Similarly, >7 missed doses between week 9 through 
week 26 inclusive, i.e., bedaquiline dose of 100mg BDQ, will require 
a make up for completion of treatment. The final treatment visit 
should be pushed out to the date of last dose. It is not necessary to 
have an unscheduled visit at the time when the end of treatment visit 
would have been.     


TB Alliance 
Protocol Number: Pa-824-CL-012 
Protocol Version: V4.0 07 APR 2022 
Protocol Name:    BPaMZ/SEM 
 
TMP-C-SOP01-B V1.0 30-JAN-2019 
CONFIDENTIAL
Page 13 of 79
 
Name of 
Sponsor/Company 
Global Alliance for TB Drug Development
Name of Finished 
Products:
Bedaquiline tablets (B), pretomanid tablets (Pa), moxifloxacin tablets (M), 
pyrazinamide tablets (Z)
Greater than 35 consecutive doses: discontinue treatment and 
withdraw participant from the trial.  
If the participant misses a total (sum) of 56 cumulative doses, 
discontinue treatment and withdraw participant from the trial. 
 
Statistical Methods: 
A general description of the statistical methods planned to be used to analyse safety and efficacy data 
is outlined below. Specific details will be provided in the statistical analysis plan (SAP), which will be 
written and signed off prior to the first participant enrolled in the trial. 
Sample Size:
Sequential assessment of semen parameters in a cohort of 20 men followed for 26 weeks on 
treatment. 
Objective of the trial:                                                                                                                                 
This study is intended to rule out clinically significant severe adverse effects on testicular function. 
Criteria for Evaluation: 
Primary Endpoint: 
 
Change from baseline in total sperm count at 26 weeks. 
Secondary Endpoint(s):  
 
Change from baseline in total sperm count at 13 and 44 weeks. 
 
The change from baseline in male reproductive hormones at Week 2, 4, 8, 12, 16, 26, 35, 44, 
52, 65, 78, and at early withdrawal.   Reproductive hormones: luteinizing hormone (LH), 
follicle-stimulating hormone (FSH), Inhibin B and testosterone). 
Other Secondary Endpoints: 
Efficacy:
 Incidence of bacteriologic failure or relapse or clinical failure at78 weeks after the start of 
therapy.  
 Proportion of participants with sputum culture conversion to negative status in liquid culture 
(MGIT) at Week 4, 8, 12, 16, 22, 26, 35,44, 52, 65 and 78. 
Safety and Tolerability: 
 Change in weight from baseline. 
 Incidence of Treatment Emergent Adverse Events (TEAEs) presented by incidence, severity, 
drug relatedness, seriousness, leading to early withdrawal, and leading to death.  
 Quantitative and qualitative clinical safety laboratory measurements, including observed and 
change from baseline. 


TB Alliance 
Protocol Number: Pa-824-CL-012 
Protocol Version: V4.0 07 APR 2022 
Protocol Name:    BPaMZ/SEM 
 
TMP-C-SOP01-B V1.0 30-JAN-2019 
CONFIDENTIAL
Page 14 of 79
 
Name of 
Sponsor/Company 
Global Alliance for TB Drug Development
Name of Finished 
Products:
Bedaquiline tablets (B), pretomanid tablets (Pa), moxifloxacin tablets (M), 
pyrazinamide tablets (Z)
Quantitative and qualitative electrocardiogram (ECG) results (heart rate, RR interval, PR 
interval, QRS interval, QT interval and QTc interval, including observed QT/QTc intervals and 
change from baseline) will be categorized. 
Trial Duration:
Estimated date of first Participant enrolled: 
 
Quarter 3Q2021 
Estimated date of last Participant enrolled: 
 
Quarter 4Q2022 
Estimated date of last Participant completed: 
             Quarter 2Q2023 
 
Duration of trial: 
 
Approximately 3 years: up to 52 weeks enrollment period plus up to 2-week screening period plus 26 
weeks treatment and 52 weeks follow-up after stop of treatment. 
 


TB Alliance
Protocol Number: Pa-824-CL-012
Protocol Version: V4.0 07 APR 2022
Protocol Name:   BPaMZ/SEM
TMP-C-SOP01-B V1.0 30-JAN-2019
CONFIDENTIAL
Page 15 of 79
Synopsis Flow Chart and Procedures
Period
Screening
Treatment 
Follow Up
Visit
a
Visit Window
N/A
+/- 3 days
+/-7 days
+/-14 days
Written Informed 
Consent
X
Demography/Medic
al 
Treatment/Smoking 
History
X
Inclusion/Exclusion
X
X
b
Sputum Sampling
X
X
X
X
X
X
X
X
X
X
X
X
X
X
c
HIV Status and CD4 
Count
X
d
Urine Drug Screen
X
e
Safety Laboratory 
Test
X
X
X
X
X
X
X
X
X
X
X
X
X
X
f
Semen Sampling
QX
BX
g
Male Reproductive 
Hormone Tests
X
X
X
X
X
X
X
X
X
X
X
X
X
h
12-Lead ECG
X
X
X
X
X
X
X
X
X
X
X
X
X
X
i
Chest X-Ray
X
X
Vital Signs and 
Weight
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
j
Physical Exam –
Full
X
X
X
j
Physical Exam –
Limited
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


TB Alliance 
Protocol Number: Pa-824-CL-012 
Protocol Version: V4.0 07 APR 2022 
Protocol Name:    BPaMZ/SEM 
 
TMP-C-SOP01-B V1.0 30-JAN-2019 
 
CONFIDENTIAL 
Page 16 of 79 
 
 
Period 
Screening 
 
 
Treatment  
 
 
Follow Up 
Footnote 
Visit 
Day -21 to -1 
Day 1 (Baseline) 
Week 2 
Week 3 
Week 4 
Week 5 
Week 6 
Week 7 
Week 8 
Week 12 
Week 12 to 13 
Week 16 
Week 22  
Week 26 (EOT) 
Week 26 to 27 
Week 35  
Week 44 
Week 44 to 45 
Week 52 
Week 65  
Week 78 
Early Withdrawal 
a 
Visit Window 
N/A 
+/- 3 days 
+/-7 days 
 
+/-14 days 
k 
Pharmacokinetic 
Sampling 
 
 
X 
 
X 
 
 
 
X 
X 
 
X 
X 
X 
 
 
X 
 
 
 
 
X 
l 
IMP Assignment 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
m
IMP dispensing and 
compliance Check 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
 
 
 
 
 
 
X 
Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
n
Investigator 
Assessment 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
X 
X 
o
Paternity 
Questionnaire  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 


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Protocol Number: Pa-824-CL-012 
Protocol Version: V4.0 07 APR 2022 
Protocol Name:    BPaMZ/SEM 
 
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GENERAL: Vital signs, ECGs and blood draws are to be performed pre-dosing unless 
otherwise specified. Vital signs and/or ECGs should be done prior to blood draws (safety 
and PK) on days with those assessments.
b.
Visit Schedule
i. 
Screening Visit 
Screening assessments may occur over several days prior to Day 1 of dosing (i.e., not all 
screening procedures must be performed on the same day).  
ii. 
Day 1 (Baseline) 
All procedures are to be completed prior to dosing. 
iii. 
Unscheduled Visits (due to unforeseen circumstances) 
If the duration of treatment is extended due to dose interruptions / pauses, the last visit of 
the treatment period and all subsequent visits should also be pushed out to the date of 
last dose. It is not necessary to have an unscheduled visit at the time that the last visit of 
the treatment period would have been. 
iv. 
Follow-up Visits for Early Withdrawal Participants:  
Once a participant has been permanently withdrawn from the trial, they will be required to 
attend Early Withdrawal visit.   At Early Withdrawal visit, we will collect Serious Adverse 
Event (SAE) information (including verification of survival) and participant reported TB 
outcome information only and may be telephonic, at home or a site visit. 
v. 
Visit Windows 
The windows noted on the flowchart for timing of visit also apply to timing within a visit.  
Procedures should be performed within +/- 3 days of scheduled visit from Day 1 to Week 8 
or +/- 7 Days of scheduled visit from Week 9 to Week 26 or +/- 14 days of scheduled visit 
at or after Week 30.  Sites should make every effort to ensure all procedures are done on 
the same day, when possible. 
b. Sputum Sampling & Mycobacteriology Characterization 
 
The sputum sampling methodology/requirements and tests will be described in a separate 
document, the Mycobacteriology Laboratory Manual.  
 
i.Screening, Days -21 to -1
Two spot sputum samples taken at least 30 minutes apart will be collected under the 
coaching and observation of the trial staff. The following analyses will be performed on the 
first of these samples:  
 
Smear microscopy for Acid-Fast Bacilli (AFB);  
 
Rapid molecular tests for rifampicin and isoniazid resistance;  
 
Rapid molecular tests for fluoroquinolone resistance;  
 
Liquid Culture (MGIT) for Mycobacterium tuberculosis (Mtb) with identification to 
detect the presence or absence of Mtb and obtain the time to positivity (TTP) when positive 
and not contaminated;  
The second sample is collected as a back-up sample to the first sample in case it is 
technically not possible to obtain a result/s from the first sample. If the Day -21 to -1 
(Screening) spot sputum shows a negative or indeterminate molecular test result, the back-
up sample or a newly collected spot sputum may be used.  
 
ii.Baseline to Week 78, including Early Withdrawal and Unscheduled Visits  


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Protocol Number: Pa-824-CL-012 
Protocol Version: V4.0 07 APR 2022 
Protocol Name:    BPaMZ/SEM 
 
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Two spot sputum samples taken at least 30 minutes apart will be collected under the 
coaching and observation of the trial staff.  
 
If there is an Mtb positive culture (after the participant has previously converted to culture 
negative) at or after the last visit of the treatment period (Week 26), the participant should 
return for an unscheduled visit(s) to give additional sputum samples a minimum of 7 days after 
the previous sample, or to document that the participant is not able to produce sputum.   
 
Additional samples may be required to define a participant sputum outcome status. 
 
The following analyses will be performed on these samples: 
 
Liquid Culture (MGIT) for Mtb, followed by an identification test to detect presence or 
absence of Mtb and obtain the time to positivity (TTP) when culture positive and not 
contaminated will be performed on all samples.  
 
Susceptibility Testing for bedaquiline (B), moxifloxacin (M), pyrazinamide (Z) and 
pretomanid (Pa) on the following cultures: 
o 
The 1st positive non-contaminated Mtb positive culture from Screening up to Week 
4; 
o 
On Mtb positive cultures, after the participant has previously converted to culture 
negative at or after the last visit of the treatment period (Week 26); 
o 
At Early Withdrawal; 
o 
At Bacteriological failure, which is defined as failing to attain culture negative status 
at or before the end of treatment (Week 26).  The last available positive culture will 
be used for susceptibility testing e.g., the Early Withdrawal or Week 26 culture of a 
participant who withdrew and/or started re-treatment before the Week 78 visit or 
the Week 78 culture of a participant who has not started re-treatment. 
 
  
c. HIV Testing & CD4 Count  
If HIV status is a confirmed known positive, a repeated HIV test is not needed provided that a 
documented HIV test result is available. If HIV status is unknown or suspected negative, a HIV test 
will be requested. If an ELISA and/or Western Blot and/or Electro-Chemiluminescence based HIV 
test was performed within 4 weeks prior to screening, it should not be repeated if documentation of 
testing method and negative HIV results can be provided. Repeated HIV testing during the Screening 
period is permitted for indeterminate HIV results. 
 
CD4 count is required for HIV-positive participants.  
 
d.
Urine Drug Screening
Cannabinoids, cocaine, amphetamines, opiates, benzodiazepines, barbiturates, at Screening only. 
Investigator to utilize this result to determine whether participant meets Exclusion criteria. Positive 
results will not automatically exclude a participant from the trial.  
 
e. Safety Laboratory Assessments  
The Safety Laboratory sampling methodology and requirements will be described in a separate 
document, the Safety Laboratory Manual, which will be provided prior to the trial start. The 
following analyses will be performed: 
 
Full Blood Count (hemoglobin, hematocrit, red blood cell count, white blood cell count with 
differential, platelet count).   
 
Clinical Chemistry (albumin, urea, creatinine, direct, indirect and total bilirubin, uric acid, 
total protein, alkaline phosphatase [ALP], aspartate aminotransferase [AST], alanine 
aminotransferase [ALT], lipase, phosphate, sodium, potassium, calcium (corrected for albumin), 
chloride, magnesium, glucose, bicarbonate/carbon dioxide [CO2], creatine phosphokinase 
[CPK]).   
 
Urinalysis (pH, specific gravity, protein, glucose, micro-albumin, ketones, bilirubin, 
creatinine, nitrite, sodium, urobilinogen, blood, leukocytes). Microscopy will be completed as 


TB Alliance 
Protocol Number: Pa-824-CL-012 
Protocol Version: V4.0 07 APR 2022 
Protocol Name:    BPaMZ/SEM 
 
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follow-up to abnormal urinalysis per discretion of Investigator. Only at screening and Baseline-Day 
1).
 
When managing participants with elevated liver enzymes, refer to the Hepatotoxicity 
Manual.  
 
Hepatitis B and C test to be performed during screening visit.  
 
f. 
Semen Sampling (Two semen samples within a 14 day window) 
A single qualifying semen sample (QX) during screening. (Days -13 to -1) is required during 
screening to determine whether a participant qualifies for the Male Fertility Analysis per the 
inclusion/exclusion criteria.  
 
48 hours of sexual abstinence is required prior to obtaining semen sample (QX).  Sexual 
abstinence is the practice of refraining from all sexual intercourse, including masturbation.    
 
There is allowance for repeat collection of a qualifying semen sample (QX) for cases of sample 
handling or collection errors (e.g., spillage of sample by participant or by site staff prior to shipment 
of sample to lab, or sample gets misplaced/lost prior to shipment).   
 
Qualifying semen sample (QX) will be reviewed by an andrologist prior to enrollment. 
 
Another semen sample (BX) will be collected on Day 1, or Day 2. These two samples (QX and 
BX) are averaged to make up the baseline semen sample for the analyses.  
 
All semen samples must be separated by no less than 48 hours and preceded by no less 
than 48 hours of sexual abstinence.   
At week 12-13, week 26-27, and week 44-45 timepoint two (XX) semen samples must be collected 
within those weeks. These two (XX) samples will be averaged to make up the week 12, week 26 
and week 44 semen sample values.  
 
For week 12-13, week 26-27 and week 44-45 timepoints, a 14-day collection window is allowed 
with the aim of the (XX) semen samples to have about a 7-day separation between samples for 
these timepoints.  
 
Early withdrawal: After 18 weeks of treatment at any early withdrawal thereafter, two (XX) semen 
samples must be collected. These two samples per timepoint will also be averaged to make up the 
early withdrawal week semen sample value. 
g. Male Reproductive Hormone Tests 
Total Testosterone, follicle-stimulating hormone (FSH), luteinizing hormone (LH) and Inhibin B.  
Sample timepoints will be required at screening and at week 2, 4, 8, 12, 16, 26, 35, 44. 52, 65, 78 
and at early withdrawal. 
h. 12-Lead ECG 
Single 12-Lead ECG: To every extent possible, this should be performed at approximately the same 
time every day during trial procedures (+-1 hour). 
At visits when pre-dose PK samples are also scheduled, i.e., Weeks 2, 4, 8, 12, 16, 26, ECGs should 
be performed prior to PK sampling. PK samples will also be collected at Week 44 and Early 
Withdrawal.  
i. 
Chest X-Ray 
A chest x-ray (digital image only) within 6 months prior to screening or during day -21 to day -1, will 
be obtained and read locally by the Investigator or designee to confirm TB. 


TB Alliance 
Protocol Number: Pa-824-CL-012 
Protocol Version: V4.0 07 APR 2022 
Protocol Name:    BPaMZ/SEM 
 
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A chest x-ray (digital image only) at Week 26 EOT will be obtained and read locally by the investigator 
or designee to confirm TB treatment outcome.  
j. 
Physical Examination  
 
Physical – Full: Height (m) will only be collected at Day -21 to -1 (Screening). 
 
Physical Exam – Limited: Limited physical exams will include weight and gross neurological, 
pulmonary, cardiovascular and abdominal exam(s). 
k. Pharmacokinetic (PK) Sampling 
This process will be described in the safety laboratory manual.  Blood draws for PK samples collected 
pre-dose must be done after the ECG is performed. The dates and times of the doses of IMP taken 
prior to all pre-dose PK samples will be collected. Specific Pretomanid PK blood draws will be 
obtained pre-dose (within 2 hours prior to dosing at weeks 2, 4, 8, 12, 16, 22, 26, 44 or at early 
withdrawal if prior to week 26). 
l. 
Investigational Medicinal Product (IMP) Randomization/Assignment 
Enrolment may occur once all the Screening results are available, and the Investigator has 
determined that the participant is eligible for the trial. 
m. IMP/Compliance Check 
IMP administration will be supervised per local site practice to assure compliance to regimen. 
Performed at all visits and Early Withdrawal (EWD), if during the treatment period. 
n. Investigator Assessment 
Investigator to review participant status and assess whether IMP at current visit is considered a 
“success” or “failure”.  If considered a failure, the Investigator should specify if based on bacteriology 
and/or clinical deterioration and/or radiological deterioration. Investigator Assessment to be 
completed, as shown on the flowchart, and at any time Investigator determines that participant fulfils 
criteria for outcome of treatment failure. 
o. Paternity Questionnaire 
Collect information regarding fathering of children during and after the trial   
 
 


TB Alliance 
Protocol Number: Pa-824-CL-012 
Protocol Version: V4.0 07 APR 2022 
Protocol Name:    BPaMZ/SEM 
 
TMP-C-SOP01-B V1.0 30-JAN-2019 
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Page 21 of 79
 
 
2 
 Introduction and Rationale
Tuberculosis (TB) in humans is an infectious disease caused by the bacterium Mycobacterium
tuberculosis (Mtb), which typically affects the lungs (pulmonary TB) but can affect other sites as 
well (extrapulmonary TB). While incidence rates and mortality for TB have been falling, it remains 
the ninth leading cause of death worldwide, the world’s leading cause of death from a single 
infectious disease and is responsible for more deaths than human immunodeficiency virus (HIV). 
In 2018, 10.0 million (range, 9.0 - 11.1 million) new cases of TB were reported. (World Health 
Organization [WHO] Global TB Report 2019) (1). 
The current TB treatment regimens have a lengthy duration of treatment, involve multi-drug 
therapy, many tolerability issues, and require large commitments of resources and infrastructure. 
High rates of noncompliance are common, which often results in increased mortality, chronic, 
infectious, and drug-resistant cases. The present TB epidemic and treatment conditions 
demonstrate the clear need in patients with drug-sensitive or drug-resistant TB for novel drugs 
and drug regimens that will shorten the current treatment duration and be safe and well tolerated. 
In addition, new TB drugs and regimens should also be affordable, easy to adopt and implement, 
suitable for pediatric use and for co-administration with antiretroviral therapy in individuals 
co-infected with Mtb and HIV. Following the declaration of TB as a global emergency by the 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. 
There are several drugs which are in different stages of development but only a few have 
advanced to phase 3 clinical trials and are being tested alone or in combination with other anti-TB 
drugs(2).  Pretomanid (Pa-824) is one of these new drugs and recently received U.S. approval (on 
14th August 2019) in a combination regimen with Bedaquiline and Linezolid (BPaL) for people with 
XDR-TB or treatment-intolerant/non-responsive MDR-TB. Pretomanid is also being developed for 
the treatment of drug sensitive (DS)- and Drug Resistant (DR)-TB. Study NC-008 (An 
Open-Label, Partially Randomized Trial to Evaluate the Efficacy, Safety and Tolerability of a 
4-month Treatment of Bedaquiline plus Pretomanid plus Moxifloxacin plus Pyrazinamide (BPaMZ) 
Compared to a 6-month Treatment of HRZE/HR (Control) in Adult Participants with 
Drug-Sensitive Smear-Positive Pulmonary Tuberculosis (DS-TB) and a 6-month Treatment of 
BPaMZ in Adult Participants with Drug Resistant, Smear-Positive Pulmonary Tuberculosis 
(DR-TB) is currently ongoing. 
 
2.1
Trial Rationale
Pretomanid is being used in an antimicrobial combination regime(s) to treat patients with 
pulmonary tuberculosis. The primary purpose of the Male Reproductive Safety – 
“BPaMZ/SEM”- clinical study is to evaluate the potential effect of Pretomanid on human 
testicular function whilst being used in a 6 months antimicrobial combination regime 
consisting of Bedaquiline (B) plus Pretomanid (Pa) plus Moxifloxacin (M) and Pyrazinamide (Z) 
(BPaMZ).  
 


TB Alliance 
Protocol Number: Pa-824-CL-012 
Protocol Version: V4.0 07 APR 2022 
Protocol Name:    BPaMZ/SEM 
 
TMP-C-SOP01-B V1.0 30-JAN-2019 
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Background 
The findings of testicular toxicity in animal species have been a challenge in pharmaceutical drug 
development (2).  As an example, over the Past 10 years formal studies have been conducted on 
the effects of PDE5 inhibitors on human semen and spermatogenesis (3,4). Studies of the effects 
of these drugs on semen parameters in humans are challenging to implement and have generally 
been evaluated in patients but also in healthy young male volunteers who have been 
administered the drug daily for 6-12 months. 
Pretomanid is a new antimicrobial compound recently approved to be used in a 6-month 
antimicrobial combination regime [Bedaquiline (B) plus Pretomanid (Pa) plus Linezolid (L) [BPaL] 
regime] to treat patients with XDR pulmonary tuberculosis. Pretomanid is also being studied for 
the treatment of TB in a 4 month and 6 months antimicrobial combination regime consisting of 
Bedaquiline (B) plus Pretomanid (Pa) plus Moxifloxacin (M) and Pyrazinamide (Z) (BPaMZ) in 
drug sensitive (DS)- and Drug Resistant (DR) -TB. The primary purpose of this male reproductive 
safety study (Pa-824-CL012 – “BPaMZ/SEM”-) is to evaluate the potential effect of once-a-day 
pretomanid (200mg) on human testicular function whilst being dosed as an antimicrobial regimen 
consisting of Bedaquiline (B) plus Pretomanid (Pa) plus Moxifloxacin (M) and Pyrazinamide (Z) 
(BPaMZ) for 6 months in DR-TB patients.  
In nonclinical toxicology studies of PA-824 (Pretomanid), testicular degeneration/atrophy has 
occurred in rats with repeated doses of PA-
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-
with decreased sperm count and motility. This effect on fertility in male rats was partially 
reversible. Repeat toxicology studies were conducted in the monkey (0, 50, 150, 300 mg/kg/day 
for 3 months; 20-week recovery period) to further explore the male reproductive system effects of 
PA-824. In this trial direct testes effects (semen morphology, organ weights, histopathology), or 
effects on hormones [testosterone, follicle-stimulating hormone (FSH), inhibin-B]) were not 
observed at any point during dosing or during the 20-week recovery period.  
In follow-up to the non-clinical findings, males in the 8-week Phase 2 Trial NC-002-(M-Pa-Z) were 
evaluated by plasma sampling for the reproductive hormones Luteinizing Hormone (LH), FSH and 
Testosterone at baseline and at the end of the treatment period.  If the trial drug regimen caused 
testicular toxicity, the most sensitive measure from these hormones would be an increase in 
levels of FSH. Among participants 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 (N=21 with samples at baseline and Day 56).  
Among participants 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 (N=19 with samples at baseline and 
Day 56). Men in the rifampicin 150 mg plus isoniazid 75 mg plus pyrazinamide 400 mg plus 
ethambutol 275 mg combination tablets (HRZE) control group had a mean baseline of 7.394 U/L 
which decreased to 6.714 at the end of therapy (N=23 with samples at baseline and Day 56).  
This gives relative reassurance that pretomanid is not likely to cause testicular toxicity in men.   
 
 


TB Alliance 
Protocol Number: Pa-824-CL-012 
Protocol Version: V4.0 07 APR 2022 
Protocol Name:    BPaMZ/SEM 
 
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Trial Design Rationale 
The primary purpose of this Male Reproductive Safety – “BPaMZ/SEM”- clinical study is to 
generate data to evaluate the potential effect of once daily 200mg Pretomanid on human 
testicular function whilst being dosed for 6 months in patients with Drug Resistant (DR-TB) 
Pulmonary Tuberculosis. The 6 months dosing period covers current use of pretomanid is an 
approved antimicrobial regimen for the treatment of TB. (Pretomanid in combination regimen with 
Bedaquiline and Linezolid (BPaL) for people with XDR-TB or treatment-intolerant/non-responsive 
MDR-TB). It is not feasible to evaluate the potential testicular toxicity of once daily 200mg 
Pretomanid in this BPaL regime, as Linezolid has shown toxicity on testicular function in 
non-clinical studies. Therefore, the study will be conducted using the antimicrobial regimen 
consisting of Bedaquiline (B) plus Pretomanid (Pa) plus Moxifloxacin (M) and Pyrazinamide (Z) 
(BPaMZ) for 6 months in DR-TB patients. Participants will also be followed up to 18 weeks post 
dose to evaluate and ensure coverage of potential recovery of semen parameters which 
encompasses one and one-half cycles (cycle length is around 75 days) of the seminiferous 
epithelium. This also includes epididymal transit time (since we are sampling and evaluating 
semen), which adds another ~10 days. Thus, in days 75 + 37.5 + 10 = 122.5 days or 17.5 weeks, 
therefore 18 weeks should be sufficient for follow-up period. 
The safety of pretomanid has been tested in 10 single- and multi-dose Phase I studies with 
healthy adult male and female participants, receiving single oral doses of pretomanid ranging 
from 50 to 1500 mg and multiple oral doses ranging from 200 to 1000 mg/day given for up to eight 
days. Pretomanid has also been studied in combination regimens in patients for up to 9 months in 
Phase 2 and 3 studies. For this study adult male DR-TB patients who can complete the trial will 
be required. 
For assessment of the male reproductive safety profile the following parameters will be evaluated 
in adult male participants with Drug Resistant (DR-TB) Pulmonary Tuberculosis.  
For assessment of the male reproductive safety profile the following parameters will be evaluated. 
Primary Endpoint
Change from baseline in total sperm count at 26 weeks. 
Secondary Endpoints
Change from baseline in total sperm count at 13 and 44 weeks: 
A key secondary endpoint will be the change from baseline (at screening) in male reproductive 
hormones at Week 2, 4, 8,12,16, 26, 35, 44, 52, 65, 78, and at early withdrawal. Reproductive 
hormones: luteinizing hormone (LH), follicle-stimulating hormone (FSH), Inhibin B and 
testosterone. 
Other Secondary Endpoints: For assessment (other secondary endpoints) of the Pulmonary 
Tuberculosis the following parameters will evaluated. 


TB Alliance
Protocol Number: Pa-824-CL-012
Protocol Version: V4.0 07 APR 2022
Protocol Name:   BPaMZ/SEM
TMP-C-SOP01-B V1.0 30-JAN-2019
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Page 24 of 79
Efficacy:
Incidence of bacteriologic failure or relapse or clinical failure at 78 weeks after the start of 
therapy. 
Proportion of participants with sputum culture conversion to negative status in liquid 
culture (MGIT) at Week 4, 8, 12, 16, 22, 26, 35, 44, 52, 65 and 78. 
Safety and Tolerability:
Change in weight from baseline.
Incidence of Treatment Emergent Adverse Events (TEAEs) presented by incidence, 
severity, drug relatedness, seriousness, leading to early withdrawal, and leading to death. 
Quantitative and qualitative clinical safety laboratory measurements, including observed 
and change from baseline. 
Quantitative and qualitative electrocardiogram (ECG) results (heart rate, RR interval, PR 
interval, QRS interval, QT interval and QTc interval, including observed QT/QTc intervals 
and change from baseline) will be categorized.
Obtaining findings of testicular toxicity has been a challenge in pharmaceutical drug development 
and the evaluations of the above reproductive parameters will give us important and adequate 
insight as we continue to develop pretomanid.  
2.2
Drugs used in the TB Antimicrobial BPaMZ regimen
Pretomanid [5] 
2.2.1.1
Structure and Mechanism of Action  
Pretomanid, a nitroimidazooxazine, with a molecular weight of 359 daltons [5,6]. Figure 1 shows the 
chemical structure.
Figure 1: Chemical Structure of Pretomanid
Pretomanid kills actively replicating Mycobacterium tuberculosis (Mtb) by inhibiting mycolic acid 
biosynthesis thereby blocking cell wall production. Under hypoxic conditions, against
non-replicating bacteria, pretomanid acts as a respiratory poison following nitric oxide release.
All these activities require nitro-reduction of pretomanid within the mycobacterial cell by the
deazaflavin-dependent nitro reductase (Ddn), which is dependent on the reduced form of the


TB Alliance 
Protocol Number: Pa-824-CL-012 
Protocol Version: V4.0 07 APR 2022 
Protocol Name:    BPaMZ/SEM 
 
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cofactor F420. Reduction of F420 is accomplished by the F420-dependent glucose-6-phosphate
dehydrogenase, Fgd1. 
2.2.1.2 Nonclinical Studies
Pretomanid has demonstrated in vitro activity against Mtb complex, including genetically diverse 
clinical isolates, and mono resistant and polyresistant/multidrug resistant (MDR) Mtb, with the 
exception of delamanid-resistant Mtb where cross-resistance has been observed for pretomanid 
against some but not all tested delamanid-resistant strains. This indicates that pretomanid activity 
is not affected by Mtb phylogeny, or Mtb resistance phenotype, apart from delamanid-resistance in 
some cases. 
 
Pretomanid has also demonstrated anti-Mtb activity as both a monotherapy and as part of 
combination regimens in animal models of TB. Regimens with pretomanid plus bedaquiline, 
including BPaL, the regimen that also included linezolid, demonstrated efficacy superior to the 
combination of rifampicin, isoniazid, and pyrazinamide (RHZ). 
 
No central nervous system (CNS), cardiovascular, or respiratory effects were seen at pretomanid 
exposures consistent with those seen in humans at the maximum recommended human dose 
(MRHD) in a series of safety pharmacology studies in rats and monkeys; effects were evident at 
pretomanid exposures that were >3-fold higher than those seen with the MHRD. 
No mutagenic or clastogenic effects were detected in both an in vitro bacterial reverse mutation 
assay and an in vitro mammalian chromosome aberrations assay using a Chinese hamster ovary 
cell line. Pretomanid was negative for clastogenicity in a mouse bone marrow micronucleus assay. 
 
Cataracts were observed in rats treated with pretomanid at doses of 300 mg/kg/day for 13 weeks 
or 100 mg/kg/day for 26 weeks. There were no cataracts observed in rats given oral pretomanid at 
30 mg/kg/day (approximately twice the human exposure for a 200 mg dose) for 26 weeks. 
In a 13-week monkey toxicity study, no cataracts were observed at the end of 13-week dosing, but 
at the end of the 13-week recovery two animal showed cataracts in the 400/300 mg/kg group. In a 
subsequent study, cataracts were not observed following 13-week treatment with up to 300 
mg/kg/day oral pretomanid or during the 20-week post treatment recovery period. No cataracts 
were observed in monkeys given oral pretomanid at 100 mg/kg/day for 39 weeks with a 12-week 
post treatment recovery. 
 
Testicular toxicity was observed in repeat-dose toxicity studies in rats and mice, but not monkeys. 
 
Pretomanid was not teratogenic, and no peri-postnatal effects occurred at doses that did not also 
produce maternal toxicity in rats. 
 
Pretomanid has phototoxic potential at high doses in rats. 
 
2.2.1.3 Pharmacokinetics
Important drivers of pharmacokinetic (PK) variability are dosing with or without food, and 
co-administration of medications that induce CYP3A4. 
 
Bioavailability in the fasted state was about half that in the fed state, when administered at the 
clinical dose of 200 mg. Pretomanid should be administered in the fed state. 
 


TB Alliance 
Protocol Number: Pa-824-CL-012 
Protocol Version: V4.0 07 APR 2022 
Protocol Name:    BPaMZ/SEM 
 
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In the presence of rifampicin and efavirenz, pretomanid average concentration over a dosing
interval (Cavg) was reduced 66% and 35%, respectively. Such strong and moderate CYP3A4 
inducers should be avoided with pretomanid. 
 
No clinically significant differences in the pharmacokinetics of pretomanid were observed based on 
sex, body weight, race (black, Caucasian, or other), pulmonary TB status, or human 
immunodeficiency status (HIV) status. The effect of renal or hepatic impairment on the 
pharmacokinetics of pretomanid is unknown. 
 
2.2.1.4 Efficacy and clinical studies
As a single agent, pretomanid showed mycobactericidal activity over 14 days spanning a wide
range of doses from 50 to 1200 mg/day: 200, 600, 1000, and 1200 mg/day were tested in CL-007; 
and 50, 100, 150, and 200 mg/day were tested in CL-010. The bactericidal activity of pretomanid 
was similar for all doses tested except 50 mg, which showed less activity than the higher doses. 
 
As treatment of TB requires a combination of multiple drugs, pretomanid was also tested in different 
combination regimens, measuring bactericidal efficacy over 14 days of treatment in the NC-001 
and NC-003 studies, to inform the selection of candidate regimens for later stage clinical 
development. All pretomanid-containing arms in these two studies showed bactericidal activity. The 
two best regimens were the combination of pretomanid, moxifloxacin, and pyrazinamide (PaMZ) in 
NC-001 and the combination of bedaquiline, pretomanid, and pyrazinamide (BPaZ) in NC-003. Both 
PaMZ and BPaZ showed daily reductions in colony-forming unit (CFU) counts that were like or 
greater than those in subjects administered the standard-of-care 4-drug regimen of isoniazid, 
rifampicin, pyrazinamide, and ethambutol (HRZE). 
 
PaMZ and BPaZ were further tested over an 8-week treatment period in studies NC-002 and NC-
005. In NC-002, subjects with DS-TB were treated with PaMZ, with either 100 or 200 mg/day 
pretomanid doses. The same combination with 200 mg/day pretomanid was tested in MDR-TB 
subjects. Results indicated that the bactericidal activity of the 200 mg pretomanid regimen was 
significantly greater than that of HRZE. In contrast, no significant differences were observed 
between the 100 mg pretomanid regimen and HRZE. 
 
In NC-005, DS-TB subjects were treated with BPaZ with bedaquiline administered as either a 
loading dose (400 mg/day) for 14 days, followed by 3 times a week at 200 mg/day, or administered 
consistently at 200 mg/day. Data from this study demonstrated significantly greater bactericidal 
activity for the BPaZ regimen than for HRZE. The efficacy of the regimen with bedaquiline at 200 
mg/day was like the efficacy of the regimen with bedaquiline administered as recommended per 
label (i.e., loading dose and then 3 times a week). In this study, one study arm of MDR-TB subjects 
was treated with BPaZ (bedaquiline at 200 mg/day) plus moxifloxacin (BPaMZ). The BPaMZ 
regimen in MDR-TB subjects showed the greatest bactericidal activity and the shortest time to 
culture conversion among all treatment arms, although conclusions for this population were limited 
by the absence of a randomized control arm.7 
 
The Phase 3 study NC-006 tested the combination PaMZ in DS-TB subjects under 3 different 
dosing schedules: 6 months with pretomanid at 200 mg/day, 4 months with pretomanid at 100 


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mg/day, or 4 months with pretomanid at 200 mg/day. An MDR-TB population was also treated with 
PaMZ for 6 months (pretomanid at 200 mg/day). This study was placed on partial clinical hold in 
2015 due to deaths associated with hepatotoxicity. Following investigations, the partial clinical hold 
was lifted on 17 August 2016. However, due to delays in enrollment and the promising results of 
other pretomanid-containing drug regimens, TB Alliance chose not to re-open enrollment when the 
partial clinical hold was removed, but the already enrolled subjects (N = 284) were followed to the 
study endpoints. With this reduced sample size, the study failed to demonstrate noninferiority in the 
efficacy of the PaMZ regimens compared with the efficacy of the standard-of-care regimen (HRZE) 
at 6 months. 
 
In Nix-TB, the first clinical trial ever to evaluate the 3-drug, all-oral, 6-month BPaL regimen, 
approximately 90% of subjects with highly resistant TB achieved relapse-free cure status 6 months 
after the end of treatment. The Nix-TB rate of favorable outcomes is like the rates of treatment 
success for DS-TB (World Health Organization [WHO] 2018). The study met the prespecified 
threshold for success, with the lower bound of the confidence interval (CI) for a favorable outcome 
far exceeding 50%. Furthermore, the percentage of patients who had a favorable status following 
this 6-month regimen was substantially higher than the rate of favorable outcomes in the reported 
literature with existing regimens lasting 18 months or longer. Nix-TB received FDA approval of 
pretomanid in the BPaL regimen combination in August 2019.  
 
Favorable outcome rates were similar for patients with XDR-TB or treatment intolerant/ 
nonresponse (TI/NR) MDR-TB and across subgroups defined by demographic and baseline 
disease characteristics and the linezolid treatment regimen (600 mg twice daily [BID], as was 
originally implemented, or 1200 mg once daily [QD], after a protocol amendment). 
 
Patients on the BPaL regimen converted to culture-negative status quickly, with a median time of 
less than 6 weeks. Patients improved clinically; a reduction of TB symptoms and increased body 
weight accompanied the change in TB status. Most patients remained relapse-free at 6 months 
after the end of treatment with preliminary 24-month data indicating that virtually all 
patients with culture conversion remained relapse free. 
Another Phase 3 study, ZeNix, with the BPaL regimen, is ongoing. The objective of this study is to 
optimize the treatment duration and dosage of linezolid, in MDR, pre-extensively drug resistant 
(XDR) and XDR patients. A Phase 2c study, SimpliciTB, also known as NC-008, is also ongoing to 
further study the BPaMZ regimen in both drug susceptible (DS) and drug resistant (DR) patients. 
At the time of the IB update, the efficacy data from both studies are not yet available and thus, are 
not incorporated. 
 
At the time of IB data cut-off data, 26 May 2019, pretomanid, either alone or as part of a combination 
regimen, has been used in at least 26 clinical trials sponsored by either TB Alliance or another entity 
in more than 1,664 subjects.  
 
As both ZeNix and SimpliciTB are still ongoing, detailed safety data from these two studies are not 
incorporated into this IB. Safety data for pretomanid are summarized based on 1,153 subjects from 
the other 19 trials, including 208 subjects with either extensively drug resistant tuberculosis (XDR-


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TB) or MDR-TB, 656 subjects with drug susceptible (DS)-TB, and 289 healthy volunteers. Safety 
data are summarized in Section 5.3 of the investigator brochure.
2.2.1.4.1 Safety
The adverse drug reactions were identified from the pooled safety database of reported AEs in 
the Phase 1 studies where placebo arm was available, and Phase 2/3 clinical studies where a 
standard of care arm was available, with data from other non-controlled studies, including results 
from exposure/response modeling of Nix-TB as supporting evidence. Adverse drug reactions for 
pretomanid include the following: 
Mild to Moderate (G1 to G2) nausea (preferred term [PT]) and vomiting (PT).
G1 and G2 rash (grouped terms, including the following PTs; rash; rash popular; rash 
maculopapular; rash erythematous; and rash vesicular).
Transaminases increased (grouped terms, including the following PTs: transaminases 
abnormal; transaminases increased; ALT abnormal; AST abnormal; ALT elevated; AST 
elevated; hepatic enzyme increased; hepatic enzyme abnormal; liver function test 
abnormal; liver function test increased; hepatic function abnormal).
Hepatic enzyme increases have been seen in participants treated with pretomanid in combinations
with various other medications during the clinical development program. It is difficult to assign 
specific causality to any one drug within a regimen; nonetheless, the trial will include specific 
monitoring of hepatic enzymes.
For additional information refer to pretomanid IB. [5]
Information regarding other compounds used with in the 
BPaMZ
2.2.2.1
Bedaquiline [8,9]
Bedaquiline (TMC207; SirturoTM package insert) [8] is a novel agent approved for TB treatment. As 
detailed in the Investigator’s Brochure, [9] Bedaquiline is a diarylquinoline that offers a novel 
mechanism of anti-tuberculosis action by specifically inhibiting mycobacterial adenosine 
triphosphate synthase.
[10, 11] In vitro, bedaquiline potently inhibits both drug-sensitive and 
drug-resistant M. Tb isolates,[11, 12], and is also bactericidal against non-replicating M. Tb.[13] In the 
murine model of TB, bedaquiline was as active as the triple combination of isoniazid (H), rifampcin
(R), and pyrazinamide (Z). Addition of bedaquiline to HRZ results in accelerated clearance of M. 
Tb.[14, 15] 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.[16] Collectively, 
these findings in the mouse model have led to the suggestion that regimens containing bedaquiline
and pyrazinamide could be effective in the treatment of both DS- and MDR-TB and shorten 
treatment duration in patients. While the combination of bedaquiline and pretomanid in the murine 
model of TB appeared somewhat antagonistic relative to Bedaquiline alone, it was as active as the 
triple combination of HRZ[16] and in a subsequent trial it was more active in the mouse model than 
HRZ.[17] Thus, a novel regimen with a bedaquiline plus pretomanid core could be effective in the 
treatment of MDR-TB by providing two novel drugs for which there is no known pre-existing 
resistance.


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2.2.2.1.1 Clinical Studies 
In the clinical studies conducted to date, a total of approximately 645 participants (including 265 DR-
TB patients) have been exposed to Bedaquiline in the Phase 1 and 2 clinical trials conducted as a 
part of the development program for the treatment of MDR-TB. An additional 45 participants 
received Bedaquiline, either as monotherapy (B) or in combination with other agents (B-Pa or B-Z) 
in trial NC-001, and 45 more in trial NC-003 (B-Pa-Z, B-Pa-C, B-Pa-Z-C). In the Nix-TB (B-Pa-L) 
trial, 109 participants received Bedaquiline that led to an FDA approval in August 2019. Four short-
term Phase 2a trials enrolled treatment-naïve participants (C202, TMC207-CL001, NC-001 and NC-
003). One long-term, open-label, Phase 2 trial, in MDR-TB participants (Bedaquiline- TiDP13-C209) 
and one long-term, Phase 2b trial, consisting of 2 different stages in participants infected with newly 
diagnosed sputum smear-positive pulmonary MDR-TB (Bedaquiline-TiDP13-C208), have been 
completed. Full details of the completed clinical studies are provided in the current bedaquiline IB,[9]
and Sirturo
™label.[8]. 
2.2.2.1.2 Safety 
Adverse Drug Reactions for Bedaquiline 
Participants in the Any Bedaquiline group compared to the Any Placebo group (difference > 5.0%) 
had headache (23.5% versus 11.4%, respectively), nausea (35.3% versus 25.7%, respectively), 
arthralgia (29.4% versus 20.0%, respectively), and transaminases increased (6.9% versus 1.0%, 
respectively).and diarrhoea (11.4% versus 5.9%, respectively). 
Cardiovascular safety 
During clinical studies with Bedaquiline a prolongation of QTc interval was observed. An ECG 
should be obtained prior to and after initiation of therapy with Bedaquiline to monitor the QTc 
interval. 
Bedaquiline treatment initiation is not recommended in patients with: 
 
Heart failure 
 
QTcF interval > 450 ms (confirmed by repeat electrocardiogram) 
 
A personal or family history of congenital QT prolongation 
 
A history of or ongoing hypothyroidism 
 
A history of or ongoing bradyarrhythmia 
 
A history of TdP 
 
Concomitant administration of fluoroquinolone antibiotics that have a greater potential for 
significant QT prolongation (i.e., gatifloxacin, moxifloxacin and sparfloxacin) 
 
Bedaquiline treatment must be discontinued if the patient develops clinically significant ventricular 
arrhythmia. An additive or synergistic effect on QT prolongation of Bedaquiline when 
co-administered with other medicinal products that prolong the QT interval cannot be excluded. 
Caution is recommended when using Bedaquiline concomitantly with medicinal products with a 
known risk of QT prolongation. If co-administration of such medicinal products with Bedaquiline is 
necessary, clinical monitoring including frequent ECG assessment is recommended. 
In this trial, moxifloxacin will be co-administered with Bedaquiline. This is to prevent the 
development of resistance to the other drugs in the regimen in case the participant’s strain of MTB 


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is resistant to pyrazinamide. ECG assessments will be performed on all participants at screening, 
baseline, and at treatment visits specified in the flow chart.   
Hepatic safety
Increases in transaminases were seen in clinical studies during administration of Bedaquiline with 
the background regimen. Participants should be monitored during treatment. 
Other hepatotoxic medicinal products and alcohol should be avoided while taking Bedaquiline, 
especially in participants with diminished hepatic reserve. 
 
2.2.2.2 Moxifloxacin [18, 19]
Moxifloxacin (M)[18]   is a microbial compound, approved in most countries around the world for the 
treatment of acute bacterial sinusitis, acute bacterial exacerbation of chronic bronchitis, 
community-acquired pneumonia, skin and soft tissue infections.  Clinical studies have been carried 
out for many additional indications (urinary tract infections, pelvic infections, pharyngitis/tonsillitis, 
and tuberculosis). Moxifloxacin is an 8-methoxyquinolone whose oral formulation (which will be 
used in this trial) has enhanced activity against Gram-positive pathogens, and anaerobes while 
retaining useful activity against Gram-negative organisms. Moxifloxacin is not metabolized by or 
induces the cytochrome P450 system; thus, the risk of clinically relevant drug interactions is 
reduced. It has a positive safety profile within the fluoroquinolone class at the approved daily dose 
of 400 mg. Moxifloxacin while not approved for TB by most regulatory authorities, it is regularly 
used in second line MDR-TB treatment. The WHO TB Treatment Guidelines place moxifloxacin in 
the category of Group 3 drugs and notes that “all patients [with MDR-TB] should receive a Group 3 
medication if the Mtb strain is susceptible or if the agent is thought to have efficacy. One of the 
higher generation fluoroquinolones, such as levofloxacin or moxifloxacin, is the fluoroquinolone of 
choice.[20]” It is currently in late stage clinical development for first-line TB treatment in combination 
with other TB drugs, including pyrazinamide in two different four-month long regimens.  
Moxifloxacin is commonly used as second line therapy for TB (e.g., MDR- TB) and has also been 
evaluated in several clinical studies of participants with TB, including four 8-week treatment period 
Phase 2b studies.  
In the usual daily doses of 400 mg/day, moxifloxacin is well tolerated.  As stated in the Package 
Insert [18]  the most frequent individual drug related AEs observed in clinical trials with 400 mg oral 
moxifloxacin therapy were nausea (7.5%) and diarrhoea (5.8%). Fluoroquinolones, including 
moxifloxacin, are associated with an increased risk of tendinitis and tendon rupture in all ages.   
A known but rare side effect of fluoroquinolones, including moxifloxacin is exacerbation of 
myasthenia gravis. In addition, moxifloxacin has been shown to prolong the QT interval of the 
electrocardiogram in some participants. It should be used with caution in participants being treated 
concomitantly with other drugs where an additive effect on the QT interval cannot be excluded.  
Serious and sometimes fatal hypersensitivity reactions, including anaphylactic reactions, as well as 
peripheral neuropathy may occur after the first or subsequent doses of moxifloxacin. For additional 
information, refer to the moxifloxacin package insert.[18]  


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For additional information on moxifloxacin, refer to the IB[19] and the manufacturer’s package 
insert.[18]  
2.2.2.3 Pyrazinamide  
Pyrazinamide (Z)[21] is a pyrazine analogue of nicotinamide and an approved anti-tuberculosis 
agent which is indicated for the initial treatment of active tuberculosis in adults and children when 
combined with other anti-tuberculosis agents and contributes significantly to the sterilization of 
lesions and thus treatment shortening.[22]
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. Z is active against TB in vitro and it potentiates the bactericidal and sterilizing 
activity of both Bedaquiline and  pretomanid in mouse models of TB infection.[9, 5] Pyrazinamide 
enhanced the bactericidal activity of both Bedaquiline and  pretomanid in Trial NC-001-(J-M-Pa-Z) 
as noted by decreases over 14 days in the CFU counts in sputum among participants. 
The dose of pyrazinamide that will be used in this trial is an approved dosage for the treatment of 
TB. The most serious side-effect of pyrazinamide is hepatotoxicity and its frequency appear to be 
dose related. The pyrazinamide investigator brochure 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, occasionally accompanied by arthralgia, and may lead to attacks 
of gout. Photosensitivity and skin rash have been reported less frequently. Other side-effects that 
have been reported are anorexia, nausea and vomiting, malaise, fever, sideroblastic anaemia and 
dysuria. Pyrazinamide may decrease the efficacy of gout therapy (e.g., allopurinol, colchicine, 
probenecid or sulphinpyrazone) and dosage adjustments of these medications may be necessary.  
For additional information on pyrazinamide, refer to the investigator brochure.[23]
 
2.3
Overall Benefit/Risk Assessment
The primary purpose of the Male Reproductive Safety – “BPaMZ/SEM”- clinical study is to 
evaluate the potential effect of pretomanid on human testicular function whilst being used in a 
6-month antimicrobial combination regime. All participants in this trial will be given an antibiotic 
treatment regimen consisting of a 6-month Combination Treatment for Pulmonary Tuberculosis of 
Bedaquiline plus Pretomanid plus Moxifloxacin plus Pyrazinamide (BPaMZ). These drugs 
individually and in combination are not expected to have an adverse impact on Male Reproductive 
Safety, based on nonclinical and available clinical data. Similarly, these drugs individually and in 
combination are known to have anti-tuberculosis activity and is not expected to have an adverse 
impact on the ultimate cure of TB in these participants Based on NC-005 and other regimens using 
each of the regimen drugs in different combinations there is good evidence that this may be a highly 
effective therapy for both DS-TB and DR-TB. The same BPaMZ regime is also being studied in 
another ongoing clinical study NC-008 (the SimpliciTB study) This trial (SimpliciTB) will evaluate 
and support that, in additional to previous studies evaluated with BPaMZ, that this drug regimen 
(BPaMZ) will be safe and effective, is well-tolerated and could potentially shorten the current 
treatment duration compared to Standard HRZE/HR treatment for patients with drug sensitive TB 


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disease. This trial will also evaluate if this drug regimen (BPaMZ) given for 6 months will be safe 
and effective in drug resistant TB disease. 
In addition to treating participant’s pulmonary tuberculosis in the planned BPaMZ-SEM study we 
plan to assess the male reproductive safety profile of pretomanid with the same regimen (BPaMZ). 
Participants in this trial will have their TB infection carefully characterized, with drug sensitivity 
profiles established, and they will receive treatment with trial drugs that have demonstrated activity 
against Mtb.   
Participants will receive individualized medical attention; this will allow a continuous monitoring of 
the health conditions of each participant, any of whom can be withdrawn at any stage of the trial 
and removed from trial treatment should his/her condition suggest to the Investigator that this would 
be in his/her best interest. Multiple blood samples will be taken for safety laboratory studies, and 
ECGs will be taken at multiple time points. 
The trial drugs in the proposed regimens to be tested in this trial have all demonstrated safety and 
efficacy in the treatment of pulmonary tuberculosis in non-clinical and clinical studies. Specifically, 
the regimen B-Pa-Z was generally well-tolerated and demonstrated bactericidal activity in a 14-day 
EBA trial. The potential risks associated with the trial drugs and regimens has been identified as 
outlined below and will be monitored carefully throughout the conduct of the trial. 
One concern, the combination of two agents with known QT-prolonging effects (Bedaquiline and 
moxifloxacin), has been addressed specifically by carefully identifying and excluding participants 
with risk factors that might predispose them to cardiac arrhythmias, screening all participants for 
evidence of existing cardiac disease and monitoring all participants with ECGs throughout the trial.  
The BPaMZ regimen is a novel regimen treatment expected to be effective, safe, and well-tolerated 
and might even shorten the current treatment duration for patients with TB. Based on data from 
previous trial evaluations of key monitoring and safety information as outlined suggests an overall 
favourable benefit-to-risk ratio.  
3
Trial Objectives
3.1
Primary Objective:
To assess the male reproductive safety of pretomanid in the regimen (BPaMZ) of bedaquiline 
200mg daily for 8 weeks then 100 mg daily for 18 weeks, together with pretomanid 200 mg (1x 
daily) + moxifloxacin 400 mg (1x daily) + pyrazinamide 1500 mg (1x daily) for 26 weeks in 
participants with Drug-resistant (DR) pulmonary TB. 
3.2
Secondary Objective: 
To evaluate the efficacy, safety and tolerability after 26 weeks of active treatment for TB and 
follow up for 52 weeks after start of the above-described treatment regimen in participants with 
Drug-resistant (DR) pulmonary TB. 
 


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4 
Trial Endpoints
4.1 Primary Endpoint
 
Change from baseline in total sperm count at 26 weeks. 
4.2
Secondary Endpoints
 
Change from baseline in total sperm count at 13 and 44 weeks. 
 
A key secondary endpoint will be the change from baseline in male reproductive 
hormones at Week 2, 4, 8,12,16, 26, 35, 44, 52, 65, 78, and at early withdrawal.  
Reproductive hormones: luteinizing hormone (LH), follicle-stimulating hormone (FSH), 
Inhibin B and testosterone. 
4.3
Other Secondary Endpoints:
Efficacy:
 
Incidence of bacteriologic failure or relapse or clinical failure at 44 weeks after the start of 
therapy.  
 
Proportion of participants with sputum culture conversion to negative status in liquid 
culture (MGIT) at Week 4, 8, 12, 16, 22, 26, 35, 44, 52, 65, and 78.  
Safety and Tolerability: 
 
Change in weight from baseline. 
 
Incidence of Treatment Emergent Adverse Events (TEAEs) presented by incidence, 
severity, drug relatedness, seriousness, leading to early withdrawal, and leading to death. 
 
Quantitative and qualitative clinical safety laboratory measurements, including observed 
and change from baseline. Quantitative and qualitative electrocardiogram (ECG) results 
(heart rate, RR interval, PR interval, QRS interval, QT interval and QTc interval, including 
observed QT/QTc intervals and change from baseline) will be categorized.
Pharmacokinetics (PK): 
Plasma concentration of pretomanid from sparse sampling will be summarized as descriptive 
statistics. 
5 
Trial Design 
5.1 Summary of Trial Design 
This is a Phase 2, multi-center, open-label clinical trial in DR-TB in male participants aged 18 years 
and older.    
The trial requires 20 evaluable and eligible male participants who meet all the inclusion criteria and 
none of the exclusion criteria diagnosed with DR-TB.  All participants will receive the same regimen 
of BPaMZ once daily for 26 weeks.  All participants must give written informed consent at screening 
visit (-21 day) to participate in this trial and continue with screening procedures during the screening 
period (Day -21 to Day -1).   


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5.2
Treatment Plan: Schedule of Assessments 
 
Screening Period (Day -21 to Day -1) 
 
Treatment Period (Day 1 to Week 26) 
 
Follow -up Period (Week 26 to Week 78)  
Refer to: 
 
Trial Flow Chart (Section 1.1) for the timing of all procedures and laboratory 
samples to done at each visit.   
 
Trial Procedures (Section 8) for details regarding specific procedures or 
laboratory tests. 
The Test Treatment Regimen, BPaMZ consists of a combination of the following products: 
Table 1: Products 
Product 
Tablet Strength
Abbreviation  
Bedaquiline 
100 mg
(B)
Pretomanid 
200 mg
(Pa) 
Moxifloxacin
400 mg
(M) 
Pyrazinamide 
500 mg
(Z) 
Participants will receive Bedaquiline 200 mg once daily for 8 weeks then 100 mg once daily for 18 
weeks, together with pretomanid 200 mg + moxifloxacin 400 mg + pyrazinamide 1500 mg once 
daily (BPaMZ) for 26 weeks.  
Participants will enter post- treatment follow-up which continues until Week 78.  
6 
Trial Population 
Participant must meet all inclusion and no exclusion criteria within the screening period.  The 
screening period of -21 to -1 days provides flexibility for allowed retesting of applicable 
mycobacteriology, safety, or ECG parameters.  Only one qualifying semen sample during screening 
is allowed within the -13 to -1 day period.  Refer to Trial Flow Chart (Section 1.1) footnote f for 
further details.   Sponsor may consider replacements of withdrawn participants. 
 
 
6.1
Inclusion Criteria 
Participants are required to meet all the following inclusion criteria during the screening period to 
be enrolled. Patients must abstain from ejaculation for at least 2 days prior to screening clinic 
visit. 
1. Understands study procedures and voluntarily provides written informed consent prior to 
the start of any study-specific procedures.  
No protocol waivers will be granted by the TB Alliance


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2.
Male gender 18 years or over.
3. 
 
4. A positive molecular test for tuberculosis in sputum either at screening or within one month 
prior to enrollment. 
5. Disease Characteristics: 
 
Participants must have been diagnosed with TB prior to or at screening. 
 
Participants’ TB should be resistant to rifampicin and/or isoniazid (historical 
evidence of resistance to rifampicin and/or isoniazid is acceptable within 3 months 
prior to screening), and susceptible to fluoroquinolones by rapid sputum-based 
tests 
 
Participants who have had previous treatment for DR-TB for more than 3 months 
at start of screening should be discussed with the medical monitor. 
6. A chest x-ray, within 6 months prior to or at the screening visit, which in the opinion of the 
Investigator is compatible with pulmonary TB. 
7. Participants will be required to use a double contraceptive method during the whole 
treatment duration and 18 weeks post dose. 
8. Can comply with the protocol and the assessments therein, including all restrictions. 
6.2
Exclusion Criteria
Participants will be excluded from participation if they meet any of the following criteria. 
Medical History and Concurrent Conditions:
1. Resistant to fluoroquinolones by rapid molecular test. 
2. History of male infertility or vasectomy. 
3. Unable to produce semen sample.  
4. Evidence at screening of azoospermia. 
5. Known erectile dysfunction that would prevent ejaculation. 
6. Historical or active disease process of the male reproductive tract that would compromise 
sperm production. e.g., Tuberculous epididymitis. 
7. History of any illness that, in the opinion of the Investigator, might confound the results of 
the study or poses an additional risk to the participant by their participation in the study. 
8. Abuse of alcohol or illegal drugs that in the opinion of the Investigator would compromise 
the participants’ safety or ability to follow through with all protocol-specified restrictions, 
visits, and evaluations. 
9. Being, or about to be, treated for malaria. 
10. Is critically ill and, in the judgment of the Investigator, has a diagnosis likely to result in death 
during the trial or the follow-up period. 
11. TB meningitis or other forms of extrapulmonary tuberculosis with high risk of a poor 
outcome, or likely to require a longer course of therapy (such as TB of the bone or joint), as 
judged by the Investigator. 


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12. History of allergy or hypersensitivity to any of the trial IMP or related substances, including 
known allergy to any fluoroquinolone antibiotic, history of tendinopathy associated with 
quinolones. 
13. For HIV infected participants any of the following: 
a) CD4+ count <100 cells/µL  
b) Received intravenous antifungal medication within the last 90 days 
14. Participants with newly diagnosed tuberculosis and HIV that require initiation of appropriate 
HIV therapy before participants has received at least 2 weeks of an antituberculosis 
regimen.  
15. Participants with any of the following at the Screening visit (per measurements and reading 
done by ECG): 
a. QTcF interval on ECG >500 msec.  Participants with QTcF > 450 must be 
discussed with the Sponsor Medical Monitor before enrollment. 
b. Heart failure 
c. A personal or family history of congenital QT prolongation 
d. A history of or known, untreated, ongoing hypothyroidism, except for well treated 
hypothyroidism.  
e. A history of or ongoing bradyarrhythmia 
f. 
A history of Torsade de Pointe 
16. Unstable Diabetes Mellitus which required hospitalization for hyper- or hypo-glycaemia 
within the past year prior to start of screening. 
17. Receiving any form of hormone or hormone-like (nutraceuticals) therapy, except for well 
treated hypothyroidism. 
18. Received Pretomanid and/or Delamanid to treat TB.  
19. Known chronic hepatitis B or C. 
Previous and Concomitant Therapy
20. Use of any drug within 30 days prior to randomisation known to prolong QTc interval 
(including, 
but 
not limited to, amiodarone, 
amitriptyline, bepridil, 
chloroquine, 
chlorpromazine, 
cisapride, 
clarithromycin, 
disopyramide 
dofetilide, 
domperidone, 
droperidol, erythromycin, halofantrine, haloperidol, ibutilide, levomethadyl, mesoridazine, 
methadone, pentamidine, pimozide, procainamide, quinacrine, quinidine, sotalol, 
sparfloxacin, thioridazine). 
21. For HIV infected participants: 
a. The following antiretroviral therapy (ART) should not be used:  
1. Stavudine  
2. Zidovudine 
3. Didanosine  
4. Triple NRTI regimen is not considered optimal for HIV treatment (poor efficacy) 
 


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b.
A standard NRTI backbone may be combined with the following: 
1.
Rilpivirine
2. Dolutegravir  
3. Raltegravir 
4. Nevirapine  
5. Lopinavir/r  
6. Participants who are on efavirenz, atazanavir/r or darunavir/r at the time of 
screening and have an undetectable viral load, should have their ART switched 
to one of the agents listed above (1-5). It would be preferable to switch to another 
permissible ARV within the same class accompanied by the same nucleoside 
backbone.
c. ART regimen choice should be discussed with the Sponsor Medical Monitors if there 
are any concerns. 
Confirmed plans to use Isoniazid prophylaxis for HIV positive participants during the treatment 
and follow up period is not permitted. 
Diagnostic and Laboratory Abnormalities
22. Participants with the following toxicities at screening as defined by the enhanced Division of 
Microbiology and Infectious Disease (DMID) adult toxicity table (Draft November 2007) 
(Appendix 2) where applicable: 
a. Platelets <75,000/mm3
b. Creatinine >1.5 times upper limit of normal (ULN)  
c. 
 
d. Haemoglobin <8.0 g/dL 
e. Serum potassium less than the lower limit of normal for the laboratory. This may be 
repeated once 
f. 
AST: 
 
 
 
results between 1.5 x ULN and 3 x ULN must be discussed with and 
approved by the Sponsor Medical Monitor 
g. ALT: 
 
 
 
greater than ULN must be discussed with and approved by the Sponsor 
Medical Monitor 
h.  ALP: 
 
 
 
2.0 – <3.0 x ULN must be discussed with and approved by the Sponsor 
Medical Monitor 
i. 
Total bilirubin: 
 
>1.5 x ULN to be excluded 
 
Greater than ULN must be discussed with and approved by the Sponsor 
Medical Monitor  
j. 
Direct bilirubin: 
 
greater than 1x ULN to be excluded 


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k.
Positive hepatitis B surface Ag, or hepatitis C antibody
 
All the inclusion and none of the exclusion criteria must be met. If no single variable/value is outside 
of the ranges of acceptability, but when multiple values are close to the limits and/or whenever the 
Investigator has reason to suspect that there might be a health problem (other than TB), enrolment 
should only be considered after discussing the case with the Sponsor Medical Monitor. 
 
6.3
Restrictions
Concomitant medications should be kept to a minimum during the treatment period of the trial.  
However, if concomitant medications are necessary for the participant’s welfare and are unlikely to 
interfere with the IMP, they may be given at the discretion of the Investigator. For any concomitant 
medications given as a treatment for a new condition or a worsening of an existing condition 
occurring after signing of the Informed Consent Form, the condition must be documented on the 
Adverse Event pages of the electronic Case Report Form (eCRF). 
The prescribing information for all concomitant medication should be consulted and reviewed 
carefully. The determinations listed in the respective contraindicated, warning, and precaution 
sections must be respected to prevent any potentially serious and/or life-threatening drug 
interactions. 
The following recommendations should be followed with regards to concomitant medication to avoid 
possible drug interaction with the IMP: 
Moxifloxacin: The IMP should be taken either 4 hours before or 8 hours after taking the 
following products: 
 
An antacid, multivitamin, or other product that has magnesium, aluminium, iron, or zinc 
 
Sucralfate 
 
Didanosine 
 
The following medicinal products are prohibited from the Screening visit and during the treatment 
period: 
 
Quinolone antimalarial (e.g., chloroquine and quinacrine). Participants who have malaria 
at screening are to be excluded. However, if a participant develops malaria during the 
trial, the Investigator is advised to consult the Malaria Treatment Guidance document 
regarding the interaction between moxifloxacin and bedaquiline with anti-malarial drugs. 
Investigators may also contact the Sponsor Medical Monitor for further guidance. 
 
Medicinal products used to treat pulmonary TB: including but not limited to gatifloxacin, 
amikacin, cycloserine, rifabutin, kanamycin, para-aminosalicylic acid, rifapentine, 
thioacetazone, capreomycin, other quinolones except moxifloxacin, thioamides, and 
metronidazole. 


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The following medicinal products should be avoided from Day 1 (Baseline visit) and during the 
treatment period as much as possible. Investigators may also contact the Sponsor Medical Monitor 
for further guidance. 
 
Any drug known to prolong QTc interval (including but not limited to amiodarone, 
bepridil, chloroquine, chlorpromazine, cisapride, clarithromycin, disopyramide dofetilide, 
domperidone, 
droperidol, 
erythromycin, 
halofantrine, 
haloperidol, 
ibutilide, 
levomethadyl, mesoridazine, methadone, pentamidine, pimozide, procainamide, 
quinidine, sotalol, sparfloxacin, thioridazine). The exception is moxifloxacin and 
Bedaquiline administered as part of the trial IMP, with ECG monitoring, to help ensure 
participant safety. 
 
Any 
drug 
known 
to 
be 
hepatotoxic 
(including 
but 
not 
limited 
to 
acetaminophen/paracetamol, acetazolamide, allopurinol, amiodarone, amitriptyline, 
amoxicillin, amprenavir, atorvastatin, augmentin/co-amoxiclav, azathioprine, baclofen, 
bumetanide, captopril, carbamazepine, celecoxib, chlorpromazine, clindamycin, 
clopidogrel, co-trimoxazole, darunavir, delavirdine, diclofenac, doxycycline, enalapril, 
fluconazole, fluoxetine, fosamprenavir, furosemide, gliclazide, glimeperide, glipizide, 
ibuprofen, irbesartan, ketoconazole, lisinopril, loperamide, losartan, methotrexate, 
metolazone, mirtazepine, nitrofurantoin, omeprazole, other non-steroidal anti-
inflammatory drugs, paroxetine, phenobarbital, phenothiazines, phenytoin, pravastatin, 
probenecid, prochlorperazine, risperidone, rosuvastatin, sertraline, simeprevir, 
simvastatin, sodium valproate, sotalol, sulfasalazine, sumatriptan, tamsulosin, 
terbinafine, tetracycline, theophyllin/uniphyllin, tipranavir, tolazamide, tolbutamide, 
topiramate, trazodone, tricyclic antidepressants, trimethoprim, verapamil).  
Discontinuation from Treatment/Trial
The following may result in the discontinuation of trial treatment:  
 
Withdrawal of informed consent. 
 
Investigator considers that for safety reasons it is in the best interest of the participant that 
he be withdrawn, including a concern that the participant has symptomatic TB and/or 
bacteriological failure/relapse and requires a change in TB treatment. 
 
Adverse event resulting in death. 
 
Lost to follow-up. 
 
Termination of the trial by the sponsor. 
A participant may withdrawal from the trial at any time at his/her request (withdrawal of consent) or 
may be withdrawn at any time at the discretion of the Investigator for safety, behavioral, compliance 
or administrative issues. When a participant withdrawals consent for the trial, no additional follow-
up visits will be performed. 
Participants who withdraw from the trial before 9 months maybe replaced and should be discussed 
with the Sponsor medical monitor. 
All Participants withdrawal from trial treatment/received at least one dose of IMP will be requested 
to return for an early withdrawal visits and applicable safety Follow Up visits, as per flow chart 
(Section 1.1.1). 


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Early Withdrawal
In case of early withdrawal during the treatment or follow-up period, all efforts shall be made to 
complete the Early Withdrawal assessments. At the Early Withdrawal visit the following information 
will be collected and procedures performed:
Two Spot sputum samples at least 30 minutes apart will be collected under the coaching 
and observation of the trial staff.  
Semen sampling collection: one pair of semen samples one week apart, each sample must 
be collected at least 2 days after abstinence from ejaculation.
Laboratory safety sampling (including male reproductive hormone tests: LH, FSH, inhibin B 
and testosterone)
Pharmacokinetic sampling (pre-dose within 2 hours prior to dosing)
Single 12-lead ECG
Vital signs 
Full physical examination, including weight
IMP compliance check (if participant on IMP)
Concomitant medications
Adverse Events
Unscheduled Visits
Any visit which is conducted in addition to those required by the Synopsis Flow Chart and 
Procedures (Section 1.1.1), should be considered unscheduled regardless of the reason for the 
visit.  The assessments which are undertaken as part of an Unscheduled visit should be as clinically 
indicated.
If the duration of treatment is extended due to dose interruptions/pauses, the last visit of the 
treatment period should also be pushed out to the date of the last dose. It is not necessary to have 
an unscheduled visit at the time that the last visit of treatment period would have been.
Lost-to-Follow-up
Every reasonable attempt must be made to minimise Lost-to-Follow-up (LTFU) participants. A 
minimum of three contact attempts (telephonic/home visit) will be made for participants who do not 
arrive for their scheduled trial visits. If these attempts are unsuccessful the participant will be 
considered LTFU. All attempts to contact the participant must be clearly documented in the 
participant’s source documents.
Early Withdrawal due to TB
Ultimately it is the Investigator’s decision whether a participant requires early withdrawal from the 
trial due to a concern that the participant has symptomatic worsening of TB and/or bacteriological 
failure/relapse. 
Early withdrawal is usually not indicated for a single positive culture. Should a participant have a 
single positive culture result after being converted to culture negative, the Investigator is to 
evaluate whether the participant has signs and symptoms suggestive of active inadequately 
treated TB and whether it is in the participants best interest that he/she be withdrawn. Prior to 
early withdrawal of a participant due to TB, the Investigator must discuss the participant with the 


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Sponsor Medical Monitor, unless the Investigator cannot contact the Sponsor Medical Monitor 
and considers that early withdrawal must occur immediately due to immediate safety concerns 
with respect to the participant.   
If the Investigator decides to withdraw a participant due to TB, additional sputum samples may 
need to be collected to ensure the participant’s outcome status as determined in Section 1.1.1.  
All early withdrawn participants who are confirmed sputum positive (two sequential sputum 
positive cultures) and/or have symptomatic TB will require further TB treatment. These 
participants will be referred to their applicable DR local community TB clinics for standard anti-
tuberculosis chemotherapy according to local treatment guidelines. 
The participant will be provided with a referral letter from the Investigator to take with them to their 
local treatment clinic and the referral letter, at a minimum, should include all treatment received by 
the participant and information about any suspected/confirmed adverse event/reaction related to 
any of the trial IMP’s and or concomitant medications. A follow-up call should be made by the trial 
site staff to the clinic to ensure the participant attended their local treatment clinic. 
6.4
Participant Progress Definitions
Table 2: Participant Progress Definitions 
Status 
Treatment
Follow-Up 
Screen Failure 
Participants from whom informed consent is obtained and is documented 
in writing (i.e., participant signs an informed consent form) but who is not 
entered into the study
Completed 
Treatment / 
Completed FU* 
Participants who complete 
the full course of IMP 
Participants who complete all follow-up 
visits 
Completed 
Treatment / 
Discontinued FU
Participants who complete 
the full course of IMP 
Participants who do not complete all 
applicable follow-up visits, regardless of 
the reason (excluding LTFU) 
Completed 
Treatment / Lost 
to Follow-Up
Participants who complete 
the full course of IMP 
Participants who are unable to be 
contacted on or before their final visit 
Discontinued 
Treatment / 
Completed FU
Participants who discontinue 
treatment prior to completion 
of the protocol-defined 
treatment course
Participants who complete all applicable 
follow-up visits 
Discontinued 
Treatment / 
Discontinued 
FU** 
Participants who discontinue 
treatment prior to completion 
of the protocol-defined 
treatment course
Participants who do not complete all 
applicable follow-up visits, regardless of 
the reason (excluding LTFU) 
Lost to Follow-Up 
Participants who are unable to be contacted on or before their final 
treatment visit and it cannot be confirmed whether treatment was 
completed 
* 
Note that this includes treatment failures who complete all applicable follow-up visits 
** Early Withdrawal 


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6.5
Trial Stopping Rules
The Sponsor has the right to stop the trial or a specific trial site at any time, although this should 
only occur after consultation between the involved parties. Should this occur, the local and central 
Ethics Committee/Institutional Review Board (EC/IRB) and Regulatory Authorities will be informed.   
Should a trial site be closed prematurely, all trial materials (except source documentation that must 
remain at the site) will be returned to the Sponsor or applicable vendor. The Investigator will retain 
all other documents until notification given by the Sponsor for destruction. Participants currently on 
trial IMP will receive an appropriate regimen and all participants will be referred to their applicable 
DR-TB NTP clinic. 
For potential stopping rules regarding reproductive safety, refer to safety monitoring Section 9.4. 
7
Treatment 
7.1
IMP Administration 
 
Treatment will be administered orally once daily, to be taken with a meal approximately the 
same time each day with a glass of water (approximately 240 ml) for 26 weeks in the 
following dosing scheme: 
o Bedaquiline 200 mg once daily for 8 weeks then 100 mg once daily for 18 weeks, 
together with pretomanid 200 mg + moxifloxacin 400 mg + pyrazinamide 1500 mg 
once daily for 26 weeks (total treatment duration 6 months).  
7.2
Participant Compliance 
During treatment visits, the IMP will be administered by the Investigator(s)/designated site 
personnel and when possible, the check for IMP compliance via the hand-and-mouth procedure 
(both the hand and the mouth of the participant will be checked to ensure that the participant has 
swallowed the IMP). During the trial, sites will be responsible for ensuring participants are taking 
IMP correctly and are fully trained on how the IMP is to be taken, as well as to check the IMP cards 
for unused tablets in the containers at each visit during the treatment phase.  
7.3
Treatment Modification(s)
The importance of adherence to the treatment schedule will be reinforced at each visit.  Non-
adherence should prompt the Investigator to identify and address the cause(s) (e.g. side effects).  
 
A 'dose of IMP’ is defined as the correct medication strength of bedaquiline + pretomanid + 
moxifloxacin + pyrazinamide as required to be taken for the day per protocol. 
 
Participants that do not take: 
 
 
Up to 7 consecutive doses of IMP doses: restart IMP, no extension of IMP required. 
 
ve doses of IMP: restart IMP and extend the IMP treatment 
by the number of consecutive doses missed. In this scenario, missed doses between 
Baseline (Day 1) through week 8 inclusive i.e., bedaquiline dose of 200mg BDQ, will need 
to be caught up before the participant can start week 9 treatment visit.  Similarly, missed 
doses between week 9 through week 26 inclusive, i.e., bedaquiline dose of 100mg BDQ, 
will require a make up for completion of treatment. The final treatment visit should be pushed 


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out to the date of last dose. It is not necessary to have an unscheduled visit at the time when 
the end of treatment visit would have been.     
 
If more than 35 consecutive doses of IMP, discontinue IMP and withdraw participant from 
the trial. 
 
If the participant misses a total (sum) of 56 cumulative missed doses, discontinue the IMP 
and withdraw the participant from the trial. 
 
All missed doses should be completed as part of the BPaMZ regimen (i.e., do not complete missed 
doses as monotherapy).  
Any participant for whom the trial IMP is discontinued (including for non-adherence) will be 
discussed with the Sponsor Medical Monitor and, if applicable, the participant will be restarted on 
trial IMP as soon as possible.  
7.4 IMP Packaging and Labelling 
The complete formulations of the IMP, namely Bedaquiline and pretomanid are found in the 
respective Investigator Brochures. [9, 5, 23] The complete formulations of bedaquiline, moxifloxacin 
and pyrazinamide are found in the Package Inserts. [8, 18, 21] 
The IMP will be packaged in weekly cards as follows: 
 
 


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Week 1 to 8 Cards: Dispensed treatment
IMP 
Strength 
Number of tablets 
Abbreviation 
Bedaquiline 
100 mg
14 
B
Pretomanid
200 mg
7
Pa
Moxifloxacin
400 mg
7
M
Pyrazinamide
500 mg
21 
Z
Week 9 to 26 Cards: Dispensed treatment
IMP
Strength
Number of tablets
Abbreviation
Bedaquiline 
100 mg
7 
B
Pretomanid
200 mg
7 
Pa
Moxifloxacin 
400 mg
7 
M
Pyrazinamide
500 mg
21 
Z
The packaging of each weekly cards will be labelled with, at a minimum, the following information: 
 
Name, address of Sponsor. 
 
Name of medication. 
 
Dosage, quantity, and method of administration.  
 
Reference/Lot Number. 
 
The statement “For Clinical Trial Use Only”. 
 
Space for completion of Name of Investigator and Site Number. 
 
Kit number, as applicable. 
 
The statement “Keep out of reach of children” as applicable. 
 
Storage conditions. 
 
Period of Use. 
 
Expiry Date. 
 
Directions for use. 
 
Space for completion of participant number and visit/date dispensed. 
7.5
Method of Treatment Assignment
All participants will receive the same regimen of BPaMZ. 
7.6
Blinding and Procedures for Breaking the Blind 
As this is an open label trial there is no need for blinding or procedures to break the blind. The 
trial participants, the site staff, Sponsor, and CROs will not be blinded to treatment assignment.  
7.7
Handling, Storage and Accountability 
The investigator or designee must confirm appropriate temperature conditions as per details on 
IMP labeling, have been maintained during transit for all trial treatment received and any 
discrepancies are reported and resolved before use of the trial treatment. 
Only participants enrolled in the trial may receive trial treatment and only authorized site staff may 
supply or administer trial treatment at treatment visits. All trial treatments must be stored in a secure, 


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environmentally controlled, and monitored (manual or automated) area in accordance with the 
labeled storage conditions with access limited to the investigator and authorized site staff. 
The investigator, institution, or the head of the medical institution (where applicable) is responsible 
for trial treatment accountability, reconciliation, and record maintenance (i.e., receipt, reconciliation, 
and final disposition records). Upon completion or termination of the trial, all unused and/or partially 
used IMPs must either be returned to Sponsor (or designated vendor: who will arrange for 
destruction or destroyed at site as agreed by Sponsor after final accountability has been confirmed. 
The Investigator/designee will immediately inform the Sponsor of any quality issues arising with 
respect to the trial medication. The Sponsor will take whatever action is required should such a 
situation arise. 
Further guidance and information for the handling, storage, accountability, and final disposition of 
unused trial treatment are provided in the pharmacy manual. 
8
Trial Variables and Procedures
The Synopsis Flow Chart and Procedures (Section 1.1.1) should be referenced for timing, 
sequence of assessments, and specific procedures. 
8.1
Demographic and Background Variables and Procedures 
The following demographic and background variables will be collected: 
 
Written Informed Consent 
 
Visit dates 
 
Participant disposition 
 
Demography (date of birth, race, and gender) 
 
Inclusion and exclusion criteria 
 
Clinically significant medical and TB treatment history (including past and current TB diagnosis, 
smoking and alcohol use) 
 
Semen Sampling: Single semen sample required at screening to determine whether 
participant qualifies for the study 
 
Male Reproductive Hormones (LH, FSH, inhibin B, testosterone) 
 
Two spot sputum samples taken at least 30 minutes apart will be collected under the 
coaching and observation of the trial staff: 
o Smear microscopy for Acid-Fast Bacilli (AFB). 
o Rapid molecular tests for isoniazid, rifampicin, fluoroquinolones resistance Mtb. 
o Liquid Culture (MGIT) for Mycobacterium tuberculosis (Mtb), with speciation to detect 
presence or absence of Mtb and obtain time to positivity (TTP) when positive and not 
contaminated. 
o Second sample is a back-up sample in case it is not possible to obtain a result/s from the 
first sample.  If initial screening sputum shows a negative or indeterminate molecular test 
result, the test may be repeated on the back-up sample or a newly collected spot sputum 
can be used.  
 
Serology: HIV and CD4 count.  Where required by regulatory authorities or ethics 
committees, a separate (EC/IRB approved) HIV informed consent form will be obtained from 
participants: 


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o
Prior to HIV testing and on receipt of the results, participants will be counselled on HIV by 
trained counsellors if they have indicated as such on the HIV consent form. If requested by 
the participant, HIV counselling that is provided to the participant by the trial site should be 
clearly documented in the participant’s medical records/source. Participants have the right 
to decline to know or receive their HIV test results. This decision should be clearly 
documented in the participant’s medical records/source.  
Chest X-Ray: A chest X-ray digital image within 6 months prior to or during the Screening 
visit, will be obtained and read locally by the Investigator or designee. A chest X-ray digital 
image will also be obtained and read locally by the Investigator or designee at Week 26 EOT.
Digital images will be provided to the Sponsor. The investigator is responsible for review and 
analysis of the chest X-ray for participant’s inclusion.
Urine drug test
Concomitant medications
8.2
Trial Variables and Procedures
Semen Sample Test Parameters
48 hours of sexual abstinence is required prior to obtaining each semen sample during the trial. 
Sexual abstinence is the practice of refraining from all sexual intercourse, including masturbation.
A single qualifying semen sample (QX) during screening (Days -13 to -1) is required during 
screening to determine whether a participant qualifies for the Male Fertility Analysis per the 
inclusion/exclusion criteria. There is allowance for repeat of collection of a qualifying semen sample 
(QX) for cases of sample handling or collection errors (e. g., spillage of sample by participant or by 
site staff prior to shipment of sample to lab, or sample gets misplaced/lost prior to shipment).  
Qualifying semen sample (QX) will be reviewed by an andrologist prior to enrollment.  
Another semen sample (BX) will be collected on Day 1, or Day 2. These two samples (QX and BX) 
are averaged to make up the baseline semen sample for the analyses. All semen samples must be 
separated by no less than 48 hours and preceded by no less than 48 hours of sexual abstinence.  
At week 12-13, week 26-27, and week 44-45 timepoint two (XX) semen samples must be collected 
within those weeks. These two (XX) samples per timepoint will be averaged to make up the week 
12, week 26 and week 44 semen sample values. 
For week 12-13, week 26-27 and week 44-45 timepoints, a 14-day collection window is allowed 
with the aim of the (XX) semen samples to have about a 7-day separation between samples for 
these timepoints. 
Early withdrawal: After 18 weeks of treatment at any early withdrawal thereafter, two (XX) semen 
samples must be collected.  These two samples per timepoint will be averaged to make up the early 
withdrawal week semen sample value.
Analyses will be performed on the total sperm count.
The semen sampling and methodology follow the WHO requirements for the examination and 
processing of human semen(24). This can be found in the safety and/or andrology laboratory manual.


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Laboratory Male Reproductive Hormone Blood Sample Test 
Parameters
The following male reproductive hormones will be assessed at the time points described in 
Synopsis Flow Chart and Procedures (Section 1.1.1):
Serum Endocrinology: LH, FSH, inhibin B and testosterone and total testosterone
TB Efficacy Variables and Procedures
Refer to Section 8.1 for Screening sample collection and analyses. At baseline and subsequent 
visits, refer to Section 1.1.1 (Synopsis Flow Chart and Procedures). Two spot sputum samples are 
collected at least 30 minutes apart at the research site under the coaching and observation of the 
trial staff. 
The mycobacteriology sampling methodology and requirements will be described in a separate 
document, the Mycobacteriology Laboratory Manual, which will be provided prior to the trial start. 
Sputum samples may not be obtained by induction.
The following analyses will be performed:
Liquid culture (MGIT), to detect presence or absence of Mtb and obtain the TTP when culture 
positive and not contaminated followed by a speciation test when applicable:
Susceptibility Testing for bedaquiline (B), moxifloxacin (M), pyrazinamide (Z) and pretomanid 
(Pa) on the following cultures:
•
The 1st positive, non-contaminated Mtb positive culture from Screening up to week 
4;
•
On Mtb positive cultures, after the participant has previously converted to culture 
negative at or after the last visit of the treatment period (Week 26); 
•
At Early Withdrawal;
•
At bacteriological failure is defined as failing to attain culture negative status at or 
before the end of treatment (Week 26).  The last available positive culture will be 
used for susceptibility testing e.g. the Early Withdrawal or Week 26 culture of a 
participant who withdrew and/or started re-treatment before the Week 78 visit, or the 
Week 78 culture of a participant who has not started re-treatment.  
Using these observed variables, the following derived variables will be assessed for evaluation of 
the efficacy endpoints:
Bacteriologic failure/relapse  
Time to sputum culture conversion
Number of participants with sputum culture conversion
Every effort must be made to collect sputum samples. However, in general, the inability to produce 
sputum is treated as being equivalent to having a negative culture (favourable) result.  A participant 
who never achieves culture negative status due to the inability to produce sputum but has 
completed Week 26 and post treatment follow-up (Weeks 35 to 78) and is without clinical or 
biological evidence of relapse, will be considered to have a favourable outcome.


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8.3
Safety and Tolerability Assessments 
The following safety and tolerability variables will be collected at the time points described in the 
Synopsis Trial Flow chart and Procedures (Section 1.1.1) 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 trial start. The following analyses will be performed: 
o Full Blood Count (haemoglobin, haematocrit, red blood cell count, white blood cell count 
with differential, platelet count). 
o Clinical Chemistry (albumin, serum urea, creatinine, direct, indirect and total bilirubin, 
uric acid, total protein, ALP, AST, ALT, lipase, phosphate, sodium, potassium, calcium 
(corrected for albumin), chloride, magnesium, glucose, bicarbonate/CO2, creatine 
phosphokinase (CPK). 
o Hepatitis B and C test.  
o When managing participants with elevated liver enzymes at an Unscheduled visit, 
the investigator can request additional tests, in addition to the repeat LFT [e.g. 
Gamma Glutamyl Transferase (GGT), screening for Hepatitis A, B, C; to assist in 
ruling out other causes of a dysfunctional liver test (e.g. alcohol induced hepatic 
cell injury, hepatobiliary disease, hepatic viral infection)]. 
o Urinalysis -(pH, specific gravity, protein, glucose, micro-albumin, ketones, bilirubin, 
creatinine, nitrite, sodium, urobilinogen, blood, leukocytes) At screening and baseline-
Day1. Microscopy will be completed as follow up to abnormal urinalysis per discretion 
of Investigator.  
 
Single 12 lead Electrocardiogram (ECG): 
o Investigator Assessment: Normal, Abnormal 
o Methodology: 
 
Timing and registration technique for ECGs will be standardized for all 
participants; 
 
Participants 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; 
 
All ECGs are to be performed in single 
 
ECGs should be done before any labs when both included in a visit 
 
For each participant, the ECGs should, to every extent possible, be collected 
at approximately the same time of day (+/- 1 hours) and in the same fed/fast 
state throughout the trial (e.g. 4 hours after lunch). 
 
ECGs are to be performed at Screening, Day 1, Weeks 2 through 8, Week 12, 
Week 16, Week 26, Week 44, if applicable, at Early Withdrawal. At visits when 
pre-dose PK samples are also scheduled, I.e., Weeks 2, 4, 8, 12, 16, 26, ECGs 
should be performed prior to PK sampling. 
 
Vital Signs 
o Vital signs, including weight (should be done before any labs) 
o Systolic and diastolic blood pressure (mmHg) to be measured supine (after 5 
minutes of rest) using an appropriately sized cuff, and using the same type of 
sphygmomanometer, if possible, by the same observer, at each relevant visit.  
o Heart rate (bpm) 


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o
Respiratory rate (breaths per minute)
 
Axillary/aural/other body temperature (°C)  
 
Physical Exam 
o Height is measured at screening only. 
o Full (complete) and Limited (gross neurological, pulmonary, cardiovascular and 
abdominal) examinations will be performed, and any clinically significant findings will 
be recorded.   
o Weight (kg) (in light clothing with no shoes).  
o Using the observed variables weight and height, calculated body mass index (BMI) 
will be derived. 
 
Adverse Events 
 
Investigator Assessment:  
o The Investigator will review the participant status at specified visits in the Synopsis 
Flow Chart and Procedures (Section 1.1.1), including any time the Investigator 
determines that the participant fulfils the criteria for the primary outcome of treatment 
failure. The Investigator will assess whether TB treatment is considered a “success” or 
“failure”. If it is considered a failure, the Investigator should specify if the assessment is 
based on bacteriology and/or clinical deterioration and/or radiological deterioration. 
 
8.4
PK Variables and Procedures
Plasma concentrations from sparse sampling (Synopsis Flow Chart and Procedures, Section 1.1.1) 
will be summarized as descriptive statistics.  
 
8.5
Mycobacteriology Characterization Variable and Procedures 
Refer to the Mycobacteriology Laboratory Manual for full details.
 
The 1st positive, non-contaminated Mtb positive culture from Screening to Week 4; 
 
Mtb positive cultures (after the participant has previously converted to negative) at or after 
the last visit of the treatment period (Week 26);  
 
At Early Withdrawal; 
 
At bacteriological failure, which is defined as failing to attain culture negative status at or 
before the end of treatment (Week 26). The last available positive culture will be used for 
susceptibility testing e.g., the Early Withdrawal or Week 26 culture of a participant who 
withdrew and/or started re-treatment before the Week 78 visit, or the Week 78 culture of a 
participant who has not started re-treatment.   
 
Mycobacterial Characterization - Mtb isolates (from the first Mtb positive culture) will be 
processed for: 
 
Susceptibility Testing for bedaquiline (B), moxifloxacin (M), pyrazinamide (Z) and 
pretomanid (Pa).  
 
All Mtb isolates must be stored at the local mycobacteriology laboratories, until trial closure.   


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9
Adverse Events
9.1
Definitions
Adverse Event (AE)
Any untoward medical occurrence in a clinical investigation participant, temporally associated with 
the use of a trial treatment whether considered related to trial treatment. An adverse event can 
therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease (new or exacerbated) temporally associated with the use of a trial treatment, 
whether or not related to the trial treatment.
Serious Adverse Event (SAE)
Any untoward medical occurrence that at any dose:
Results in death
Is life threatening (any event in which the participant was at risk of death at the time of the event; 
it does not refer to an event, which hypothetically might have caused death if it were more 
severe);
Requires inpatient hospitalization or prolongation of existing hospitalization; In general, 
hospitalization signifies that the participant has been detained (usually involving at least an 
overnight stay) at the hospital or emergency ward for observation and/or treatment that would 
not have been appropriate in the physician’s office or outpatient setting. Complications that 
occur during hospitalization are AEs. If a complication prolongs hospitalization or fulfills any 
other serious criteria, the event is serious. When in doubt as to whether “hospitalization” 
occurred, or was necessary, the AE should be considered serious. Hospitalization for elective 
treatment of a pre-existing condition that did not worsen from baseline is not considered an AE.
Results in persistent or significant disability/incapacity; the term disability means a substantial 
disruption of a person’s ability to conduct normal life functions. This definition is not intended to 
include experiences of relatively minor medical significance such as uncomplicated headache, 
nausea, vomiting, diarrhea, influenza, and accidental trauma (e.g., sprained ankle) which may 
interfere with or prevent everyday life functions but do not constitute a substantial disruption.
Is a congenital anomaly/birth defect; or
Is a medically important event.
Note:  Medical and scientific judgment should be exercised in deciding which is a medically 
important event that may not be immediately life-threatening or result in death or hospitalization but
may jeopardize the participant or may require medical or surgical intervention to prevent one of the 
outcomes listed above.  Examples of such events are intensive treatment in an emergency room 
or at home for allergic bronchospasm, blood dyscrasias or convulsions that do not result in 
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”.    
Attribution/Causality
The investigator is obligated to assess the relationship between trial treatment and each 
occurrence of each AE/SAE.
The investigator will use clinical judgment to determine the relationship.


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Alternative causes, such as underlying disease(s), concomitant therapy, and other risk factors, 
as well as the temporal relationship of the event to trial treatment administration will be 
considered and investigated.
The investigator will also consult the Investigator’s Brochure (IB) and/or Product Information, 
for marketed products, in his/her assessment.
For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.
There may be situations in which an SAE has occurred, and the investigator has minimal 
information to include in the initial report to the Sponsor/designee. However, it is very important 
that the investigator always assess causality for every event before the initial transmission of 
the SAE data to the Sponsor/designee.
The investigator may change his/her opinion of causality considering follow-up information and 
send a SAE follow-up report with the updated causality assessment.
Table 3: 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).  
Severity
Table 4: Definitions for Adverse Event Severity Gradings


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Grade
Severity Rating
Definition
GRADE 1 
Mild 
Transient or mild discomfort (< 48 hours); no medical 
intervention/therapy required.
GRADE 2 
Moderate 
Mild to moderate limitation in activity - some assistance 
may be needed; no or minimal medical 
intervention/therapy required. 
GRADE 3 
Severe 
Marked limitation in activity, some assistance usually 
required; medical intervention/therapy required, 
hospitalizations possible.
GRADE 4 
Potentially Life-
Threatening 
Extreme limitation in activity, significant assistance 
required; significant medical intervention/therapy 
required, hospitalization or hospice care probable.
See Appendix 2 for full DMID Toxicity Tables. Above ratings should be used to estimate the grade 
for abnormalities NOT found elsewhere in the Toxicity Tables. 
9.2
Reporting 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and non-
leading verbal questioning of the participant is the preferred method to inquire about AE 
occurrences. 
All AEs will be collected by the Investigator from the time a participant signs the Informed Consent 
Form through to their Week 78 follow-up visit. The exception to this is early withdrawal participants 
who will only have SAEs collected from their time of early withdrawal to their Week 78 follow-up 
visit at the timepoints specified in the Synopsis Flow Chart and Procedures (Section 1.1.1) and 
recorded in the CRF.   
Medical occurrences that begin after obtaining informed consent will be recorded as adverse 
events. If an adverse event started before signing of the informed consent, but is ongoing at trial 
start, it should be recorded as medical history. If the pre-existing medical occurrence worsens 
during the study, and adverse event will be recorded. 
All SAEs will be recorded and reported to the sponsor or designee within 24 hours of the information 
becoming known to the Investigator, as noted in the SAE reporting guidelines. The investigator will 
submit any updated SAE data to the sponsor within 24 hours of information becoming known to the 
investigator.  
The sponsor/designee will forward Safety Notification letters to the Investigator for submission to 
the IEC/IRB if required. 
Investigators are not obligated to actively seek AE or SAE information in former trial participants. 
However, if the investigator learns of any SAE, including a death, at any time after a participant has 
been discharged from the trial, and he/she considers the event to be reasonably related to the trial 
treatment or trial participation, the investigator must promptly notify the sponsor, IEC/IRB and 
regulatory authorities on an expedited basis in accordance with local requirements and ICH 
guidelines for GCP. 


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Reporting of expedited safety reports such as SUSARs (or IND safety reports as applicable) to the 
sites, RA and ECs (where it is the Sponsor responsibility) will cease 30 days after LPLV for the 
primary endpoint is completed, unless there is a specific local requirement that would go beyond 
this time point.  Distribution of aggregated safety reports and investigator brochures to relevant 
destinations will cease once LPLV of the entire study is completed. 
Follow up of Adverse Events
All AEs will be followed until:
Satisfactory clinical resolution or stabilization; or
The end of the follow-up period; and 
All queries on these AEs have been resolved.  
Certain long-term AEs cannot be followed until resolution within the setting of this protocol. In these 
cases, follow-up will be the responsibility of the treating physician. However, this will have to be 
agreed upon with the Sponsor Medical Monitor.
The investigator is obligated to perform or arrange for the conduct of supplemental measurements 
and/or evaluations as medically indicated or as requested by Sponsor or representative to elucidate 
the nature and/or causality of the AE or SAE as fully as possible. This may include additional 
laboratory tests or investigations, histopathological examinations, or consultation with other health 
care professionals. Investigator should contact sponsor/designee to discuss appropriate medical 
follow-up if consultation required. 
If a participant dies during participation in the trial or during a recognized follow-up period, the 
investigator will provide sponsor/representative with a copy of any post-mortem findings including 
histopathology.
New or updated information will be recorded in the originally completed CRF and submitted to 
sponsor within 24 hours of receipt per SAE reporting guidelines.
Clinical Laboratory Adverse Events
Changes in the results of the Clinical Laboratory assessment results which the Investigator feels 
are clinically significant will be reported as adverse events. It is the Investigators’ responsibility to 
review the results of all laboratory tests as they become available. This review must be documented
by the Investigators’ dated signature on the laboratory report. For each abnormal laboratory test 
result, the Investigator needs to ascertain and document if this is a clinically significant change from 
baseline for that individual participant. This determination, however, does not necessarily need to 
be made the first time an abnormal value is observed. The Investigator may repeat the laboratory 
test or request additional tests to verify the results of the original laboratory tests. If this laboratory 
value is determined by the Investigator to be a clinically significant change from baseline for that 
participant, it is an adverse event.
Disease under Study
Symptoms of the disease under trial (Tuberculosis) experienced by the participant while on the trial 
will be assessed by the Investigator.  If the symptom has:
worsened while the participant is in the trial; and
the Investigator assesses it as clinically significant.


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it will be recorded as an adverse event. 
If there is:
no change; and  
 
the Investigator assesses the symptom as due to the participant’s TB; and 
not clinically significant.
it will not be recorded as an AE and this will be noted in the participant’s source documentation. 
All TB related symptoms that meet SAE criteria will be recorded and reported as a SAE.
Overdose
Overdose of IMP experienced by the participant while on the trial, will be assessed by the 
Investigator to determine whether the overdose led to an Adverse Event, including if the taking of 
the suspect medicine led to suicidal intention and subsequent overdose of the suspect medicine, 
or other medication. In this case it will be recorded as an adverse event. If it does not lead to an 
Adverse Event, it will not be recorded as an AE and this will be noted in the participant’s source 
documentation.
Drug Interaction
If the Investigator becomes aware that the participant has experienced a drug interaction which has 
resulted in an adverse event, it will be recorded as an adverse event.
9.3
Monitoring for Specific Toxicities 
Monitoring for specific toxicities is based upon target organs as defined in the preclinical toxicity 
studies of the Investigator’s Brochures[5, 9, 19, 23] and Package Inserts. [8, 18, 21]  
AEs still ongoing at the end of treatment in the trial will be followed until satisfactory clinical 
resolution or stabilization or until the end of the follow-up period and until all queries on these AEs 
have been resolved. Grade 3 and grade 4 laboratory abnormalities and laboratory abnormalities 
considered clinically significant should be followed until satisfactory resolution or stabilization.
Note: For Grade 3 or 4 laboratory toxicities, participants should have a confirmatory 
measurement within 48 hours where possible. The recommendation for managing participants 
below assumes the laboratory abnormalities of concern have been confirmed.
ALT, AST and Bilirubin
The Investigator should refer to the Hepatoxicity Management Guideline, to appropriately monitor 
significant elevations of AST, ALT or Bilirubin. A separate Hepatoxicity Management Guideline 
document has been developed to aid investigators in the management of participants.
When managing participants with elevated liver enzymes at an Unscheduled visit, the Investigator 
can request additional tests, in addition to the repeat LFT [e.g. Gamma Glutamyl Transferase 
(GGT), screening for Hepatitis A, B, C; to assist in ruling out other causes of a dysfunctional liver 
test (e.g. alcohol induced hepatic cell injury, hepatobiliary disease, hepatic viral infection)].


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Lipase
Contact Sponsor Medical Monitor to review. Investigator should consider participants with 
confirmed Grade 3 or 4 elevations of lipase for temporary or permanent discontinuation from 
the full regimen.
Musculoskeletal System and Cardiac Muscle Myalgia
Grade 2 (muscle tenderness at a site other than sites of injection and/or venepuncture or with 
moderate impairment of activity) or Grade 3 (severe muscle tenderness with marked impairment of 
activity) or Grade 4 (frank myonecrosis):
Participants with Grade 2 signs and symptoms should be followed closely. Participants with 
Grade 3 or 4 signs and symptoms should be discussed with the Sponsor Medical Monitor 
to consider pausing trial IMP, pending further evaluation.
Cardiac Rhythm Disturbances
Cardiac rhythm disturbances that are Grade 3 (recurrent, persistent, symptomatic arrhythmia 
requiring treatment) or Grade 4 (unstable dysrhythmia requiring treatment):
Participants should be monitored closely. The Investigator should discuss with the Sponsor 
Medical Monitor to consider pausing the full regimen, pending further evaluation.
QTc prolongation 
If QTcF is equal to or greater than 500 msec, the ECG should be repeated, and serum electrolytes 
should be evaluated. If the second ECG also has a QTcF of > 500 msec, the Sponsor Medical 
Monitor should be consulted to consider pausing the full regimen, pending further evaluation.
New left bundle branch block (LBBB) or Mobitz type 2 or complete heart block. Recordings with 
artefacts that interfere with the interpretation of the ECG should be repeated to confirm the findings. 
If the finding is from the ECG machine reading, the result is to be checked and confirmed by the 
Investigator. If this is confirmed by the Investigator, dosing is to be paused and the participant is to
be treated per the Investigator’s clinical judgment. If it is the investigator judgement to withdraw the 
participant from the full regimen, the Sponsor Medical Monitor should be contacted for further 
review.  
9.4
Safety Monitoring 
Medical Monitoring:
During the conduct of the study, it is the responsibility of the sponsor-appointed medical monitor of 
the study to consult with the investigator(s) and fertility experts regarding any medical concerns or
questions that arise. When requested by an investigator, the Medical
Monitor discusses and
reviews potential participants and helps the investigator ensure that only participants who are
appropriate and who meet the protocol inclusion and exclusion criteria are enrolled in the study.
The Medical Monitor also ensures that the protocol-specified procedures are followed, especially
safety and tolerability data, and that there are no potential safety concerns. The Medical Monitor
will review all SAE’s regarding this study and any Severe AEs and clinically significant safety concerns.


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Regarding the reproductive safety of this study, a reproductive safety monitoring committee will be 
formed consisting of three fertility experts – these fertility experts should have previously served on 
a reproductive safety monitoring committee – and the medical monitor. This reproductive safety 
monitoring committee will convene after the first 4 patients enrolled and then quarterly thereafter to 
review the reproductive parameters. 
Stopping rules:  
Stopping rules will be developed with the help and guidance of the fertility experts after the first 4 
patients are enrolled and sufficient information is available about the baseline sperm counts seen 
for this population. 
Regarding the nonreproductive safety of this study, this will be monitored by the medical monitor 
together with the NC-008 safety monitoring committee (comprising the medical monitors and sponsor 
study physician for the trial). This NC-008 safety monitoring committee is an appointed group of 
physicians that are currently monitoring study NC-008. In this study (NC-008) patients with 
pulmonary TB are being treated with the same (BPaMZ) antibiotic treatment regime. The Medical 
Monitor will participate in teleconferences with this NC-008 safety monitoring committee to review all 
SAE and Severe AEs regarding this and any safety concerns that are new or are being tracked. 
Paternity Questionnaire: 
This questionnaire is aimed at collecting additional data on male reproduction after treatment 
completion of this regimen containing pretomanid. The questionnaire at week 78 or early 
withdrawal. Will include a general question whether the participant has fathered any children 
during or after treatment with the pretomanid-containing regimen 
If yes, the number of children and the month and year of their birth will be obtained. 
A completed questionnaire will be entered into the database for all participants.  Data will be
analyzed descriptively based on the data collected in this trial.   
Data collected may be added to the ongoing paternity survey of male reproduction which is 
currently being collected from previous and ongoing TB Alliance trials with pretomanid containing 
regimens (i.e., STAND, Nix-TB, SimpliciTB and ZeNix). See Appendix 5 for the questionnaire 
questions.  
10 Statistical Analysis
The statistical analysis plan (SAP), which will contain details of the analyses specified in this 
section, will be written, and signed off prior to first patient randomized. 
10.1 Analysis Population
Semen Analysis Population will include data from all participants who receive at least one dose of 
IMP. 
TB Efficacy Analysis Population will include data from all participants who receive at least one dose 
of IMP. 
Safety and tolerability population will include data from participants who received at least one dose 
of IMP.  


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10.2 Sample Size
To assess the male reproductive safety profile of pretomanid in the regimen (BPaMZ) of Bedaquiline
200mg daily for 8 weeks then 100 mg daily for 18 weeks, together with pretomanid 200 mg (1x 
daily) + moxifloxacin 400 mg (1x daily) + pyrazinamide 1500 mg (1x daily) for 26 weeks in 
participants with Drug-sensitive (DS) or Drug-resistant (DR) pulmonary TB.
The sample size is not based on formal statistical considerations. It is based on practicality of 
enrolment and to rule out any severe effect of the regimen on semen parameters.
10.3 Interim Analyses
No formal interim analyses are planned. 
10.4 Primary and Secondary Endpoint Analysis
Analyses will be performed at 26, 44 and 78 weeks.  The Statistical Analysis Plan (SAP) will 
outline the data endpoints that will be included in each analysis. 
Primary Endpoint Analysis
Change from baseline in total sperm count at 26 weeks
Secondary Endpoints 
Change from baseline in total sperm count at 13 and 44 weeks
A key secondary endpoint will be the change from baseline in male reproductive hormones 
at Week 2, 4, 8, 12, 16, 26, 35, 44, 52, 65, 78, and at early withdrawal.  Reproductive 
hormones: luteinizing hormone (LH), follicle-stimulating hormone (FSH), Inhibin B and 
testosterone.
Other Secondary Endpoints
10.4.3.1 Efficacy (TB)
10.4.3.1.1
Clinical Outcome at 78 Weeks  
For the secondary endpoint of clinical outcome (bacteriologic failure or relapse or clinical 
failure), participants will be classified as having a favourable, unfavourable, or un-assessable 
outcome status which will be defined in detail in the SAP. In general, participants achieving 
and maintaining culture negative status without any additional treatment will be considered 
favourable; participants who fail on treatment or relapse in follow-up will be considered 
unfavourable and participants who are not assessable (and who have not already been 
declared as unfavourable) will be considered un-assessable and excluded from the analysis.
10.4.3.1.2
Culture Conversion to Negative Status at Week 4, 8, 12, 17, 22 
and 26
Proportion of participants with sputum culture conversion to negative status in liquid culture 
(MGIT) at 4, 6, 12 and 17 weeks to be explored as a potential biomarker of outcome at 
78 weeks from start of therapy.


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10.5 Safety and Tolerability Analysis
 
The incidence of all-cause mortality will be summarized. 
 
All adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) and will be presented by Preferred Term within each MedDRA System Organ Class 
(SOC). 
 
Treatment-emergent adverse events (TEAEs) are defined as AEs which started at or after the 
first administration of IMP and includes those events started prior to the first administration of 
IMP but which worsened after the first intake. Adverse events starting after the last 
administration of IMP until the last scheduled visit/assessment/measurement will be regarded 
as treatment emergent. 
 
The incidence of the following events will be summarized for further medical analysis: 
o Incidence of TEAEs; 
o Incidence of TEAEs by Severity; 
o Incidence of TEAEs by DMID toxicity grade; 
o Incidence of Drug-Related TEAEs; 
o Incidence of Serious TEAEs; 
o Incidence of TEAEs Leading to Early Withdrawal; 
o Incidence of TEAEs leading to Death. 
10.6 Pharmacokinetics
For each analyte and each scheduled sampling time/window, the plasma concentration will be 
summarized by descriptive statistics including the mean, SD, coefficient of variation (CV), median, 
minimum, maximum, geometric mean and geometric CV (%). 
In addition, mean and/or median concentration-versus-time graphs will be provided, with error bars 
and/or scatter plots as appropriate. 
10.7 Pharmacokinetics/Pharmacodynamics
Relationships may be explored between drug exposure and efficacy and safety endpoints, as 
appropriate. If so, planning details and results will be included in a separate modelling plan and 
report. 
11 Records Management 
11.1 Data Collection
All relevant CRF/eCRF pages will be completed for each participant who receives any amount of 
IMP, depending on visits attended. For screening failure participants specific eCRF pages will be 
completed as described in the eCRF Completion Guidelines. For participants who are prematurely 
withdrawn, all the visits the participant attended including withdrawal and follow-up visits need to 
be completed. 


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11.2 Source Documents 
Source documents are defined as all information in original records and certified copies of original 
records of clinical findings, observations, or other activities in a clinical trial necessary for the 
reconstruction and evaluation of the trial. Source documents will include, but are not limited to, 
progress notes, in-Patient hospital records, electronic data, screening logs, and recorded data from 
automated instruments. 
All source documents pertaining to this trial will be maintained by the Investigators.  The Investigator 
has to permit trial related monitoring, audits, Independent Ethics Committee/Institutional Review 
Board (IEC/IRB) review and regulatory inspections providing authorized personnel direct access to 
source documents, including documents required to confirm inclusion/exclusion and relevant 
in-Patient records while participants is on trial treatment. 
11.3 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. 
11.4 Records Retention at the Trial Centre 
The Investigator is obliged to retain records and data from the trial for safety reasons and for audit 
and inspection after trial completion. The essential documents should be retained for not less than 
2 years after the last approval of a marketing application and until there are no pending or 
contemplated marketing applications or at least 2 years have elapsed since the formal 
discontinuation of clinical development of the IMP. Investigator should notify sponsor/designees 
prior to destroying any records pertaining to the trial. 
12 Quality Control and Assurance 
12.1 Site Procedures 
The Investigator undertakes to perform the clinical trial in accordance with this protocol, local 
regulations, International GCP, and the ethical principles that have their origin in the Declaration of 
Helsinki.  
The Investigator undertakes to complete the CRFs according to the Sponsor’s requirements, in a 
timely, accurate and legible manner. CRF entries will be verifiable to source documentation other 
than the CRF. 
Site Standard Operating Procedures will be adhered to for all clinical and bioanalytical activities 
relevant to the quality of the trial.  Participant compliance will be monitored throughout the trial. 
The Investigator will sign and date any analysis results (e.g., laboratory, ECG, etc.) to verify that 
the results have been reviewed. 
The Investigator may appoint other sub-investigators to assist with the trial. However, the 
Investigator maintains responsibility for the trial and will supervise the sub-investigators. Written 
IEC/IRB approval of the trial will be obtained prior to involvement in the trial. 


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The Investigator will ensure that all site personnel are adequately trained in GCP, local regulations, 
the protocol, IBs/package inserts and all trial procedures and requirements. 
12.2 Monitoring 
The Investigator is responsible for the validity of all data collected at the clinical site and must accept 
the various monitoring procedures employed by the Sponsor. The purpose of monitoring is to verify 
that the rights and well-being of human participants are protected; that trial data are accurate, 
complete and verifiable with source data; and that the trial is conducted in compliance with the 
protocol, International GCP, the ethical principles that have their origin in the Declaration of Helsinki 
and the applicable regulatory requirements.  
Monitors assigned by the Sponsor will conduct regular site visits before, during and after the trial 
for the purpose of monitoring various aspects of the trial, and to assure appropriate conduct of the 
trial in accordance with ICH GCP. Visits will take place usually within a predetermined interval, but 
this may vary during the trial. The Investigator and site staff will allow the trial monitor and authorized 
representatives of the Sponsor to (1) inspect all CRFs, written informed consent documents and 
corresponding source documents (e.g., original medical records), patient records and laboratory 
raw data, site SOPs, training records, facilities, and other trial related systems/processes, and (2) 
access clinical supplies, dispensing and storage areas. The Investigator and site staff should also 
(1) agree to assist with monitoring activities if requested and (2) provide adequate time and space 
for monitoring visits.  
The monitor will query any missing, confusing, spurious, or otherwise ambiguous data with the 
Investigator. All queries should be resolved in a timely manner. A monitoring log will be 
maintained recording each visit, the reason for the visit, the monitor’s signature and Investigator 
or designee’s confirmation signature. 
12.3 Protocol Deviations
A protocol deviation is any noncompliance with the clinical trial protocol, GCP, or Monitoring Plan 
requirements. The noncompliance may be either on the part of the participant, the investigator, or 
the study site staff. As a result of deviations, corrective actions are to be developed by the site and 
implemented promptly.  
It is the responsibility of the site to use continuous vigilance to identify and report deviations. All 
deviations must be addressed in study source documents and reported to Sponsor/designee. 
Protocol deviations must be sent to the local IRB per their guidelines. The site PI/study staff is 
responsible for knowing and adhering to their IRB requirements. 
12.4 Auditing 
For compliance with International GCP and regulatory agency guidelines, it may be necessary for 
Sponsor-authorized Quality Assurance personnel and/or authorized personnel from an external 
regulatory agency to conduct an audit or inspection of the investigational site. The purpose of an 
audit is to assess the quality of data regarding 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 trial. The 


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audit will involve the review of all trial-related documentation required by GCP to be maintained by 
each site; drug storage, dispensing and return; all trial-related supplies; and source documents 
against the CRFs to assure the adequacy and accuracy of the information which has been recorded, 
including the verification of any AEs which have occurred. The auditors or inspectors may also 
review site SOPs, training records, site facilities and other trial related systems/processes. 
In the event of the site being notified of a Regulatory Inspection, the Sponsor will help with 
preparation. It is essential that the Sponsor be notified of the inspection as soon as possible. 
13 Ethics and Regulatory
13.1 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. 
13.2 Independent Ethics Committee/Institutional Review Board (IEC/IRB) Review
The protocol and required trial related documents will be reviewed by the sites respective IEC/IRB.  
The trial will not start until the IEC/IRB has approved the protocol, written informed consent, any 
written information to be provided to the participant or any modification thereof, plus any other trial 
related documents required for review. The IEC/IRB shall be constituted and shall operate in 
accordance with International GCP, the ethical principles that have their origin in the Declaration of 
Helsinki. The Investigator will maintain an accurate and complete record of all submissions made 
to, and responses from the IRB/IEC. The records should be filed in the Investigator’s Trial File, and 
copies will be sent to the Sponsor. 
13.3 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. 
13.4 Informed Consent
Written informed consent will be obtained from all participants (or legally acceptable representative) 
before any trial-related procedures (including any screening or pre-treatment procedures) are 
performed. Investigators may discuss the availability of the trial and the opportunity for entry with a 
potential participant without first obtaining consent. However, informed consent must be obtained 
and documented prior to initiation of any procedures that are performed solely for the purpose of 
determining eligibility for research, including withdrawal from current medication(s). When this is 
done in anticipation of, or in preparation for, the research, it is part of the research. 
The Investigators have both ethical and legal responsibility to ensure that each participant being 
considered for inclusion in this trial is given a full explanation of the protocol. Participants must be 
informed that their participation is voluntary. The investigator or his/her representative will explain 
the nature of the trial to the participant or his/her legally authorized representative and answer all 
questions regarding the trial. This shall be documented on a written informed consent form that 
shall be approved by the same IEC/IRB responsible for approval of this protocol. Each informed 


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consent form shall include the elements required by the international GCP and must adhere to the 
ethical principles that have their origin in the Declaration of Helsinki.  
The trial will be included and updated in the appropriate Country registry and referenced in the ICF. 
Once the appropriate essential information has been provided to the participant and fully explained 
by the Investigators (or qualified designees) and it is felt that the participant understands the 
implications of participating, the IEC/IRB approved written informed consent form will be signed and 
dated by both the participant and the person obtaining consent (Investigators or designees), and 
by any other parties required by the IEC/IRB. Ongoing participants must be re-consented to the 
most current version of the ICF(s) during their participation in the trial. 
The original signed informed consent form will be kept with the trial records and a copy of signed 
informed consent form will be provided to the participant or the participant’s legally authorized 
representative. Another copy of the signed informed consent form and a source document 
identifying the trial and recording the dates of participation will be placed in the participant’s medical 
record. 
The monitor will inspect the original completed consent form(s) for all participants. 
13.5 Confidentiality
All site staff, the Sponsor, and any sponsor representatives will preserve the confidentiality of all 
participants taking part in the trial, in accordance with International GCP, applicable local 
legislation/regulations. Participant to the requirement for source data verification by the trial 
personnel by reference to the participant’s notes, confidentiality of all participant identities will be 
maintained.  Unique identifiers will be used on the CRF and in all trial correspondence, as permitted.  
No material bearing a participant’s name will be kept on file by the Sponsor. The written informed 
consent will contain a clause granting permission for review of the participants’ source data by the 
sponsor or designees. 
14 Publication Policy 
The definition of publication for this purpose is any public presentation of the data emerging from 
this trial.  
All unpublished information given to the Investigator by the Sponsor shall not be published or 
disclosed to a third party, other than to the responsible 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 
trial in the form of a joint publication(s) between Sponsor and Investigator(s), including site clinical 
and laboratory investigators, as appropriate. Publication and authorship will be in accord with the 
International Association of Journal Editors.  
Because the Study is funded, in whole or in part, by the Bill and Melinda Gates Foundation (the 
“Foundation”), all peer-reviewed published research relating to the Study must comply with the 
Foundation’s 
Open 
Access 
Policy 
as 
described 
from 
time 
to 
time 
at 
http://www.gatesfoundation.org/How-We-Work/General-Information/Open-Access-Policy. 


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Specifically, (a) all peer-reviewed published research relating to the Study must be submitted for 
publication by TB Alliance through the Chronos Open Access Publishing Service established by the 
Foundation to ensure the immediate and unrestricted access and reuse of all peer-reviewed 
published research funded, in whole or in part, by the Foundation without any embargo period, and 
(b) all data underlying the peer-reviewed published research results must be immediately made 
accessible and open to the public in accordance with the Foundation’s Open Access Policy. 
15 Protocol Amendment Policy
Any change to the protocol will be affected by means of a protocol amendment. Any changes which 
affect participant safety or welfare will be submitted to the 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 
participant’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. 
16 Sponsor, Financial Aspects, Insurance, and Indemnity 
The trial sponsor is the Global Alliance for TB Drug Development (TB Alliance). The TB Alliance is 
a not for profit, product development partnership accelerating the discovery and development of 
new TB drugs that will shorten treatment, be effective against susceptible and resistant strains, be 
compatible with antiretroviral therapies for those HIV-TB participants currently on such therapies 
and improve treatment of latent infection. 
The TB Alliance works with public and private partners worldwide. It is committed to ensuring that 
approved new regimens are affordable, adopted, and available to those who need them. 
The TB Alliance operates with funding mainly from the Bill & Melinda Gates Foundation, the 
Netherlands Ministry of Foreign Affairs (DGIS), the United Kingdom Department for International 
Development (DFID), and the United States Agency for International Development (USAID). 
The participants will not receive any incentives for their involvement in the trial. The sponsor has 
made provision to reimburse the participants for out-of-pocket expenses such as travelling to and 
from the trial site and other miscellaneous costs because of their trial participation. 
The sponsor certifies that it has liability insurance coverage for itself and will provide an associated 
certificate upon request. The insurance does not relieve the Investigators of the obligation to 
maintain their own liability insurance as required by applicable law. The sponsor does not assume 
any obligation for the medical treatment of other injuries and illnesses.


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17 References 
1. 
Organization, W.H.,.Global Tuberculosis Report, 2019. 
2. 
Rodrigues, LC, Diwan VK, and Wheeler JG. Protective effect of BCG against tuberculosis 
meningitis and miliary tuberculosis: a meta-analysis.  Int J Epidemiol. 1993; 22(6): 1154-
1158. 
3. 
Colditz GA, et al.  Efficacy of BCG vaccine in the prevention of tuberculosis. Meta-analysis 
of the published literature.  JAMA 194; 271(9): 698-702. 
4. 
ATS, C., IDSA.  Treatment of tuberculosis.  MMWR Recommendations and Reports 2003; 
52 (RR-11): 1-77. 
5. 
Investigator's Brochure: Pretomanid (PA-824).  Global Alliance for TB Drug Development, 
version 20. 29 September 2020. 
6. 
Pa-824.   Tuberculosis (Edinb).  2008. 88(2): 134-136. 
7. 
Tweed C, Dawson R, Burger D, Conradie A, Crook A, Mendel C, Conradie F, Diacon AH, 
Ntinginya N, Everitt DE, Haraka F, Li M, van Niekerk C, Okwera A, Rassool M, Reither K, 
Modulakgotla AS, Staples S, Variava E, Spigelman M, (2019).  Bedaquiline, moxifloxacin, 
pretomanid, and pyrazinamide during the first 8 weeks of treatment of patients with drug-
susceptible or drug resistant pulmonary tuberculosis: a multicentre, open-label, partially 
randomised phase 2b trial.  Lancet Respir Med, 1-11 doi: 10.1016/S2213-2600(19)30366-
2. 
8. 
Package insert: Sirturo.  Janssen Therapeutics, September 2014 Available at: 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/204384s000lbl.pdf. 
9. 
Investigator’s Brochure: TMC207 (Bedaquiline).  Edition 14. Janssen Research and 
Development, 03 November 2020. 
10. 
Koul A, Dendouga N, Vergauwen K, Molenberghs B, Vranckx L, Willebrords R, et al. 
Diarylquinolines target subunit c of mycobacterial ATP synthase. Nat Chem Biol. 
2007;3(6):323-324. 
11. 
Andries K, Verhasselt P, Guillemont J, Gohlmann HW, Neefs JM, Winkler H, et al. A 
diarylquinoline drug active on the ATP synthase of Mycobacterium tuberculosis. Science. 
2005;307(5707):223-227. 
12. 
Huitric E, Verhasselt P, Andries K, Hoffner SE. In vitro antimycobacterial spectrum of a 
diarylquinoline ATP synthase inhibitor. Antimicrob Agents Chemother. 2007;51(11):4202-
4204. 


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13.
Koul A, Vranckx L, Dendouga N, Balemans W, Van den Wyngaert I, Vergauwen K, et al. 
Diarylquinolines are bactericidal for dormant mycobacteria as a result of disturbed ATP 
homeostasis. J Biol Chem. 2008;283(37):25273-25280. 
14. 
Dietze R, Teixeira L, Rocha LM, Palaci M, Johnson JL, Wells C, et al. Safety and bactericidal 
activity of rifalazil in patients with pulmonary tuberculosis. Antimicrob Agents Chemother. 
2001;45(7):1972-1976. 
15. 
Donald PR, Sirgel FA, Venter A, Parkin DP, Seifart HI, van de Wal BW, et al. Early 
bactericidal activity of antituberculosis agents. Expert Rev Anti Infect Ther. 2003;1(1):141-
155. 
16. 
Nuermberger E, Rosenthal I, Tyagi S, Williams KN, Almeida D, Peloquin CA, et al. 
Combination chemotherapy with the nitroimidazopyran PA-824 and first-line drugs in a 
murine model of tuberculosis. Antimicrob Agents Chemother. 2006;50(8):2621-2625. 
17. 
Nuermberger E, Tyagi S, Tasneen R, Williams KN, Almeida D, Rosenthal I, et al. Powerful 
bactericidal and sterilizing activity of a regimen containing PA-824, moxifloxacin, and 
pyrazinamide in a murine model of tuberculosis. Antimicrob Agents Chemother. 
2008;52(4):1522-1524. 
18. 
Package insert: Moxifloxacin.  MacLeods Pharmaceuticals Ltd., January 2014. 
19. 
Investigator's Brochure: Global Alliance for TB Drug Development, Moxifloxacin. version 
nos 02; 26 Feb 2019.  
20. 
Johnson JL, Hadad DJ, Boom WH, Daley CL, Peloquin CA, Eisenach KD, et al. Early and 
extended early bactericidal activity of levofloxacin, gatifloxacin and moxifloxacin in 
pulmonary tuberculosis. Int J Tuberc Lung Dis. 2006;10(6):605-612. 
21. 
Package insert: HR Combination Tablets.  Bayer PLC. 13 April 2019 
22. 
Zhang Y, Mitchison D. The curious characteristics of pyrazinamide: a review. Int J Tuberc 
Lung Dis. 2003;7(1):6-21. 
23. 
Investigator's Brochure: Global Alliance for TB Drug Development, Pyrazinamide. version 
2.0; 12 Mar 2019. 
24. 
WHO laboratory manual for the Examination and processing of human semen.  Fifth Edition. 
2010. 
 
 
 


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Protocol Version: V4.0 07 APR 2022 
Protocol Name:    BPaMZ/SEM 
 
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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.>> 


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Appendix 2: Division of Microbiology and Infectious Disease (DMID) Toxicity Table
Source:  U.S. National Institute of Allergy and Infectious Diseases, DMID, November 2007 (Draft)
ABBREVIATIONS:  Abbreviations utilized in the Table: 
ULN = Upper Limit of Normal 
LLN = Lower Limit of Normal
Rx = Therapy 
Req = Required 
Mod = Moderate 
IV = Intravenous
ADL = Activities of Daily Living 
Dec = Decreased
ESTIMATING SEVERITY GRADE 
For abnormalities NOT found elsewhere in the Toxicity Tables use the scale below to estimate 
grade of severity: 
Grade
Severity Rating 
Definition 
GRADE 1 
Mild 
Transient or mild discomfort (< 48 hours); no medical 
intervention/therapy required.
GRADE 2 
Moderate 
Mild to moderate limitation in activity - some assistance may be 
needed; no or minimal medical intervention/therapy required. 
GRADE 3 
Severe 
Marked limitation in activity, some assistance usually required; 
medical intervention/therapy required, hospitalizations possible. 
GRADE 4 
Potentially Life-
threatening 
Extreme limitation in activity, significant assistance required; 
significant medical intervention/therapy required, hospitalization or 
hospice care probable.
SERIOUS OR LIFE-THREATENING AEs 
ANY clinical event deemed by the clinician to be serious or life-threatening should be considered a 
grade 4 event. Clinical events considered to be serious or life-threatening include, but are not limited 
to seizures, coma, tetany, diabetic ketoacidosis, disseminated intravascular coagulation, diffuse 
petechiae, paralysis, acute psychosis, severe depression. 
COMMENTS REGARDING THE USE OF THESE TABLES 
 
Standardized and commonly used toxicity tables (Division of 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 participants in DMID trials. 
 
For parameters not included in the following Toxicity Tables, sites should refer to the “Guide for 
Estimating Severity Grade” located above. 
 
Criteria are generally grouped by body system. 
 
Some protocols may have additional protocol specific grading criteria, which will supersede the 
use of these tables for specified criteria. 
 
 


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HEMATOLOGY 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Hemoglobin
9.5 - 10.5 gm/dL 
8.0 - 9.4gm/dL
6.5 - 7.9 gm/dL
< 6.5 gm/dL
Absolute Neutrophil 
Count
1000-1500/mm3 
750-999/mm3
500-749/mm3
<500/mm3
Platelets
75,000-99,999/mm3
50,000-74,999/mm3
20,000-49,999/mm3
<20,000/mm3
WBCs 
11,000-13,000/ 
mm3
13,000-15,000 
/mm3
15,000-30,000/mm3 
>30,000 or <1,000 
/mm3 
% Polymorphonuclear 
Leucocytes + Band 
Cells 
> 80% 
90 – 95% 
>95% 
---------- 
Abnormal Fibrinogen 
Low: 
100-200 mg/dL 
High: 
400-600 mg/dL 
Low: 
<100 mg/dL 
High: 
>600 mg/dL 
Low: 
< 50 mg/dL 
 
---------- 
Fibrinogen 
associated with 
gross bleeding or 
with disseminated 
coagulation
Fibrin Split Product
20-40 mcg/ml
41-50 mcg/ml
51-60 mcg/ml 
> 60 mcg/ml 
Prothrombin Time (PT) 
1.01 - 1.25 x ULN 
1.26-1.5 x ULN 
1.51 -3.0 x ULN 
>3 x ULN 
Activated Partial 
Thromboplastin (APPT) 
1.01 -1.66 x ULN
1.67 - 2.33 x ULN 
2.34 - 3 x ULN 
> 3 x ULN 
Methemoglobin 
5.0 - 9.9 % 
10.0 - 14.9 % 
15.0 - 19.9% 
> 20.0 % 
 


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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 
(non-fasting and no 
prior diabetes)
116 - 160 mg/dL
161- 250 mg/dL 
251 - 500 mg/dL 
> 500 mg/dL or abnormal 
glucose with ketoacidosis 
or seizures
Hypocalcemia
(corrected for 
albumin) 
8.4 - 7.8 mg/dL 
7.7 - 7.0 mg/dL 
6.9 - 6.1 mg/dL 
< 6.1 mg/dL or abnormal 
calcium with life threatening 
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 is 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
 


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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
 


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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; out 
participant 
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 
 


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GASTROINTESTINAL 
Grade 1
Grade 2
Grade 3
Grade 4
Nausea
mild or transient; 
maintains 
reasonable intake 
moderate 
discomfort; intake 
decreased 
significantly; some 
activity limited
no significant 
intake; requires IV 
fluids 
hospitalization 
required; 
Vomiting
1 episode in 24 
hours 
2-5 episodes in 24 
hours 
>6 episodes in 24 
hours or needing 
IV fluids
physiologic 
consequences 
requiring 
hospitalization or 
requiring 
parenteral nutrition
Constipation
requiring stool 
softener or dietary 
modification 
requiring laxatives 
obstipation 
requiring manual 
evacuation or 
enema 
obstruction or toxic 
megacolon
Diarrhea 
mild or transient; 3-
4 loose stools/day 
or mild diarrhea 
last < 1 week 
moderate or 
persistent; 5-7 loose 
stools/day or 
diarrhea lasting >1 
week 
>7 loose stools/day 
or bloody diarrhea; 
or orthostatic 
hypotension or 
electrolyte 
imbalance or >2L 
IV fluids required  
hypotensive shock
or physiologic 
consequences 
requiring 
hospitalization   
Oral 
Discomfort/Dysphagia 
mild discomfort; no 
difficulty 
swallowing 
some limits on 
eating/drinking 
eating/talking very 
limited; unable to 
swallow solid foods
unable to drink 
fluids; requires IV 
fluids 
 


TB Alliance 
Protocol Number: Pa-824-CL-012 
Protocol Version: V4.0 07 APR 2022 
Protocol Name:    BPaMZ/SEM 
 
CONFIDENTIAL 
Page 73 of 79 
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
Participative
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
 


TB Alliance 
Protocol Number: Pa-824-CL-012 
Protocol Version: V4.0 07 APR 2022 
Protocol Name:    BPaMZ/SEM 
 
CONFIDENTIAL 
Page 74 of 79 
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; prurits 
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
 
 


TB Alliance 
Protocol Number: Pa-824-CL-012 
Protocol Version: V4.0 07 APR 2022 
Protocol Name:    BPaMZ/SEM 
 
CONFIDENTIAL 
Page 75 of 79 
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% 
cannot work 
unable to care for 
self 


TB Alliance 
Protocol Number: Pa-824-CL-012 
Protocol Version: V4.0 07 APR 2022 
Protocol Name:    BPaMZ/SEM 
 
CONFIDENTIAL 
Page 76 of 79 
Appendix 3: WHO Clinical Staging of HIV/AIDS for Adults and Adolescents 
Primary HIV Infection 
Asymptomatic
Acute retroviral syndrome 
Clinical Stage 1
Asymptomatic
Persistent generalized lymphadenopathy
Clinical Stage 2
Moderate unexplained weight loss (<10% of presumed or measured body weight)
Recurrent respiratory infections (sinusitis, tonsillitis, otitis media, and pharyngitis) 
Herpes zoster 
Angular cheilitis 
Recurrent oral ulceration 
Papular pruritic eruptions 
Seborrheic dermatitis 
Fungal nail infections
Clinical Stage 3
Unexplained severe weight loss (>10% of presumed or measured body weight)
Unexplained chronic diarrhea for >1 month 
Unexplained persistent fever for >1 month (>37.6ºC, intermittent or constant) 
Persistent oral candidiasis (thrush) 
Oral hairy leukoplakia 
Pulmonary tuberculosis (current) 
Severe presumed bacterial infections (e.g., pneumonia, empyema, pyomyositis, bone or joint 
infection, meningitis, bacteremia) 
Acute necrotizing ulcerative stomatitis, gingivitis, or periodontitis 
Unexplained anemia (hemoglobin <8 g/dL) 
Neutropenia (neutrophils <500 cells/µL) 
Chronic thrombocytopenia (platelets <50,000 cells/µL)
Clinical Stage 4
HIV wasting syndrome 
Pneumocystis pneumonia
Recurrent severe bacterial pneumonia 
Chronic herpes simplex infection (orolabial, genital, or anorectal site for >1 month or visceral 
herpes at any site) 
Esophageal candidiasis (or candidiasis of trachea, bronchi, or lungs) 
Extrapulmonary tuberculosis 
Kaposi sarcoma 
Cytomegalovirus infection (retinitis or infection of other organs) 
Central nervous system toxoplasmosis 
HIV encephalopathy 
Cryptococcosis, extrapulmonary (including meningitis) 
Disseminated nontuberculosis mycobacteria infection 
Progressive multifocal leukoencephalopathy 
Candida of the trachea, bronchi, or lungs 
Chronic cryptosporidiosis (with diarrhea) 
Chronic isosporiasis 
Disseminated mycosis (e.g., histoplasmosis, coccidioidomycosis, penicilliosis) 
Recurrent nontyphoidal Salmonella bacteremia 


TB Alliance 
Protocol Number: Pa-824-CL-012 
Protocol Version: V4.0 07 APR 2022 
Protocol Name:    BPaMZ/SEM 
 
CONFIDENTIAL 
Page 77 of 79 
Lymphoma (cerebral or B-cell non-Hodgkin)
Invasive cervical carcinoma
Atypical disseminated leishmaniasis 
Symptomatic HIV-associated nephropathy 
Symptomatic HIV-associated cardiomyopathy 
Reactivation of American trypanosomiasis (meningoencephalitis or myocarditis)
REF: World Health Organization. WHO Case Definitions of HIV for Surveillance and Revised Clinical Staging and Immunological 
Classification of HIV-Related Disease in Adults and Children; 2007
 
 


TB Alliance 
Protocol Number: Pa-824-CL-012 
Protocol Version: V4.0 07 APR 2022 
Protocol Name:    BPaMZ/SEM 
 
CONFIDENTIAL 
Page 78 of 79 
Appendix 4: Cardiovascular Safety
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” 
 
 
 
<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” 
- 
-
<110 mmHg 
mmHg-
<180 mmHg 
21-25 
Breaths per minute 
“Grade 3 or severe” 
- 
 
 
>25 
Breaths per minute 
“Abnormally high or Grade 
4” 
 
- 
- 
Intubation 
ECG 
All-important abnormalities from the ECG readings will be reported. 
The percentage of participants with increases in QTc of <30, 30-60, or > 60 ms from baseline will 
also be tabulated at each time point. 
Abnormality Code
ECG parameter 
HR 
PR 
QRS 
QT Corrected 
Abnormalities on actual values
“Abnormally low”
NAP 
-
“Abnormally high”
 
 
-
[“[450 ms, 480 ms]
-
- 
-
[“[480 ms, 500 ms]
-
- 
-
“More than 500 ms
-
- 
-
QTc > 500 ms 
Abnormalities on changes from baseline
“[30; 60] ms”
-
- 
-
[30; 60] ms 
“> 60 ms”
-
- 
-
> 60 ms 


TB Alliance 
Protocol Number: Pa-824-CL-012 
Protocol Version: V4.0 07 APR 2022 
Protocol Name:    BPaMZ/SEM 
 
CONFIDENTIAL 
Page 79 of 79 
Appendix 5: Paternity Questionnaire
Paternity Questionnaire 
Please answer the following questions:  
Did you father a child(ren) after your start of the trial?  
 
o If yes, how many? ______________ 
o What month and year was/were your child(ren) born?  
(Add more lines if necessary) 
 
Child 1:  MMM/YYYY 
 
Child 2:  MMM/YYYY  
 
Child 3:  MMM/YYYY  
Yes 
No 











SAP_001.pdf: 
$e99ea6d7fb39$444BA899E925427E9983C5C26E76F8E0.docx                                                                                                             
Page 1 of 12
Protocol Title
An Open-Label Phase 2 Trial to Evaluate the Male Reproductive Safety of a 6-month 
Combination Treatment for Pulmonary Tuberculosis of Bedaquiline plus Pretomanid plus 
Moxifloxacin plus Pyrazinamide (BPaMZ) in Adult Male Participants with Drug Resistant 
(DR-TB) Pulmonary Tuberculosis
Statistical Analysis Plan
Version 2.0 Dated 19 April 2023
Protocol number: Pa-824-CL-012
Author name:
Lindsay Thompson
Author position:
Statistician, UCL
Author signature and date:
Approval name:
Paul Bruinenberg
Approval position:
Study Physician, TB Alliance
Approval signature and date:


 
$e99ea6d7fb39$444BA899E925427E9983C5C26E76F8E0.docx                                                                                                              Page 
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Contents Page 
1. 
Introduction ......................................................................................................................................4 
2. 
Objectives .........................................................................................................................................4 
3. 
Sample Size .......................................................................................................................................4 
4. 
Primary Outcome .............................................................................................................................4 
5. 
Secondary male reproductive toxicity outcomes .............................................................................4 
6. 
Other secondary outcomes  .............................................................................................................5 
6.1. 
TB Efficacy Outcomes .............................................................................................................. 5 
6.2. 
Safety and tolerability outcomes ............................................................................................ 5 
7. 
Definitions and Data Handling Issues ...............................................................................................6 
7.1. 
Semen Samples ....................................................................................................................... 6 
7.2. 
Positive and Negative TB Status .............................................................................................. 6 
7.2.1. 
Positive culture ................................................................................................................ 6 
7.2.2. 
Isolated Positive Cultures ................................................................................................ 6 
7.2.3. 
Culture negative status ................................................................................................... 7 
7.2.4. 
Inability to produce sputum ............................................................................................ 7 
7.3. 
Adequate treatment ................................................................................................................ 7 
7.4. 
Major protocol deviations for analysis .................................................................................... 7 
7.5. 
Trial Timings ............................................................................................................................ 8 
7.6. 
General Statistical Considerations for Analysis ....................................................................... 8 
7.7. 
Newly notable abnormalities .................................................................................................. 9 
8. 
Analysis Populations and Definitions ...............................................................................................9 
8.1. 
Primary Semen Analysis populations ...................................................................................... 9 
8.1.1. 
The intent-to-treat (ITT) population ................................................................................ 9 
8.1.2. 
The per-protocol (PP) population .................................................................................... 9 
8.2. 
TB efficacy analysis populations .............................................................................................. 9 
8.2.1. 
The TB-specific modified intent-to-treat (TB-MITT) population ...................................10 
8.2.2. 
The TB-specific per-protocol (TB-PP) population ..........................................................10 
8.3. 
The Safety analysis population ..............................................................................................10 
8.4. 
Pharmacokinetics (PK) analysis population ...........................................................................10 
9. 
Statistical Analysis ......................................................................................................................... 10 
9.1. 
Primary semen outcome analysis ..........................................................................................11 
9.2. 
Secondary outcome analyses ................................................................................................11 
9.3. 
Pharmacokinetics (PK) analysis .............................................................................................11 
 
 
 


 
$e99ea6d7fb39$444BA899E925427E9983C5C26E76F8E0.docx                                                                                                              Page 
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Version History: 
 
Version Number/Date
Change
1.0 / 15 Feb 2021 
Initial version   
1.1 / 20 Dec 2022 
Updates made to outcome analysis and circulated for comment 
1.2 / 30 Jan 2023 
Updates made to Statistical analysis and circulated for further comments
1.3/ 06 Feb 2023 
Updates made to outcome sections to align more with the protocol
Additional analysis details added 
1.4/ 02 Mar 2023
Updates made post expert review
1.5/ 14 Mar 2023 
Further updates made after expert review 
1.6/ 17 April 2023 
Updates made to section on pharmacokinetics 
 
 
 


 
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1. Introduction 
This document outlines the statistical analysis for the BPaMZ/SEM trial, Protocol Version 4.0, dated 07 
April 2022. 
 
Pretomanid is being used in an antimicrobial combination regimen(s) to treat patients with pulmonary 
tuberculosis. The primary purpose of 
 is to evaluate the potential effect of 
pretomanid on human testicular function whilst being used in a 26-week antimicrobial combination 
regimen consisting of bedaquiline (B) plus pretomanid (Pa) plus moxifloxacin (M) and pyrazinamide (Z) 
(BPaMZ).  
 
All participants will receive the same regimen of BPaMZ once daily for 26 weeks.   
 
The participant population will be patients with drug resistant TB (DR-TB) defined as Mycobacterium 
tuberculosis (MTB) that is sensitive to fluoroquinolones but   
1. Mono-resistant to rifampicin or isoniazid, OR  
2. Resistant to both rifampicin and isoniazid (MDR-TB) 
 
2. Objectives 
The primary objective is to assess the male reproductive safety of pretomanid in the regimen (BPaMZ) 
of bedaquiline 200mg (200mg daily for 8 weeks then 100 mg daily for 18 weeks), together with 
pretomanid 200 mg (1x daily) + moxifloxacin 400 mg (1x daily) + pyrazinamide 1500 mg (1 x daily) for 
26 weeks in participants with Drug-resistant (DR) pulmonary TB. 
 
The secondary objective is to evaluate the efficacy, safety and tolerability after 26 weeks of active 
treatment for TB and follow up for 52 weeks after start of the above described treatment regimen in 
participants with Drug-resistant (DR) pulmonary TB. 
 
3. Sample Size 
A total of 20 evaluable male participants diagnosed with DR-TB who completed the trial will be 
required.  
Twenty-five participants (25) will be enrolled in the trial assuming a 20% participant dropout of the 
trial.  If the dropout rate is higher than 20% before finishing 26 weeks of treatment, the enrolment of 
additional participants may be considered to assure that 20 complete. 
The sample size is not based on formal statistical considerations.  It is based on practicality of 
enrolment and to rule out any severe effect of the regimen on sperm production. 
4. Primary Outcome 
The primary outcome (endpoint) will be change from baseline in total sperm count at 26 weeks of 
therapy. 
 
5. Secondary male reproductive toxicity outcomes  
 
1. Change from baseline in all semen parameters (semen count and semen concentration) at 13, 


 
$e99ea6d7fb39$444BA899E925427E9983C5C26E76F8E0.docx                                                                                                              Page 
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26 and 44 weeks. 
 
2. The proportion of subjects experiencing an increase or decrease in sperm count and sperm 
concentration from baseline to the timepoint of interest (26 weeks and 44 weeks) will be 
calculated. 
 
3. The proportion of subjects experiencing at least a 50 percent increase or decrease in sperm 
count and sperm concentration from baseline to the timepoint of interest (26 weeks and 44 
weeks) will be calculated. 
 
4. Change from baseline (at screening) in male reproductive hormones at Week 2, 4, 8, 12, 16, 
26, 35, 44, 52, 65, 78 and at early withdrawal.  Reproductive hormones: luteinizing hormone 
(LH), follicle-stimulating hormone (FSH), Inhibin B, testosterone, and total testosterone 
 
5. Plasma concentration of pretomanid from sparse sampling will be summarised as descriptive 
statistics.  
 
6. Other secondary outcomes  
 
6.1. 
TB Efficacy Outcomes 
 
1. Clinical outcome (incidence of bacteriologic failure or relapse or clinical failure) at 78 weeks 
(52 weeks after end of therapy). Participants will be classified as having a favourable, 
unfavourable or unassessable outcome status.  Patients achieving and maintaining culture 
negative status without any additional treatment will be considered favourable; participants 
who fail on treatment (or do not complete treatment for any reason) or relapse in follow-up 
will be considered unfavourable.  Patients completing treatment and clinically well when last 
seen but lost to follow-up before week 78 will be considered unassessable. 
 
2. Proportion of participants with sputum culture conversion to negative status in liquid culture 
(MGIT) at Week 4, 8, 12, 16, 22, 26, 35, 44, 52, 65 and 78. 
 
6.2. 
Safety and tolerability outcomes  
1. Change in weight from baseline 
2. The incidence of all-cause mortality will be summarised. 
3. 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). 
4. Treatment emergent adverse events (TEAEs) are adverse events (AEs) which started or 
worsened on or after the first administration of BPaMZ up to and including 14 days after the 
last study drug administration. In the case where it is not possible to define an AE as treatment-
emergent or not, the AE will be classified as treatment-emergent. 
a. The incidence of the following events will be summarised for further medical analysis: 
i. Incidence of TEAEs; 
ii. Incidence of TEAEs by Severity; 


 
$e99ea6d7fb39$444BA899E925427E9983C5C26E76F8E0.docx                                                                                                              Page 
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iii. Incidence of TEAEs by DMID toxicity grade; 
iv. Incidence of Drug-Related TEAEs; 
v. Incidence of Serious TEAEs; 
vi. Incidence of TEAEs Leading to Early Withdrawal; 
vii. Incidence of TEAEs leading to Death. 
5. Quantitative and qualitative clinical safety laboratory measurements (newly notable grade 3 
or 4 laboratory parameters according to DMID grading), including observed and change from 
baseline. 
6. Electrocardiogram (ECG) results (heart rate, RR interval, PR interval, QRS interval, QT interval 
and QTc interval, including observed QT/QTc intervals and change from baseline) will be 
categorised. 
7. Results of any paternity outcome during or after treatment with pretomanid at early 
withdrawal and week 78 follow-up will be tabulated. 
 
7. Definitions and Data Handling Issues 
7.1. 
Semen Samples 
The semen parameters (semen count and semen concentration) at baseline and during treatment will 
represent the mean of two semen samples collected a few days apart at each time point. 
In the case of one missing sample at a time point the only sample available will represent the value for 
that timepoint. 
Any sample that was retaken within 2 weeks of the planned sample, due to technical/practical issues, 
will be included. 
 
7.2. 
Positive and Negative TB Status 
7.2.1. Positive culture 
Positive culture refers to the culture being positive for Mycobacterium tuberculosis (MTB). The MGIT 
culture results that are positive with contamination will be considered positive. The MGIT culture 
results that are contaminated or with no result will be treated as missing. Two sputum samples per 
visit are collected at each visit throughout treatment and follow-up. The culture result for a given visit 
is established using all samples obtained for that visit. A positive culture takes precedence over a 
negative or contaminated culture at the same visit and a negative culture takes precedence over a 
contaminated culture at the same visit. 
 
7.2.2. Isolated Positive Cultures 
It 
is, a positive culture preceded by a series of negative cultures and followed thereafter by at least two 
negative cultures without an intervening positive result. This phenomenon may be the result of a 
sealed cavity breaking down or laboratory contamination and does not in itself signify that the 
participant is relapsing. In the event of a single positive culture result occurring in a participant who 
has previously been classified as having culture negative status (in the absence of any retreatment), 
the participant will not be classified as a recurrence unless a second positive culture result is obtained 
at a separate visit (at least 7 days apart), without an intervening negative culture or unless the 


 
$e99ea6d7fb39$444BA899E925427E9983C5C26E76F8E0.docx                                                                                                              Page 
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participant is lost to follow up or completes the study (and is unable to be brought back) before two 
negative cultures are obtained. As there is a higher incidence of isolated positives with liquid culture 
considered in deciding whether the participant has an unfavourable outcome and re-treatment is 
indicated.  
For example, if a participant after being culture negative has two positive cultures in a row, but is 
deemed to be doing well clinically, the investigator may choose to leave the participant untreated on 
clinical grounds. In such a case, so long as two consecutive negative cultures are eventually obtained 
in the absence of treatment, the participant will not be classified as an unfavourable outcome (defined 
in §6.1 above). 
 
7.2.3. Culture negative status 
Culture negative status is achieved when a participant produces at least two negative culture results 
at different visits (at least 7 days apart) without an intervening positive culture result for MTB. The 
date of the first negative culture (date of collection of culture) of these two is the date at which culture 
negative status was obtained. Once obtained, culture negative status continues until there are two 
positive cultures at different visits (at least 7 days apart), without an intervening negative culture, or 
until there is a single positive culture not followed by two negative cultures. Culture negative status 
can be achieved at any time during treatment or follow-up but before any re-treatment. Culture 
negative status can be re-established.  
 
Participants with two contaminated or missing samples at a given visit (from month 2 onwards) will be 
asked to return to produce two more sputum samples. 
 
7.2.4. Inability to produce sputum 
In general, inability to produce sputum is treated as being equivalent to having a negative culture result 
if no other sputum sample is produced at that visit. This includes the rare situation where a participant 
who never achieves culture negative status due to the inability to produce sputum, after TB has been 
confirmed on the applicable baseline sample, completes follow-up without clinical or microbiological 
evidence of relapse. Such participants will be considered to have a favourable outcome and an inability 
to produce sputum with no other sputum produced at that visit will be treated as a negative culture 
result. 
 
7.3. 
Adequate treatment 
The definition of adequate treatment sets a limit for the amount of treatment missed. Participants not 
taking the adequate amount of treatment by this definition will be excluded from the per protocol 
analyses (PP and TB-PP). 
 
To meet the definition of adequate treatment participants must have taken at least 146 doses (80%) 
of their allocated 182 day (26 weeks) treatment regimen within 238 days of starting therapy (i.e. 26 
weeks plus an allowable 56 day halt (including a maximum of 35 consecutive days) as per the protocol). 
 
7.4. 
Major protocol deviations for analysis 
A major protocol deviation for analysis is a protocol deviation likely to affect to a significant degree 
the scientific value of the trial and is CSR reportable. These include: 
 
participants who did not satisfy entry criteria but were entered anyway 
 
participants who developed withdrawal criteria during the study but were not withdrawn 


 
$e99ea6d7fb39$444BA899E925427E9983C5C26E76F8E0.docx                                                                                                              Page 
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participants who received the wrong treatment or incorrect dose 
 
 These participants will be excluded from the PP and TB-PP analyses. A list of all major protocol 
deviations for analysis will be approved by a review committee prior to database lock.  
 
Note: participants attending a long-term outcome visit outside the specified window will be 
evaluated and considered for potential major protocol violator. Visits within 2 weeks of the window 
opening will be considered minor protocol violators. 
 
7.5. 
Trial Timings 
Date of enrolment is Study Day 1 which is defined as the date on which a participant is administered 
the first dose of study medication. Other study days are defined relative to the Study Day 1 with Day 2 
being the day after Study Day 1 and Day -1 being the day prior to Study Day 1. 
 
For all safety endpoints, baseline is defined as the last non-missing measurement prior to first dose of 
study treatment unless otherwise stated.  
 
In all analyses, visit date rather than day or week number will be used to define the timing of events.  
 
Assessments should be collected as follows:  
 
Within ± 3 days of scheduled visit from Day 1 to Week 8 
 
Within ± 7 days of scheduled visit from Week 12 to Week 26 
 
Within ± 14 days of scheduled visit during the follow-up phase at or after Week 26 to Week 
78  
 
Unscheduled visits will be slotted into windows as appropriate. Scheduled visits falling outside of the 
defined protocol visit windows will be put into separate visits so that all data, both collected at 
scheduled and unscheduled time points, are used. 
  
The treatment period is defined as a total of 26 weeks from start of therapy. 
 
The follow-up period is defined as the period after the end of treatment to the end of follow-up. 
 
 
7.6. 
General Statistical Considerations for Analysis 
 
There are three planned analyses that will be performed. The first analysis will be done after all 
participants have completed the 26 weeks of treatment. The analysis will be on primary outcome data 
(semen data), secondary reproductive data, culture conversion data up to week 26 and safety data. 
The second analysis will be done at week 44 and will also be on the semen data available at 44 weeks, 
secondary reproductive data, culture conversion data to week 44 and safety data. The final analysis 
will take place after 78 weeks and will include analyses on all data including the TB efficacy analysis as 
outlined in §6.1.  
 
There will be no specific strategy to deal with missing data i.e. it will not be imputed. A complete case 
analysis will be performed.  
 
For the safety analysis, if there are multiple assessments in a visit, the highest grade non-missing 
value within a visit will be used in the summaries, however all will be shown in the listings. If numeric 


 
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value will be used for summary statistics.  
 
Baseline is defined as last available measurement prior to dosing and post baseline abnormalities are 
included in the summary if the subject did not meet the abnormality criteria at baseline or toxicity 
grade at post baseline is higher than that on baseline. 
 
 
 
7.7. 
Newly notable abnormalities 
A newly notable laboratory abnormality is defined as an abnormality observed post baseline that 
meets the notable criteria shown in Table 1 below and that did not exist at baseline. Participants can 
still meet the criteria for newly notable laboratory event if the baseline value is missing. 
 
Table 1: Notable Criteria for Laboratory Data 
Lab Test Type 
Laboratory Variable 
SI Units 
Liver
AST
 
> 8 x ULN 
ALT
ULN 
> 8 x ULN 
Total Bilirubin
> 2 x ULN
Alkaline Phosphatase (ALP)
> 2 x ULN
Chemistry Labs 
Other: 
ALT or AST > 3 x ULN and total bilirubin > 2 x ULN 
ALT or AST > 3 x ULN and total bilirubin > 2 x ULN and ALP <2 x 
 
Lipase
> 5 x ULN 
 
 
 
8. Analysis Populations and Definitions 
8.1. 
Primary Semen Analysis populations  
 
8.1.1. The intent-to-treat (ITT) population 
The primary and secondary semen analyses will be conducted on the ITT population, defined as all 
participants who  at took at least one dose of the study medication. All data available will be considered 
for each time-point.  
8.1.2. The per-protocol (PP) population 
The primary and secondary semen analyses will also be conducted on the PP population, defined as all 
participants who were enrolled and started treatment, excluding: 
1. Participants not meeting the definition of having received an adequate amount of 
treatment. 


 
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2. Participants classified as major protocol deviations for analysis (see §7.4). 
 
8.2. 
TB efficacy analysis populations 
 
The TB efficacy outcomes will be reported by ITT (§8.1.1) and the following populations: 
 
8.2.1. The TB-specific modified intent-to-treat (TB-MITT) population 
Defined as all participants who were enrolled and started treatment, excluding those listed below: 
1. Any late exclusions 
a. Participants enrolled and later found to be ineligible because of a protocol 
violation at enrolment (based on data collected prior to enrolment). 
b. Participants without culture confirmation of TB at Day 1 (baseline) (or screening 
to week 4 if baseline is contaminated or negative) 
2. Any participants who completed treatment and were later lost to follow-up or withdrawn 
from the study. 
3. Participants who died during treatment from violent or accidental cause. 
4. Participants who died during follow-up with no evidence of failure or relapse of TB. 
5. Participants who are able to produce sputum at the endpoint visit, but whose endpoint 
visit sputum samples are all contaminated or missing, who cannot be brought back for 
repeat cultures, provided their last positive culture was followed by at least two negative 
cultures. N.B.: This does not apply to participants who are unable to produce sputum at 
the given endpoint, or to participants who are able to be brought back subsequently and 
produce negative cultures. 
 
Participants already classified as having an unfavourable outcome will not be excluded. 
 
8.2.2. The TB-specific per-protocol (TB-PP) population 
In addition to those excluded from the TB-MITT population (§8.2.1), the following participants will be 
excluded:  
1. Participants lost-to follow-up or withdrawn for reasons other than treatment failure 
before the end of treatment. 
2. Participants whose treatment was modified or extended beyond what was permitted. 
3. Participants not meeting the definition of having received an adequate amount of 
treatment. 
4. Participants who classified as major protocol deviations for analysis (see §7.4).    
 
Participants already classified as having an unfavourable outcome will not be excluded. 
 
8.3. 
The Safety analysis population 
The safety and tolerability outcomes will be conducted on the safety population, which in this trial is 
the same as the ITT population; defined as all participants enrolled who received at least 1 dose of trial 
treatment. 
 
8.4. 
Pharmacokinetics (PK) analysis population 
Defined as all participants who were enrolled and started treatment, excluding participants who do 
not have at least one valid PK measurement. 
 


 
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9. Statistical Analysis 
All statistical analysis will be based on descriptive statistics for the whole population and by key 
subgroups.  
 
All statistical analyses tables, listings and figures will be produced using STATA Version 17.0 or higher. 
 
9.1. 
Primary semen outcome analysis 
The change from baseline in total sperm count at 26 weeks will be summarised by mean, standard 
deviation, median, IQR and range. Both the baseline value and change from baseline will be 
summarised. 
 
9.2. 
Secondary outcome analyses 
The following applies to outcomes outlined in sections 5 and 6. Continuous outcomes will be 
summarised by mean, standard deviation, median, interquartile range and range.  For change from 
baseline, both baseline value and change from baseline will be summarised.    
 
tages. Shift tables will be 
provided to summarise the status changes from baseline to week 13, week 26 and week 44. Each shift 
table will include shift analyses from within the reference range at baseline to above the reference 
range at 13, 26 or 44 weeks and from within the reference range at baseline to below the reference 
range at the same time points. 
 
9.3. 
Pharmacokinetics (PK) analysis  
The following analyses will be carried out on the PK population as outlined in §8.4: 
1. For each analyte and each scheduled sampling time/window (week 2, 4, 8, 12, 16, 22, 26, 44 
and early withdrawal), the plasma concentration will summarised using the mean, SD, 
coefficient of variation (CV), median, minimum, maximum, geometric mean and geometric CV 
(%).  
2. The plasma concentration will be summarised by those who had a 50% increase or 50% 
decrease in total sperm count and overall.  
3. Mean and/or median plasma concentration vs. time graphs will be provided, with error bars 
and/or scatter plots as appropriate. 
4. Mean of the observed Pretomanid troughs from week 2 through to week 26 will be plotted 
against the percentage change from baseline in total sperm count at week 26. 
 
 


 
$e99ea6d7fb39$444BA899E925427E9983C5C26E76F8E0.docx                                                                                                              Page 
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