Clinical trial NCT04176250
Conditions: Pulmonary Tuberculosis
Keywords: Rifampicin-sensitive pulmonary tuberculosis TBA-7371 Pulmonary tuberculosis
Sponsor: Gates Medical Research Institute
Start date: 2020-01-16; Completion date: 2022-10-05
Enrollment: 93 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
The purpose of this study is to assess the safety, early bactericidal activity (EBA) and pharmacokinetics of TBA-7371 in adult participants with rifampicin-sensitive tuberculosis and select dose regimen(s) for future studies.

Detailed description:

Arms: arm 1: None arm 2: None arm 3: None arm 4: None arm 5: None arm 6: None
Interventions: intervention 1: TBA-7371 intervention 2: TBA-7371 intervention 3: TBA-7371 intervention 4: TBA-7371 intervention 5: TBA-7371 intervention 6: HRZE
Intervention descriptions: intervention 1: Participants will receive TBA-7371 oral suspension 100 milligram (mg) once daily (QD) for 14 days. intervention 2: Participants will receive TBA-7371 oral suspension 100 mg twice daily (BID) for 14 days. intervention 3: Participants will receive TBA-7371 oral suspension 200 mg QD for 14 days. intervention 4: Participants will receive TBA-7371 oral suspension 100 mg three times daily (TID) for 14 days. intervention 5: Participants will receive TBA-7371 oral suspension 400 mg QD for 14 days. intervention 6: Participants will receive Isoniazid \[H\] / rifampicin \[R\] / pyrazinamide \[Z\] / ethambutol \[E\] (HRZE), a fixed dose combination tablet QD for 14 days, based on weight as 40-54 kilograms (kg): 3 tablets; 55-70 kg: 4 tablets and 71 kg and over: 5 tablets.

Protocol documents:
Prot_000.pdf: 
CONFIDENTIAL 
Protocol Gates MRI-TBD03-201 
Version 4, 07 Jul 2020 
Gates Medical Research Institute 
1 
Title Page 
Protocol Title: A phase 2a, dose escalation, controlled, randomized study to evaluate safety, 
early bactericidal activity (EBA) and pharmacokinetics of TBA-7371 in adult patients with 
rifampicin-sensitive pulmonary tuberculosis 
Protocol Number: Gates MRI-TBD03-201 
Original Protocol (Version 1): 03 Apr 2019 
Amendment 1 (Version 2): 17 Apr 2019 
Amendment 2 (Version 3): 25 Sep 2019 
Amendment 3 (Version 4): 07 Jul 2020 
Compound Name: TBA-7371 
Study Phase: 2a 
Short Title: Early bactericidal activity of TBA-7371 in pulmonary tuberculosis 
Sponsor Name: Bill & Melinda Gates Medical Research Institute 
Legal Registered Address: One Kendall Square, Building 600, Suite 6-301, Cambridge, MA 
02139 
Regulatory Agency Identifier Number(s): N/A 
NOTE 
This study was paused for screening and randomization by the sponsor, effective 19 March 2020, 
due to the Coronavirus Disease 2019 (COVID-19) pandemic and the Government of South 
Africa declaring a National Disaster on 15 March 2020.  Shortly thereafter a first lockdown 
(stay-at-home order) was enacted on 26 March 2020. On 13 May 2020, TB and HIV-related 
research was deemed essential by government directive. As a result, this amendment was 
implemented to enhance safety measures to include screening and monitoring for SARS-CoV-2 
infection to mitigate risks of transmission among patients and staff moving forward. Additional 
guidance is provided in Sections 1 and 8 of this document. 
 
 
 
 
NCT Number: NCT04176250  
 
 
This NCT number has been applied to the document for
 
 
 
purposes of posting on Clinicaltrials.gov


CONFIDENTIAL 
Protocol Gates MRI-TBD03-201  
Version 4, 07 Jul 2020 
 
 
Gates Medical Research Institute 
2 
Sponsor Signatory 
 
See appended electronic signature page 
 
 
 
 MD  
Clinical Development Leader 
Bill & Melinda Gates Medical Research Institute 
 
 
 
 
Date 
 


CONFIDENTIAL 
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Table of Contents 
Title Page ........................................................................................................................................1 
Table of Contents ...........................................................................................................................3 
1. 
Protocol Summary ........................................................................................................10 
1.1. 
Synopsis .....................................................................................................................10 
1.1.1. 
Protocol Title .........................................................................................................10 
1.1.2. 
Short Title ..............................................................................................................10 
1.1.3. 
Overall Goals ........................................................................................................10 
1.1.4. 
Objectives and Endpoints ......................................................................................10 
1.1.4.1. 
Primary Objectives and Endpoints ...............................................................10 
1.1.4.2. 
Secondary Objectives and Endpoints ...........................................................11 
1.1.4.3. 
Exploratory Objectives .................................................................................13 
1.1.5. 
Design ...................................................................................................................13 
1.1.6. 
Study Population and Number of Participants ......................................................14 
1.1.7. 
Intervention Groups ..............................................................................................14 
1.1.8. 
Timing ...................................................................................................................15 
1.1.9. 
Statistical Methods ................................................................................................15 
1.1.9.1. 
Bactericidal activity ......................................................................................15 
1.1.9.2. 
Safety ............................................................................................................17 
1.1.9.3. 
Power and Sample Size Considerations........................................................17 
1.2. 
Schema .......................................................................................................................17 
1.3. 
Schedule of Activities (SoA) .....................................................................................18 
2. 
Introduction ...................................................................................................................24 
2.1. 
Study Rationale ..........................................................................................................24 
2.2. 
Background ................................................................................................................25 
2.2.1. 
Tuberculosis ..........................................................................................................25 
2.2.2. 
Early Bactericidal Activity Clinical Studies .........................................................25 
2.3. 
Benefit/Risk Assessment ...........................................................................................25 
3. 
Objectives and Endpoints ............................................................................................27 
3.1. 
Primary Objectives and Endpoints .............................................................................27 
3.2. 
Secondary Objectives and Endpoints .........................................................................27 
3.3. 
Exploratory Objectives ..............................................................................................29 
4. 
Study Design ..................................................................................................................30 
4.1. 
Overall Study Design .................................................................................................30 
4.2. 
Scientific Rationale for Study Design ........................................................................31 
4.3. 
Justification for Dose .................................................................................................32 
4.4. 
End of Study Definition .............................................................................................33 
5. 
Study Population ...........................................................................................................34 
5.1. 
Inclusion Criteria .......................................................................................................34 
5.2. 
Exclusion Criteria ......................................................................................................35 
5.3. 
Lifestyle Considerations ............................................................................................37 
5.4. 
Screen Failures ...........................................................................................................37 
6. 
Study Interventions.......................................................................................................38 


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6.1. 
Study Interventions Administered .............................................................................38 
6.1.1. 
Composition ..........................................................................................................38 
6.1.1.1 
TBA-7371 Oral Suspension ..........................................................................38 
6.1.1.2 
HRZE Tablets ...............................................................................................38 
6.1.2. 
Intervention Cohorts ..............................................................................................39 
6.1.3. 
Administration .......................................................................................................39 
6.2. 
Preparation/Handling/Storage/Accountability ...........................................................40 
6.2.1. 
Preparation ............................................................................................................40 
6.2.2. 
Handling ................................................................................................................40 
6.2.3. 
Storage ...................................................................................................................40 
6.2.4. 
Accountability .......................................................................................................40 
6.3. 
Measures to Minimize Bias: Randomization and Masking .......................................41 
6.3.1. 
Randomization ......................................................................................................41 
6.3.2. 
Masking (Blinding) ...............................................................................................41 
6.3.3. 
Masking Break ......................................................................................................41 
6.4. 
Study Intervention Compliance .................................................................................41 
6.5. 
Concomitant Therapy .................................................................................................42 
6.6. 
Dose Modification .....................................................................................................42 
6.7. 
Intervention after the End of the Study ......................................................................42 
7. 
Discontinuation of Study Drug and Participant 
Discontinuation/ Withdrawal.......................................................................................43 
7.1. 
Pausing and Resumption of Study Drug and Recruitment ........................................43 
7.2. 
Participant Discontinuation/Withdrawal from the Study ...........................................43 
7.3. 
Lost to Follow-up .......................................................................................................44 
8. 
Study Assessments and Procedures.............................................................................45 
8.1. 
Screening Assessments and Procedures .....................................................................45 
8.1.1. 
Demography and Medical and Treatment History ................................................46 
8.1.2. 
Chest X-Rays ........................................................................................................46 
8.1.3. 
COVID-19/SARS-CoV-2 .....................................................................................46 
8.1.4. 
HIV Test and CD4 Count ......................................................................................46 
8.1.5. 
Urine Isoniazid Screening .....................................................................................46 
8.1.6. 
Urine Drug Screening ...........................................................................................47 
8.1.7. 
Overnight Sputum for Eligibility Assessment ......................................................47 
8.1.7.1. 
Overnight Sputum Volume ...........................................................................47 
8.1.7.2. 
Acid-fast bacilli detection .............................................................................47 
8.1.7.3. 
Molecular tests for Mtb positivity and rifampicin 
sensitivity ......................................................................................................47 
8.2. 
Bactericidal Activity Assessment ..............................................................................48 
8.2.1. 
Overnight Sputum for EBA assessment and Exploratory 
Measurements .......................................................................................................48 
8.2.2 
Samples for exploratory endpoints ........................................................................48 
8.3. 
Safety Assessments ....................................................................................................49 
8.3.1. 
Physical Examination ............................................................................................49 
8.3.2. 
COVID-19/SARS-CoV-2 .....................................................................................49 
8.3.3. 
Pregnancy Status Assessment ...............................................................................49 


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8.3.4. 
Clinical Safety Laboratory Assessments ...............................................................50 
8.3.5. 
Vital signs and body weight ..................................................................................51 
8.3.6. 
ECG .......................................................................................................................52 
8.3.7. 
Eye Assessment .....................................................................................................53 
8.3.8. 
Early Withdrawal Visit .........................................................................................54 
8.3.9. 
Unscheduled Visit .................................................................................................55 
8.3.10. 
Participant Follow-Up ...........................................................................................55 
8.4. 
Adverse Events and Serious Adverse Events ............................................................55 
8.4.1. 
Time Period for Collecting AE Information .........................................................55 
8.4.2. 
Methods of Detection of AE and SAE ..................................................................55 
8.4.2.1. 
Recording of AE and SAE ............................................................................56 
8.4.2.2. 
Assessment of Causality of AE and SAE .....................................................56 
8.4.2.3. 
Assessment of AE/SAE Expectedness .........................................................56 
8.4.2.4. 
Assessment of SAE Outcome .......................................................................57 
8.4.3. 
Reporting Requirements for SAE, Serious ADR, AESI and 
Other Events ..........................................................................................................57 
8.4.4. 
Death Events .........................................................................................................57 
8.5. 
Concomitant Treatments ............................................................................................57 
8.6. 
Treatment of Overdose...............................................................................................58 
8.7. 
Pharmacokinetics .......................................................................................................58 
8.8. 
Pharmacodynamics ....................................................................................................58 
8.9. 
Transcriptomics, Genetics and Epigenetics ...............................................................58 
8.10. 
Biomarkers and Other Exploratory Measurements ....................................................58 
8.11. 
Health Economics ......................................................................................................59 
9. 
Statistical Considerations .............................................................................................60 
9.1. 
Statistical Hypotheses ................................................................................................60 
9.2. 
Sample Size Determination ........................................................................................60 
9.3. 
Populations for Analyses ...........................................................................................60 
9.4. 
Statistical Analyses ....................................................................................................61 
9.4.1. 
Bactericidal Activity Analyses ..............................................................................65 
9.4.1.1. 
Primary Bactericidal Activity Analyses .......................................................65 
9.4.1.2. 
Secondary Bactericidal Activity Analyses ...................................................66 
9.4.2. 
Safety Analyses .....................................................................................................66 
9.4.2.1. 
Primary Safety Analyses ...............................................................................66 
9.4.2.2. 
Secondary Safety Analyses ...........................................................................67 
9.5. 
PK Analyses ...............................................................................................................67 
9.6. 
Demographic and Compliance Analyses ...................................................................68 
9.7. 
Interim Analyses ........................................................................................................68 
9.7.1. 
Independent Data Monitoring Committee (IDMC) ..............................................68 
10. 
Supporting Documentation and Operational Considerations ..................................69 
10.1. 
Appendix 1. Regulatory, Ethical, and Study Oversight 
Considerations ............................................................................................................69 
10.1.1. 
Regulatory and Ethical Considerations .................................................................69 
10.1.2. 
Study Oversight .....................................................................................................69 
10.1.3. 
Financial Disclosure ..............................................................................................70 


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10.1.4. 
Informed Consent Process .....................................................................................70 
10.1.5. 
Informed Consent Forms .......................................................................................70 
10.1.6. 
Data Protection ......................................................................................................71 
10.1.7. 
Dissemination of Clinical Study Data ...................................................................71 
10.1.8. 
Data Quality Assurance .........................................................................................72 
10.1.9. 
Source Documents ................................................................................................73 
10.1.10. Study and Site Closure ..........................................................................................73 
10.1.11. Publication Policy .................................................................................................73 
10.2. 
Appendix 2. Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting ....................................................74 
10.2.1. 
Definition of AE ....................................................................................................74 
10.2.2. 
Definition of ADR .................................................................................................75 
10.2.3. 
Definition of SAE .................................................................................................76 
10.2.4. 
Definition of Serious Adverse Drug Reaction (Serious 
ADR) .....................................................................................................................76 
10.2.5. 
Definition of AESI ................................................................................................77 
10.2.6. 
Recording and Follow-up of AEs and SAEs .........................................................78 
10.2.6.1. 
AE and SAE Recording ................................................................................78 
10.2.6.2. 
Follow-up of AEs and SAEs and Resolution................................................79 
10.2.6.3. 
Assessment of AE/SAE Intensity .................................................................80 
10.2.6.4. 
Assessment of AE/SAE Causality (Relatedness) .........................................80 
10.2.6.5. 
Assessment of AE/SAE Expectedness .........................................................81 
10.2.6.6. 
 Assessment of SAE Outcome ......................................................................81 
10.2.7. 
Reporting of SAE, Serious ADR, AESI and Other Events ...................................81 
10.2.7.1. 
Reporting to Sponsor Delegate’s (CRO Safety Team) 
Via the Electronic Data Collection Tool.......................................................81 
10.2.7.2. 
SAE  Reporting via paper CRF.....................................................................82 
10.2.7.3. 
Other Events Requiring Immediate Reporting .............................................83 
10.2.7.4. 
SAE and Serious ADR Reporting Schemes .................................................84 
10.3. 
Appendix 3. Contraceptive Guidance and Collection of 
Pregnancy Information ...............................................................................................85 
10.4. 
Appendix 4. Division of AIDS (DAIDS) Table for Grading 
Intensity (Severity) of Adverse Events ......................................................................87 
10.5. 
Appendix 5. Eye Symptom Assessment Forms .......................................................121 
10.5.1. 
Study TBA7371-002, Eye Symptom Assessment Form, 
Screening Phase ..................................................................................................121 
10.5.2. 
Study TBA7371-002, Eye Symptoms Assessment .............................................125 
10.6. 
Appendix 6. List of Prohibited Medications ............................................................129 
10.7. 
Appendix 7. Document History ...............................................................................131 
11. 
References ....................................................................................................................147 
 
 


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List of Tables 
Table 1. 
Primary Objectives and Endpoints (Synopsis Overview) ......................................... 10 
Table 2. 
Secondary Objectives and Endpoints (Synopsis Overview) ..................................... 11 
Table 3. 
Scheduled Visits and Activities ................................................................................ 18 
Table 4. 
Timing of Measurements on Days 1, 3, 4, 7, 10, and 14 of Study Treatment Phase 
(STP) ......................................................................................................................... 22 
Table 5. 
Primary Objectives and Endpoints ............................................................................ 27 
Table 6. 
Secondary Objectives and Endpoints ........................................................................ 27 
Table 7. 
Composition of the TBA-7371 Oral Suspension, 25 mg/mL ................................... 38 
Table 8 
Populations for Analyses .......................................................................................... 61 
Table 9. 
Summary of Primary and Secondary Endpoints and Analyses ................................ 62 
 
List of Figures 
Figure 1. 
Schema ...................................................................................................................... 17 
 
 
 


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List of Abbreviations 
ADR 
Adverse Drug Reaction(s)  
AE 
Adverse Event(s) 
AESI 
Adverse Event(s) of Special Interest 
AIDS 
Acquired Immune Deficiency Syndrome 
ALP 
Alkaline Phosphatase 
ALT 
ALanine aminoTransferase   
AST 
ASpartate aminoTransferase 
AP 
Antero-Posterior 
AUCinf  
AUC from 0 to Infinity 
AUClast  
AUC from 0 to Last Quantifiable Concentration   
AUCtau 
AUC from time 0 to Tau (tau represents the dosing interval of 24 hours) 
BACFU 
Slope of the log CFU counts 
BALAM 
Slope of the log LAM measurements (pg/mL) 
BATTP 
Slope of Time to (sputum culture) Positivity (days) in Mycobacteria Growth 
Indicator Tube system 
βHCG  
beta Human Chorionic Gonadotropin 
BID 
Bis in Die (latin for twice a day) 
bpm 
beats per minute 
BT 
Body Temperature 
BUN 
Blood Urea Nitrogen 
CFR 
Code of Federal Regulations 
CFU 
Colony Forming Units 
Clast 
Last Quantifiable Concentration   
Cmax 
Maximum Observed Plasma Concentration 
Cmin 
Minimum Observed Plasma Concentration 
CONSORT 
CONsolidated Standards of Reporting Trials 
COVID-19 
COronaVIrus Disease caused by SARS-CoV-2 infection-19 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CSR 
Clinical Study Report 
DBP 
Diastolic Blood Pressure 
DDI 
Drug Interaction 
DNA 
DeoxyriboNucleic Acid 
DprE1 
Deca-prenylphosphoryl-β-D-ribose 2′-epimerase 1 
EBA 
Early Bactericidal Activity 
EC90 
Expected Concentration Associated with 90% of the Maximal Effect 
EDC 
Electronic Data Collection 
EWV 
Early Withdrawal Visit 
FOCBP 
Female Of Childbearing Potential 
Gates MRI 
Bill & Melinda Gates Medical Research Institute 
GCP  
Good Clinical Practices 
h 
Hour 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human Immunodeficiency Virus 
HR 
Heart Rate 
HRZE 
Isoniazid (H), Rifampicin (R), Pyrazinamide (Z), Ethambutol (E) 
ICH 
International Council for Harmonization of technical requirements for 
pharmaceuticals for human use 
IDMC 
Independent Data Monitoring Committee 


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List of Abbreviations 
IEC 
Independent Ethics Committee 
IMP 
Investigational Medicinal Product 
IRB 
Institutional Review Board 
IUATLD 
International Union Against Tuberculosis and Lung Disease 
IUD 
Intrauterine Device 
IVRS 
Interactive Voice Response System  
IWRS 
Interactive Web Response System  
LAM 
LipoArabinoMannan 
LTBI 
Latent TB Infection 
MAD 
Multiple Ascending Dose 
MBC 
Minimum Bactericidal Concentration 
mg 
Milligrams 
MGIT 
Mycobacteria Growth Indicator Tube 
MIC 
Minimum Inhibitory Concentration 
min 
Minute 
mITT 
modified Intention to Treat 
mL 
milliLiter 
Mtb 
Mycobacterium tuberculosis 
PA 
Posterior-Anterior 
PCR 
Polymerase Chain Reaction 
PD 
PharmacoDynamics 
PE 
Physical Examination 
PI 
Principal Investigator 
PK 
PharmacoKinetics 
PP 
Per Protocol 
QD 
Quaque Die (latin for once a day) 
RR 
Respiratory Rate 
SAD 
Single Ascending Dose 
SAE 
Serious Adverse Event(s) 
SAHPRA 
South African Health Products Regulatory Authority 
SAP 
Statistical Analysis Plan 
SARS-CoV-2 
Severe Acute Respiratory Syndrome COronaVirus 2 
SBP 
Systolic Blood Pressure 
SoA 
Schedule of Activities 
SSAP 
Scientific Statistical Analysis Plan 
STP 
Study Treatment Phase 
TB 
TuBerculosis 
TEAE 
Treatment-Emergent Adverse Event 
TID 
Ter in Die (latin for three times a day) 
Tlast 
Time at Last Quantifiable Concentration   
Tmax 
Time at Maximum Plasma Concentration 
TTP 
Time To (sputum culture) Positivity 
ULN  
Upper Limit of Normal 
WBC 
White Blood Cells 
WHO 
World Health Organization 
XDR-TB 
eXtensively Drug Resistant TuBerculosis 


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Protocol Gates MRI-TBD03-201 
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1. 
Protocol Summary 
1.1. 
Synopsis 
1.1.1. 
Protocol Title 
A phase 2a, dose escalation, controlled, randomized study to evaluate safety, early bactericidal 
activity (EBA) and phannacokinetics (PK) of TBA-7371 in adult patients with rifampicin-
sensitive puhnomuy tuberculosis (TB). 
1.1.2. 
Short Title 
Early bactericidal activity of TBA-7371 in pulmonaiy tuberculosis. 
1.1.3. 
Overall Goals 
Assess the safety, EBA and PK ofTBA-7371 in adult patients with rifampicin-sensitive TB and 
select dose regimen(s) for future studies. 
1.1.4. 
Objectives and Endpoints 
All objectives will be assessed in adult patients with rifampicin-sensitive puhnonaiy TB (see 
inclusion/exclusion criteria, Sections 5.1 and 5.2). 
1.1.4.1. 
Primary Objectives and Endpoints 
Table 1. 
Primary Objectives and Endpoints (Synopsis Overview) 
Objectives 
Endpoints 
Bactericidal activity 
Demonstrate the 14-day EBA from screening ("O") 
• Slope, i.e. average change per day, from 
to Day 14 (EBA 0-14) of 5 dose regimens of TBA-
screening ("O") to Day 14 [BACFU(0-14)] of 
7371 monotherapy, and of isoniazid (H), rifampicin 
the log CFU counts. 
(R), pyrazinamide (Z), ethambutol (E) (HRZE) as 
assessed by colony fonning unit (CFU) counts on 
solid media culture. 
Safety 
Assess the severe/serious adverse event (SAE) 
• Frequency of study participants who 
burden of 5 dose regimens ofTBA-7371 
expeiienced one or more severe (2:: grade 3) 
monotherapy and HRZE over a 14-day treatment 
and/or SAEs from Day I through Day 15. 
pe1iod. 
Gates Medical Research Institute 


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1.1.4.2. 
Secondary Objectives and Endpoints 
Table 2. 
Secondary Objectives and Endpoints (Synopsis Overview) 
Objectives 
Bactericidal activity 
Demonstrate the EBA of the first 2 days 
(screening ["0"] to Day 2) and of the remaining 
12 days (Day 2 to Day 14) of 5 dose regimens 
ofTBA-7371 monotherapy and HRZE, as 
assessed bv CFU counts on solid media culture. 
Demonstrate the bactericidal activity of 5 dose 
regimens ofTBA-7371 monotherapy and of 
HRZE, as assessed by alternative methods: 
• 
time to sputum culture positivity (TTP) in 
Mycobacte1ia Growth Indicator Tube 
(MGIT) culture 
• 
sputum lipoarabinomannan (LAM) assay 
Safety 
Assess the AE profile of each dose regimen of 
TBA-7371 and HRZE over the 14-day 
treatment pe1iod. 
Endpoints 
• 
Slope, i.e. average change per day, from 
screening ("0") to Day 2 [BACFU (0-2)] and from 
Day 2 to Day 14 [BACFU (2-14)] of the log CFU 
counts. 
• 
Slope of the time to sputum culture positivity 
(TPP) in the MGIT system from screening ("0") 
to Day 14 [BAITP (0-14)], from screening to Day 
2 [BAITP (0-2)], and from Day 2 to Day 14 
[BATIP (2-14)]. 
• 
Slope of the log concentration of sputum LAM 
from screening ("0") to Day 14 [BALAM (0-14)], 
from screening to Day 2 [BALAM (0-2)], and from 
Day 2 to Day 14 [BALAM (2-14)]. 
• 
Frequency from Day 1 through Day 15 of 
participants with AE and frequency of AEs: 
overall, by body system, and pref ened te1m; by 
se1iousness, intensity (severity), expectedness 
and relatedness to study diug. 
Assess the impact on eye symptoms, visual 
From Day 1 through Day 15: 
acuity and color vision of each dose regimen of • 
Frequency of pa1ticipants with any new (vs. 
TBA-7371 and HRZE over the 14-day 
screening) eye symptom in one or both eyes. 
treatment pe1iod. 
• 
Mean and frequency distribution of duration of 
Assess the impact on herut rate, blood pressure 
and ECG profile of each dose regimen of TBA-
7371 and ofHRZE over the 14-day treatment 
period. 
Gates Medical Research Institute 
each eye symptom. 
• 
Mean and frequency distribution of percentage of 
Days with any eye symptom and each of the eye 
symptoms. 
• 
Mean/median change in visual acuity score from 
screening to lowest score dwing Days 1-15. 
• 
Frequency of pa1ticipants with any new color 
vision abno1malities (tritan, protan, deutan) in 
one or both eyes and degree of severity (Inild, 
moderate, and severe) 
From Day 1 through Day 15: 
• 
Mean and frequency distribution of changes in 
herut rate (HR), systolic blood pressure (SBP) 
and diastolic blood pressure (DBP) as measured 
by the following 2 (BP) or 3 (HR) methods: 
11 
• 
manual (vital signs), after at least 10 
Ininutes in supine position ("manual, 
supine"); 


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Objectives 
Endpoints 
• manual, after 2 (±0.5) minutes in standing 
position ("manual, 2-min standing"); 
• HR from ECG, supine position ("ECG, 
supine") 
• Frequency of pa1ticipants with 2: 25 % increase 
in HR, decrease in SBP, decrease in DBP vs. 
baseline as measured with any of the methods 
described above. 
• Mean and frequency distribution of percentage of 
days with 2: 25% increase in HR, decrease in 
SBP, decrease in DBP vs. baseline. 
• Mean/median change from screening through 
Day 15 in PR, RR, QRS, QT, QTcF values from 
baseline ECG. 
Assess whether there is tachyphylaxis over the 
• Mean change in HR, SBP and DBP from Day 1 
14-day treatment period for HR, SBP, DBP and 
to Days 4, 7, 10, 14 and 15 for each of the 
eye symptoms. 
measurement methods described above. 
• Change in frequency of pruticipants with eye 
symptoms (all, severe, sedous) and change in 
mean visual acuity score and frequency of color 
vision abno1malities (tritan, protan, deutan) in 
one or both eyes and degree of severity (mild, 
moderate, and severe) from Day 1 to Days 4, 7, 
10, 14 and 15. 
Assess whether cru·diovascular and/or 
• Mean change in HR, SBP and DBP from 
ophthalmic AEs persist or recur up to 4 weeks 
screening to Days 28 and 42 and from Day 14 to 
after discontinuation of treatment with TBA-
Days 28 and 42 for each of the measurement 
7371. 
methods desc1ibed above. 
• Change in frequency of pruticipants with eye 
symptoms (all, severe, sedous) and change in 
mean visual acuity score and frequency of color 
vision abno1malities (tritan, protan, deutan) in 
one or both eyes and degree of severity (mild, 
moderate, and severe) from screening to Days 28 
and 42 and from Days 1-15 (combined) to Days 
28-42 (combined). 
Assess whether there ru·e meaningful changes 
For each blood/sernm and mine pru·ameter: 
in safety laborato1y measurement 
• Mean, median, highest and lowest value . 
• Shift tables from screening to Day 3, Day 7, Day 
14 and Day 42. 
Secondary, PK and PK/PD 
Evaluate the PK ofTBA-7371 monotherapy 
• TBA 73 71 concentration profiles and PK 
over the 14-day treatment period. 
parameters over the 14-day treatment inte1val: 
Cmax, Truax, C1as1, T1as1, AUCinf, AUC1as,, AUCau, 
Cmm, half-life, accumulation ratios. 
Identify the lowest exposure to ofTBA-7371 
• Expected concentration associated with 90% of 
associated with maximal EBA effect. 
the maximal TBA-7371 EBA effect (EC90) 
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1.1.4.3. 
Exploratory Objectives 
Details of exploratory objectives will be included in separate operational and/or analysis plans. 
Results of exploratory objectives may be reported separately from the main clinical study report.  
Exploratory objectives may include but are not limited to:  
• exploration of the correlation between EBA and biomarkers such as mycobacterial cell-free 
DeoxyriboNucleic Acid (DNA), ribosomal RNA ratio assay, sputum and/or peripheral blood 
gene expression profiles and serum cytokines or other proteins, urine LAM, and bacterial 
genotypic evaluations for emergence of resistance;   
• testing of susceptibility to TBA-7371 (MIC);  
• population PK modeling 
1.1.5. 
Design 
This is an interventional, 5-cohort, 3-step dose escalation clinical trial in adult patients,18 to 60 
years of age, with rifampicin-sensitive TB. The escalation will occur sequentially in 3 steps: 
from Cohort I to Cohorts II and III, from Cohort III to Cohort IV and from Cohort IV to Cohort 
V (see below). Within the 2nd escalation step, participants will be randomized equally (1:1) to 
Cohort II or Cohort III, which have the same total daily dose (200 mg, see below). Within each 
cohort, participants will be randomized unequally (5:1) to TBA-7371 or HRZE (isoniazid [H] / 
rifampicin [R] / pyrazinamide [Z] / ethambutol [E]) fixed dose combination tablets as control. 
Rifafour® e-275 (Sanofi) tablets, a commercial presentation of HRZE approved and available in 
South Africa, will be used in this study 1, 2. The study is open-label, with masked laboratory 
assessments (except PK). 
Each participant will undergo 3 study phases: Screening Phase, lasting up to 7 days, with no TB 
treatment, a 14-day Study Treatment Phase on TBA-7371 or HRZE, and a 28-day Follow-up 
Phase on standard of care TB treatment.  
An Independent Data Monitoring Committee (IDMC) will make dose escalation decisions. After 
the last Cohort I participant completes the Study Treatment Phase (Day 14), the IDMC will 
decide whether Cohort II and Cohort III can start enrollment (1st escalation step). The same 
approach will be taken for the 2nd escalation step from Cohorts II & III to Cohort IV and for the 
3rd escalation step from Cohort IV to Cohort V. For each escalation step, the “go / no-go” 
decision will be based on accumulating safety data provided in an un-masked fashion to the 
IDMC. Additional data (e.g. PK) may be provided if available as supporting evidence.  
Authorized study site personnel will dispense each dose of study drug.  
This study will be open label for study participants, study site personnel, IDMC members, 
laboratory personnel involved in PK measurements, and all sponsor and Contract Research 
Organization (CRO) personnel.  
The study will instead be masked (blinded) for personnel involved in the conduct of all other 
laboratory procedures (including those for the primary endpoint).  
Study participants will be hospitalized for up to 7 days for the Screening Phase and will remain 
in hospital until the day after the last dose of study drug is dispensed (Day 15). Written informed 
consent must be given before any screening procedure is started. Participants will leave the 


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hospital on Day 15 after all procedures scheduled for that day have been completed. Thereafter, 
participants will undergo scheduled visits on Days 28 and 42 (+/- 3 days) as outpatients during 
the Follow-up Phase.  
Study procedures are summarized in the Schedule of Activities (SoA) flow-charts (Table 3 and 
Table 4) in Section 1.3. below. 
1.1.6. 
Study Population and Number of Participants 
Adult subjects between 18 and 60 (inclusive) years of age of both sexes will be eligible for the 
study if they have untreated, rifampicin-sensitive, bacteriologically confirmed, Mycobacterium 
tuberculosis pulmonary TB, without other clinically significant medical conditions (including 
extra-thoracic TB and active eye disease) or ECG abnormalities, are not of childbearing potential 
or are using effective methods of birth control, are capable of and willing to provide informed 
consent. Human Immunodeficiency Virus (HIV) positive subjects may be enrolled if CD4+ T-
cell count is ≥350 cells/µL and there is no Acquired Immune Deficiency Syndrome (AIDS)-defining 
opportunistic infection or malignancy. The complete list of inclusion and exclusion criteria can 
be found in Sections 5.1 and 5.2. 
Candidates will be screened to achieve 90 randomized study participants. Within each dose 
escalation cohort, 18 participants will be randomly assigned to TBA-7371 (N=15) or HRZE 
(N=3). The total sample size of the HRZE group (all cohorts combined) will be 15, assuming all 
cohorts will be allowed to undergo treatment.  
Within each cohort, there will be no replacement for the first 2 early withdrawals (drop-outs) 
occurring during the Study Treatment Phase. Drop-outs from the 3rd subject onwards will be 
replaced to ensure that the total number of participants completing study treatment in each cohort 
is at least 16. Participants who withdraw prematurely during the Follow-up Phase will not be 
replaced.  
1.1.7. 
Intervention Groups 
During the Screening Phase participants will not receive TB treatment. 
Eligible participants will be enrolled in one of 5 cohorts in 3 sequential escalation steps as 
follows. 
Cohort I: TBA-7371 oral suspension 100 mg once daily (100 QD) for 14 days or HRZE fixed 
dose combination tablets (H: 75 mg / R: 150 mg / Z: 400 mg / E: 275 mg [Rifafour® e-275]) QD 
for 14 days.  
➢ First escalation step: from Cohort I to Cohorts II and III 
Participants will be randomized to either Cohort II or Cohort III.  
Cohort II: TBA-7371 oral suspension 100 mg twice daily (100 BID) for 14 days or 
HRZE fixed dose combination tablets (Rifafour® e-275) QD for 14 days.  
Cohort III: TBA-7371 oral suspension 200 mg QD for 14 days or HRZE fixed dose 
combination tablets (Rifafour® e-275) QD for 14 days.  


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➢ Second escalation step: from Cohort II/III to Cohort IV 
Cohort IV: TBA-7371 oral suspension 100 mg three times daily (100 TID) for 14 days 
or HRZE fixed dose combination tablets (Rifafour® e-275) QD for 14 days. 
➢ Third escalation step: from Cohort IV to Cohort V 
Cohort V: TBA-7371 oral suspension 400 mg QD for 14 days or HRZE fixed dose 
combination tablets (Rifafour® e-275) QD for 14 days. 
The 1st dose of study drug will be administered at the same time each day for the individual 
participant. Subsequent doses will be administered 12 hours after 1st dose for BID schedules and 
7 hours and 14 hours after 1st dose TID schedule. All doses of study drug will be taken under 
direct observation of a study staff member. 
Weight-based dosage for HRZE (Rifafour® e-275) will be as follows, in line with Package 
Insert1 instructions: 
• 40-54 kg:  3 tablets 
• 55-70 kg: 4 tablets 
• 71 kg and over: 5 tablets 
On Day 15 all patients will be switched to standard of care TB treatment as determined by the 
National Health System.   
1.1.8. 
Timing 
Each participant will remain in the study for up to seven weeks, which consists of up to 7 days 
for the Screening Phase, 2 weeks for the Study Treatment Phase and 4 weeks for the Follow-up 
Phase.  
The escalation go / no-go decisions will be taken by the IDMC based on safety data after the last 
subject of Cohort I (1st step), Cohorts II and III (2nd step) and Cohort IV (3rd step) will have 
completed the Study Treatment Phase. 
The estimated duration of the study (first subject first visit [FSFV] to last subject last visit 
[LSLV]) was originally expected to be approximately 1 year. The duration of the study will 
however be extended as necessary due to COVID-19 pandemic-related restrictions. 
1.1.9. 
Statistical Methods 
This section provides a brief overview of the statistical methods to support the primary 
objectives, including sample size considerations. Details on statistical methods to support the 
secondary objectives and sensitivity analyses are provided in Section 9.4.  
1.1.9.1. 
Bactericidal activity 
The log10 CFU counts vs. time profiles over 14 days of treatment may be biphasic, i.e. the rate of 
change in log10 CFU changes over time. A simple solution is to characterize the subject-specific 
log10 CFU count vs. time profiles using a bilinear regression model, which has been proved to fit 
the data of many TB bactericidal agents quite well, especially over the time interval of 14 days. 


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However, it is also likely that some of the subject-specific log10 CFU count vs. time profiles will 
be better characterized using a simple linear regression model. 
The primary endpoint will be the slope of the log CFU counts from screening to Day 14 
[BACFU(0-14)], i.e., average change in log CFU count per day over 14 Days, where sputum for 
primary endpoint is collected twice during the screening phase and daily thereafter. This can be 
estimated for each subject, i, as the mean of the slopes over each day, i.e., 
𝐵𝐴𝐶𝐹𝑈(0 −14)𝑖= ∑
𝛽̂𝑖𝑡/14
14
𝑡=1
,  
where 𝛽̂𝑖𝑡 is the estimated slope for subject i at time t. For each subject, slopes will be estimated 
using both bilinear and simple linear regression models, and the better fit model (based on lower 
AIC) will be selected for that subject. The log CFU screening measurement used in the model 
will be the average of the two individual screening measurements. If the bilinear regression 
model is selected, the average change in log CFU count per day over 14 days will be estimated 
by: 
 𝐵𝐴𝐶𝐹𝑈(0 −14)𝑖= ∑
[𝛽̂1𝑖𝐼(𝑡≤𝜅̂𝑖) + 𝛽̂2𝑖𝐼(𝑡> 𝜅̂𝑖)]/14
14
𝑡=1
, 
where 𝛽̂1𝑖 is the estimated slope prior to the estimated inflection point 𝜅̂𝑖, and 𝛽̂2𝑖 is the estimated 
slope after the estimated inflection point 𝜅̂𝑖. The parameters of main interest include the slopes 
𝛽̂1𝑖 and 𝛽̂2𝑖, and the inflection points, 𝜅̂𝑖, and can be readily estimated using least squares. If the 
linear regression model is selected, the average change in log CFU count per day over 14 days 
will be estimated by the constant linear regression slope over time, 𝛽̂𝑖. BACFU(0-14) will be 
calculated for each patient within a treatment group individually, and then used as the response 
variable in an ANCOVA model, with a fixed effect for treatment group and screening log CFU 
count as a covariate. Treatment group means from the ANCOVA model will be used to quantify 
the evidence that each of the treatment group mean BACFU(0-14) is less than 0 (i.e., that the 
treatment group mean has a negative slope on average).  
Multiplicity will be handled by means of a step-down sequential approach. The five TBA-7371 
treatment regimens will be divided into 3 testing groups:  Group 1 = Cohort V (400 mg QD) and 
Cohort IV (100 TID); Group 2 = Cohort III (200 mg QD) and Cohort II (100 BID); and Group 3 
= Cohort 1 (100 QD). Group 1, or the group with the highest dose cohort allowed by the IDMC 
will be tested first using a Hochberg multiplicity adjustment: if the maximum and minimum one-
sided p-values are ≥ 0.05 and ≥ 0.025, respectively, formal testing will be stopped and all cohorts 
below will be declared a failure; if the maximum and minimum one-sided p-values are ≥ 0.05 
and <0.025, formal testing will be stopped but the regimen with p-value < 0.025 will be declared 
a success; if the maximum and minimum one-sided p-values are < 0.05 and <0.025, both cohorts 
will be declared a success and testing will proceed to Group 2 regimens with the same step-down 
approach to continue until a failed cohort is observed. 
Primary efficacy analyses will be performed in the modified Intention-to-Treat (mITT) 
population.  
The study will be declared a success if at least one of the TBA-7371 treatment groups achieves a 
statistically significant 1-sided p-value and demonstrates an acceptable safety profile. 


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1.1.9.2. 
Safety 
The frequency of patients who experience one or more severe and/or serious SAEs will be 
summarized by treatment group with 95% CIs. The proportion of patients with this endpoint 
within each of the TBA-7371 treatment groups will not be formally compared to the control arm 
given limitations due to small sample sizes. The primary safety analysis will be performed in the 
Safety population.  
1.1.9.3. 
Power and Sample Size Considerations 
Bactericidal Effect     
 
 
 
 
 
 
 
 
               
Based on Diacon et al, 20133, standard deviations associated with BACFU(0-14) were relatively 
consistent across 5 treatment groups, ranging from 0.05 to 0.08. If we assume conservatively that 
the true standard deviation of the BACFU(0-14) measures for the TBA-7371 treatment groups is 
equal to 0.1, then with N=15 per group we have 80% (90%) power to detect a true group mean 
BACFU(0-14) reduction of 0.067 (0.079), using a 1-sided alpha = 5%. For reference, the observed 
BACFU(0-14) reduction in Diacon et al, 20133 were 0.040, 0.056, 0.077, 0.104, and 0.112 for 
Bedaquiline 100 mg, 200 mg, 300 mg, 400 mg and standard HRZE, respectively. 
Safety   
 
 
 
 
 
 
 
 
 
 
      
With N=15 per group, we have approximately 80% (90%) probability to observe at least one AE 
if the true AE rate is 10% (15%). We have only 54% probability to observe at least one AE if the 
true AE rate is 5%. Across the five TBA-7371 treatment groups (N=75), we have 90% 
probability to observe at least one AE if the true AE rate is 3.0%. 
1.2. 
Schema 
Figure 1. 
Schema 
 
 


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1.3. 
Schedule of Activities (SoA) 
Table 3. 
Scheduled Visits and Activities 
Assessments 
Screening Day• 
Study Treatment Day 
Follow-up 
E\VV' 
Dayb 
A± 15-minute time window is 
allowed for all measurements 
-7 to -3 
-2 
-1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
28 
42 
Written informed consent 1 
X 
Hospital admission or discharge 2 
X 
X 
Demography and medical and 
X 
treatment history 
Physical examination 3 
X 
X 
X 
X 
X 
X 
Chest x-rays 4 
X 
Blood/serum sample collection for HIV 
X 
test and CD4 count 
Sernm sample collection for pregnancy 
status assessment 
X 
X 
X 
X 
Blood/serum sample collection for din. 
X 
X 
X 
X 
X 
X 
safety lab assessment5 
Urine sample collection for clinical 
X 
X 
X 
X 
X 
X 
safety lab assessment 
Urine sample collection for isoniazid 
X 
and drng screening 6 
Overnight sputum collection for 
eligibility asses. (volume, acid-fast 
X 
bacilli Mtb pos. and rifampicin 
sensitivity) 7 
Vital signs and body weight recording 8 
X 
X 
X 
X X X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECG recording 9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Eye assessment (visual acuity, color 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
vision, symptoms) 10 
Study drng (IMP) administration 11 
X 
X 
X XX X 
X 
X 
X 
X 
X 
X 
X 
X 
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Assessments 
Screening Day• 
Study Treatment Day 
Follow-up 
E\VV' 
A± 15-minute time window is 
Dayb 
allowed for all measurements 
-7 to -3 
-2 
-1 
1 
2 
3 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
28 
42 
Overnight sputum collection for EBA 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
& explorato1y measures. 12 
Spot sputum collection for exploratory 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
measurements 13 
Recording of AE, SAE (incl. serious 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ADR) and AESI 14 
Recording of concomitant treatments 14 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood/serum sample collection for PK 
X 
X 
X 
X 
measurements 15 
COVID-19/SARS-CoV-2 Testing17 
a. Screening (Days -7 to -1). Screening procedures will be conducted during the up to 7-Day screening period. Screening assessments can be done at 
any time during this period, except for the written informed consent, which must be given before any screening is sta1t ed, the overnight sputum 
collection for eligibility assessment, which must be completed on or before Day -3, and the overnight sputum collection for EBA, which must be done 
consecutively on Day-2 and Day -1. Subjects may be hospitalized for the entire screening period at the investigator's discretion, but must be 
hospitalized starting on Day -3. 
b. Follow-up (Days 15 to 42). Allowed window for Day 28 and Day 42 visits: +/- 3 Days. 
c. Early Withdrawal Visit (EWV) or Unscheduled Visit. Pa1ticipants who withdraw before Day 14 will be asked to complete the EWV assessments 
within 2 Days of withdrawal. Pa1t icipants who complete the Study Treatment Phase, but do not return for the Day 28 visit will be asked to return for 
the Day 42 visit. If access to sites is limited due to the local status of COVID-19 pandemic, the Day 28 and Day 42 visits could potentially be 
conducted by telephone. Procedures and assessments conducted during an unscheduled visit will be at the discretion of the investigator in 
consultation with the medical monitor. 
1. Written informed consent will be given before any screening procedure is started. 
2. Hospital admission and discharge. Study participants will be hospitalized by Day -3 of the Screening Phase and will remain in hospital until the Day 
after the last dose of study diug is dispensed (Day 15). Discharge from hospital will occur on Day 15 after all procedures planned for that Day are 
completed. Upon discharge, pa1t icipants will be refened to the national TB treatment program for standard of care (SoC) treatment. 
Gates Medical Research Institute 
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3. Physical examination (PE). Full PE will be conducted during the Screening Phase; focused PE (guided by medical history) will be conducted on 
Days 7, 15, 28, 42. Focused PE will be conducted at EWV if the participant discontinues between Day 1 and Day 14. Focused PE may be conducted 
during an unscheduled visit at the discretion of the investigator. 
4. Chest X-rays. Good quality Posterior-Anterior chest X-rays will be accepted if conducted within 1 week prior to Day -7. If not available, chest X-rays 
will be conducted during the Screening Phase. 
5. Blood/serum sample collection for clinical safety laboratory assessment. The Day 3 and 7 sampling will occur before the 1st dose of study drug.  
6. Urine sample collection drug screening: cannabinoids, cocaine, amphetamines, opiates, methamphetamines. 
7. Overnight sputum collection for eligibility assessment. Sputum assessment, including volume, will be performed by a Sponsor-approved central 
laboratory (see laboratory study instruction document). The 1st of the 3 overnight sputum collections (Day -7 to Day -3) conducted during the 
Screening Period will be used to assess eligibility as follows: sputum volume (must be at least 10 mL), acid-fast bacilli detection, Mycobacterium 
tuberculosis (Mtb) positivity and rifampicin sensitivity via the GeneXpert® diagnostic system (Cepheid). In case inclusion criteria cannot be met from 
the 1st overnight sputum collection, one or more of the above procedures can be conducted on a 2nd overnight sputum collected during the Day -7 to -3 
screening period if the patient is domiciled at the site for both.  
8. Vital sign and body weight recording. The following 5 vital signs will be recorded: axillary body temperature (BT), respiratory rate (RR), heart rate 
(HR), systolic blood pressure, (SBP), diastolic blood pressure (DBP). Body weight (BW) will also be recorded with vital signs. Vital signs and body 
weight will be recorded as follows: 
• Screening Phase: vital signs and BW once in the morning at approximately the same time the 1st daily dose study drug will be administered. SBP, 
DBP and HR can be repeated twice if exclusion criteria are met. 
• Study Treatment Phase: vital signs and BW once every morning (Days 1 to 14) before administration of the 1st daily dose of study drug; in addition, 
on Days 1, 4, 7, 10 and 14 vital signs will also collected 2.5h, 10.5h and 16.5h after the time of 1st daily dose of study drug (see Table 4). 
• Follow-up Phase: vital signs and BW on Day 15 in the morning before 1st daily dose of SoC medication; on Days 28 and 42 during the visit. 
• EWV: vital signs and BW if the participant withdraws from the study between Day 1 and 14. 
At each time point BT, RR and BW will be measured once, whereas HR, SBP and DBP will be measured twice as follows: after 10 min supine 
(“manual, supine”) and after 2 (±0.5) min standing (“manual, 2-min standing”). When ECG, vital signs and/or blood/serum samples are to be obtained 
at the same time point, the following order must be followed: ECG, vital signs, blood/serum sample, within 5 min of each other. 
9. ECG recording. 12-lead ECG will be recorded once at each time point after at least 10 minutes of supine rest as follows: 
• Screening Phase: once in the morning at approximately the same time the 1st daily dose study drug will be administered. 
• Study Treatment Phase: on Days 1, 4, 7, 10 and 14 before administration of the 1st daily dose of study drug and 2.5h, 10.5h and 16.5h thereafter (see 
Table 4). 
• Follow-up Phase: on Day 15 in the morning before 1st daily dose of standard of care medication; on Days 28 and 42 during the visit. 
• EWV: if the participant withdraws from the study between Day 1 and 14. 
10. Eye assessment. A trained staff member will assess:  i) eye symptoms using a standardized script (Section 10.5, Appendix 5), ii) visual acuity by 
means of the Rosenbaum Pocket Eye Screener, iii) color vision by means of the Waggoner Computerized Color Vision Test and as follows: 
• 
Screening Phase: once in the AM. 
• 
Study Treatment Phase: Days 1, 4, 7, 10, and 14, 2.5h after 1st daily dose of study drug (see Table 4). 
• 
Follow-up Phase: Days 15, 28 and 42 during the visit. 
• 
EWV: if the participant withdraws from the study between Days 1 and 14.  


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11. Study drug (IMP) administration. Study drug (TBA-7371 or HRZE) will be administered from Day 1 to Day 14 based on the randomization list by 
an authorized and trained site staff member. The 1st dose of study drug will be administered at the same time each Day for the individual participant. 
Subsequent doses will be administered as follows (see Table 4):  
• Twice daily (BID) schedules: 12h after 1st dose 
• Three times (TID) daily schedule: 7h and 14h after 1st dose   
Fasting must occur at least 2 hours before dosing and at least 1 hour after dosing. Study drug administration will be followed by 200 mL water. 
12. Overnight sputum collection for EBA assessment and exploratory measurements. Overnight sputum will be collected from 3 PM to 7 AM of the 
following Day (16 hours) on Days -2 and -1 during Screening Phase and on 14 consecutive Days during the Study Treatment Phase (Days 1 to 14) for 
EBA assessment. The last collection will finish at 7 AM of Day 15. Drug susceptibility testing for isoniazid and rifampicin, and minimum inhibitory 
concentrations (MIC) of TBA-7371 will be performed on either of Day -2 or Day -1, and again on Day 14. Aliquots from each sample, as well as 
MTB isolates from cultures, will be stored and may be used for exploratory measurements.  
13. Spot sputum collection for exploratory measurements. The participant should spontaneously produce (i.e., not induced) a spot sputum specimen 
for collection into RNA preservation media. If specimen cannot be collected due to participant inability to produce sputum, or due to operational 
limitations with RNA media collection kits, it is not considered a protocol deviation. 
14. Recording of AE, SAE (including serious ADR) and AESI; recording of concomitant treatments. Adverse events (AE), serious adverse events 
(SAE), including serious adverse drug reactions (ADR), adverse events of special interest (AESI) and concomitant treatments will be recorded from 
the time each participant has signed the informed consent form (ICF) until he/she has completed the last follow- up visit (Day 42) or the Early 
Withdrawal Visit (EWV). 
15. Blood/serum sample collection for PK measurements. WILL BE CONDUCTED ONLY IN PARTICIPANTS RANDOMIZED TO TBA-7371. 
Timing of sampling will be as follows: 
• Study Treatment Phase: Days 1, 2, 4, 7 and 14 before administration of the 1st daily dose of study drug; in addition, on Days 1, 7 and 14 samples 
will also collected 30 min (+/- 5 min) and at 1h, 2.5h, 3h, 4h, 6h, 7h, 10.5h, 12h, 16.5h (+/- 15 min) after 1st daily dose of study drug. (see Table 4).  
Patients assigned to BID dosing will not have collections at 16.5h, and the 12h sample will be taken prior to the second daily dose. Patients assigned 
to TID dosing will not have collections at 10.5h, 12h and 16.5h, and the 7h sample will be taken prior to the second daily dose.  
When timing coincides, samples must always be taken after recording of ECG and vital signs.  
16. 
17. Coronavirus Disease (COVID-19) / Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2 Testing). COVID-19 testing will be 
conducted via PCR using a test product authorized by SAHPRA at an accredited public or private sector laboratory. A specimen will be collected 
during the screening period between Day-7 to Day -3, and a negative result must be confirmed prior to randomization. For safety monitoring purposes, 
testing will also be performed at Day 7 (±2 Days), on Day 14 OR Day 15 before discharge, and/or at any other time that infection is suspected. 


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Table 4. 
Timing of Measurements on Days 1, 3, 4, 7, 10, and 14 of Study Treatment Phase (STP) 
To+ 
To+ 
To+ 
To+ 
To+ 
To+ 
To+ 
To+ 
To+ 
To+ 
To+ 
To+ 
Time 
To 
0.5 h 
lb 
2.5 h 
3h 
4h 
6h 
7 h 
9.5h 
10.Sh 
12 h 
14 h 
16.5 h 
Comments 
±5 
EWV• 
ll1lJl 
± 15-minute 
Study dmg 
X 
OD schedules 
Study dmg 
X 
X 
BID schedules 
Study dmg 
X 
X 
X 
TID schedules 
ECG recording 
x • 
X 
X 
X 
X 
• before dosing 
Vital signs 
x •+ 
X 
X 
X 
X 
• before dosing 
recording 
+bodyweight 
Blood/serum for 
• before dosing 
clinical safety 
[X]"' 
X 
[X): only Days 3 and 7 of 
assessments 
STP 
Only TBA-7371 pts. 
• Before dosing on Days 1, 
2, 4, 7, 14 ofSTP [X): only 
Days 1, 7 &14 ofSTP. For 
patients on BID dosing, 12h 
timepoint w-ill be collected 
Blood/serum for 
x • 
[X) 
[X) 
[X) 
[X) 
[X) 
[X) 
[X) 
[X) 
[X) 
[X) 
X 
before dosing, and 16.Sh 
PK measurements 
timepoint w-ill not be 
collected. For patients on 
TID dosing, 7h timepoint 
will be collected before 
dosing, and 9.Sh, 12h and 
16.Sh timepoints w-ill not be 
collected. 
Blood/serum/ 
• before dosing 
plasma for 
[X]"' 
[X): only Days 1 and 7 of 
explorato,y 
STP 
measurements 
U,-ine for clin 
[X): only Days 3 and 7 of 
safety 
[X) 
X 
assessments 
STP 
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CONFIDENTIAL 
Time 
Eye assessment 
(vis. acuity, color 
vision symptoms) 
Spot sputum 
collection 
Ovemight sputum 
collection 
AE, SAE, AES! 
To 
X 
To+ 
To+ 
0.5 h 
1 h 
±5 
ll1lJl 
To+ 
2.5 h 
X 
Protocol Gates MRI-TBD03-201 
To+ 
To+ 
To+ 
3 h 
4h 
6h 
To+ 
7 h 
To+ 
9.5 h 
± 15-minute 
Collected at an time 
To+ 
10.Sh 
To+ 
12 h 
To+ 
14 h 
To+ 
16.5 h 
EWV• 
X 
[Version 4, 07 Jul 2020 
Comments 
From 3 PM to 7 AM of the 
following Da 
a. Early Withdrawal Visit (EWV) or Unscheduled Visit. Participants who withdraw before Day 14 will be asked to complete the EWV assessments within 2 
Days of withdrawal. Pa1ticipants who complete the Study Treatment Phase, but do not retum for the Day 28 visit will be asked to retum for the Day 42 visit. 
If access to sites is limited due to the local status of the COVID-19 pandemic, the Day 28 and Day 42 visits could potentially be conducted by telephone. 
Procedures and assessments conducted during an unscheduled visit will be at the discretion of the investigator in consultation with the medical monitor. 
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2. 
Introduction 
TBA-7371 is a non-covalent inhibitor of mycobacterium tuberculosis (Mtb) deca-
prenylphosphoryl-β-D-ribose 2′-epimerase 1 (DprE1), an enzyme involved in mycobacterial cell 
wall synthesis. TBA-7371 demonstrates potent bactericidal anti-Mtb activity in vitro, with a 
minimum bactericidal concentration (MBC) similar to its minimum inhibitory concentration 
(MIC) against replicating Mtb. It has a narrow spectrum, with activity limited to mycobacteria. 
Like other cell-wall biosynthesis inhibitors, TBA-7371 is not active against low-oxygen induced 
non-replicating bacteria. TBA-7371 was highly active against a panel of 96 clinical Mtb isolates 
representative of global phylogeny and geographical origin, and with differing drug-
susceptibility profiles, including extensively drug-resistant TB (XDR-TB). The MIC90 of TBA-
7371, i.e. the MIC for at least 90% of isolates of this panel, is 0.64 µg/mL and the MIC range is 
0.04-5.12 µg/mL, where the distribution of MICs is unrelated to the drug-susceptibility or 
genotype of the strain, suggesting utility globally, and against drug-sensitive and drug-resistant 
TB. Activity against drug-resistant Mtb isolates is expected for TBA-7371 because its drug 
target, DprE1, is novel, compared to those of currently used TB drugs. Mtb mutants resistant to 
TBA-7371 are selected at a frequency of 4-7 x 10-7, similar to the reported in vitro resistance 
frequency for clinically relevant anti-TB agents like ethambutol.  
No active metabolites of TBA-7371 have been identified thus far. 
More information on the PK and pharmacodynamics (PD) of TBA-7371 is provided in the 
Investigator Brochure. 
2.1. 
Study Rationale 
The current treatments for TB have a lengthy duration, involve multi-drug regimens, must be 
taken multiple times per day and have non-trivial unwanted effects. 4,5 Furthermore, some of the 
available drugs are expensive. Two of the main consequences of this profile are - first, TB 
treatments require large commitments of resources and infrastructure, typically lacking in the 
countries where TB is most prevalent, and second, poor compliance is common, which results in 
increased severity of disease and mortality and in the emergence of drug-resistant strains. 4-6   
The shortcomings of the available treatments, combined with  massive prevalence, health impact 
and mortality of TB (see below), make a strong case for the discovery and development of novel 
TB drugs and drug regimens that will address the challenges of current treatments through one or 
more of the following features: shorter treatment duration, reduced dosing frequency, improved 
safety and tolerability profile, improved efficacy, greater affordability, suitability for pediatric 
use and for co-administration with antiretroviral therapy in individuals co-infected with Mtb and 
HIV. 
Encouraging preclinical data and a sustainable safety and tolerability profile (see Section 2.3) of 
the first trial in healthy volunteers (TBA7371-001) justify the evaluation of  TBA-7371 in an 
EBA trial in adult patients with untreated, drug-sensitive pulmonary TB. 


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2.2. 
Background 
2.2.1. 
Tuberculosis 
Tuberculosis in humans is an infectious disease caused by Mtb, which typically affects the lungs 
(pulmonary TB) but can affect other sites as well (extrapulmonary TB). It is an airborne disease 
transmitted by inhalation of infective droplets containing Mtb and expelled into the air by a 
person with active TB via coughing, sneezing, or even talking. The unique cell wall of Mtb, 
which has a waxy coating primarily composed of mycolic acids, allows the bacillus to lie 
dormant in some individuals for many years (i.e., latent TB infection). Latent TB infection 
(LTBI) is not associated with symptoms and is not infectious. However, approximately 10% of 
individuals with LTBI will develop active disease during their lifetime (i.e., a 10% lifetime risk 
of activation), often years or even decades after the initial infection and most of these cases will 
themselves become infectious.7  Individuals with LTBI who are co-infected with HIV are at an 
increased risk of developing active TB; such individuals are estimated to have an 8% annual risk 
of reactivating LTBI. 8,9 Tuberculosis is currently one of the top three killer infectious diseases, 
and there is more TB in the world today than at any other time in history. While TB is found in 
every country in the world, it disproportionately affects people in resource poor settings, 
particularly those in Asia and Africa. Nevertheless, TB outbreaks still occur in industrialized 
nations. The World Health Organization (WHO) estimates that 2 billion people, approximately 
one-third of the world’s population, are infected with Mtb worldwide. In 2015, there were an 
estimated 10.4 million new incident cases of TB (11% co-infected with HIV), and 1.4 million 
people died from TB. 10 
2.2.2. 
Early Bactericidal Activity Clinical Studies 
The ability of EBA studies to quantify the bactericidal action of anti-TB agents alone or in 
combination was established following a pioneering study in 1980. 11 In these studies, which 
typically have treatment periods ranging from 2 to 14 days, the ability of various agents and 
combinations of agents to decrease the number of CFU of  Mtb present in the sputum of study 
participants serves as an indication of the anti-TB activity of the treatment. A review of EBA 
studies conducted on the key anti-TB drugs has shown the value these studies offer to 
demonstrate the early anti-TB effect that a new therapeutic agent may have and to explore the 
relationships between dose, pharmacokinetics and bactericidal activity in patients. 12 
2.3. 
Benefit/Risk Assessment 
In this trial patients with untreated, drug-sensitive pulmonary TB will receive for 14 days either 
the test drug TBA-7371 in 1 of 5 regimens (from 100 mg QD to 400 mg QD) or commercial 
HRZE fixed combination (Rifafour® e-275) as control drug, dosed as recommended in the 
package insert. 1  
HRZE is a first line treatment for drug sensitive TB with a well-established, generally favorable, 
yet not straightforward, benefit-risk profile. The most common AEs associated with HRZE are 
peripheral neuropathy, optic neuritis, hepatitis, and gastro-intestinal AEs (see Package Insert 1 
and 2018 Safety Update 2 enclosed in study specific manual(s)). 
TBA-7371 was tested in adult healthy volunteers in 1 clinical trial (TBA7371-001), composed of 
three parts: a single ascending dose (SAD) part where single doses from 100 to 800 mg were 


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tested, a multiple ascending dose (MAD) part where 100, 200 and 400 mg QD were taken for 14 
days and a drug-drug interaction (DDI) part. The most common treatment-emergent adverse 
events (TEAEs) were increase in heart rate associated with decrease in blood pressure and eye 
symptoms (blurred vision, photophobia, altered color vision, increased lacrimation). The 
frequency of such events was dose related, starting at doses above 100 mg /day. Most were mild 
and transient. In particular, vision-related AEs were of short duration, resolved before the next 
dose and were not persistent changes. Furthermore, tachyphylaxis to changes in heart rate and 
blood pressure appeared to occur in the MAD part of the trial.  
The eye symptoms appeared to be associated with Cmax. It is therefore possible that the 
tolerability profile could improve with fractionation of the daily dose. This justifies the inclusion 
of the BID and TID dosing regimens in this trial.  
There is no information on the efficacy of TBA-7371 in humans. PK/PD modelling from animal 
experiments, supplemented with additional PK data from healthy human subjects, suggests that 
bactericidal effect could be present at 100 mg/day and then increase with dose.  
More information on TBA-7371 is provided in the Investigator Brochure.  
The overall risks associated with TBA-7371 at or below 400 mg QD are considered low and are 
mitigated by the following design features of the present protocol: 
• throughout the 14-day Treatment Phase eye symptoms, visual acuity and color vision, ECG 
will be assessed/recorded every 3-4 days, vital signs daily;  
• the escalation from QD dose level to the next will be staggered, and escalation decisions 
will be taken by an IDMC based on full unmasked safety data from the lower dose 
cohort(s); 
• it is possible that patients will experience no meaningful bactericidal effect for the duration 
of treatment with TBA-7371 of 14 days. Participants will thus be kept under close 
observation in hospital for the entire period so that in case of progression of disease, 
effective treatment can be initiated without delay;  
• at the end of Study Treatment Phase patients will be switched to standard of care TB 
treatment, trained on the importance of compliance and proper follow-up and followed for 
an additional 28 days (Follow-up Phase of the study). 
Given the safety profile observed thus far and the design features described above, the benefit-
risk assessment for this trial is considered favorable. 


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3. 
Objectives and Endpoints 
3.1. 
Primary Objectives and Endpoints 
Table 5. 
Primary Objectives and Endpoints 
Objectives 
Endpoints 
Bactericidal activitv 
Demonstrate the 14-day EBA from screening ("0") 
• Slope, i.e. average change per day, from 
to Day 14 (EBA 0-14) of 5 dose regimens of TBA-
screening ("0") to Day 14 [BACFU(0-14)] of 
7371 monotherapy and HRZE as assessed by CFU 
the log CFU coW1ts. 
coW1ts on solid media culture. 
Safety 
Assess the severe/SAE burden of 5 dose regimens 
• Frequency of study participants who 
ofTBA-7371 monotherapy and HRZE over a 14-
expeiienced one or more severe AEs (2: 
day treatment period. 
grade 3) and/or SAEs from Day 1 through 
Day 15. 
3.2. 
Secondary Objectives and Endpoints 
Table 6. 
Secondary Objectives and Endpoints 
Obiectives 
Endpoints 
Bactericidal activitv 
Demonstrate the EBA of the first 2 days (screening 
• Slope, i.e. average change per day, from 
["0"] to Day 2) and of the remaining 12 days (Day 2 
screening ("0") to Day 2 [0-2)] and from 
to Day 14) of 5 dose regimens ofTBA-7371 
Day 2 to Day 14 [BACFU(2-14)] of the log 
monotherapy and HRZE, as assessed by CFU 
CFU COWltS. 
coW1ts on solid media culture. 
Demonstrate the bactericidal activity of 5 dose 
• Slope of the time to sputum culture 
regimens ofTBA-7371 monotherapy and of HRZE, 
positivity (TTP) in the MGIT system from 
as assessed by alternative methods: 
screening ("0") to Day 14 [BATIP (0-14)], 
• time to sputum culture positivity (TIP) in 
from screening to Day 2 [BATIP (0-2)], and 
(MGIT) culture 
from Day2 to Day 14 [BATIP (2-14)]. 
• LAM assay 
• Slope of the log concentration of sputum 
LAM from screening ("0") to Day 14 
[BALAM (0-14)], from screening to Day 2 
[BALAM (0-2)], and from Day 2 to Day 14 
rBALAM c2-14)l 
Safetv 
Assess the adverse event (AE) profile of each dose 
• Frequency from Day 1 through Day 15 of 
regimen ofTBA-7371 and HRZE over the 14-day 
participants with AE and frequency of AEs: 
treatment pe1iod. 
overall, by body system, and prefeITed te1m; 
by seriousness, intensity (severity), 
expectedness and relatedness to study diug. 
Assess the impact on eye symptoms, visual acuity 
From Day 1 through Day 15: 
and color vision of each dose regimen of TBA-7371 • Frequency of pruticipants with any new (vs. 
and HRZE over the 14-day treatment pe1iod. 
screening) eye symptom in one or both eyes. 
• Mean and frequency distiibution of duration 
of each eye symptom. 
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Objectives 
Endpoints 
• 
Mean and frequency distribution of 
percentage of days with any eye symptom 
and each of the eye symptoms. 
• 
Mean/median change in visual acuity score 
from screening to lowest score during Days 
1-15. 
• 
Frequency of participants with any new color 
vision abnormalities (tritan, protan, deutan) 
in one or both eyes and degree of severity 
(mild, moderate, severe). 
Assess the impact on heart rate, blood pressure and 
ECG profile of each dose regimen of TBA-7371 and 
of HRZE over the 14-day treatment period. 
From Day 1 through Day 15: 
• 
Mean and frequency distribution of changes 
in HR, SBP and DBP as measured by the 
following 2 (BP) or 3 (HR) methods: 
▪ 
manual (vital signs), after at least 10 
minutes in supine position (“manual, 
supine”); 
▪ 
manual, after 2 (±0.5) minutes in 
standing position (“manual, 2-min 
standing”); 
▪ 
HR from ECG, supine position 
(“ECG, supine”) 
• 
Frequency of participants with ≥ 25 % 
increase in HR, decrease in SBP, decrease in 
DBP vs. baseline as measured with any of 
the methods described above. 
• 
Mean and frequency distribution of 
percentage of days with ≥ 25% increase in 
HR, decrease in SBP, decrease in DBP vs. 
baseline.  
• 
Mean/median change from screening 
through Day 15 in PR, RR, QRS, QT, QTcF 
values from baseline ECG. 
Assess whether there is tachyphylaxis over the 14-
day treatment period for HR, SBP, DBP and eye 
symptoms. 
• 
Mean change in HR, SBP and DBP from 
Day 1 to Days 4, 7, 10, 14 and 15 for each 
of the measurement methods described 
above. 
• 
Change in frequency of participants with 
eye symptoms (all, severe, serious) and 
change in mean visual acuity score and 
frequency of color vision changes from Day 
1 to Days 4, 7, 10, 14 and 15.  
Assess whether cardiovascular and/or ophthalmic 
adverse events persist or recur up to 4 weeks after 
discontinuation of treatment with TBA-7371. 
• 
Mean change in HR, SBP and DBP from 
screening to Days 28 and 42 and from Day 
14 to Days 28 and 42 for each of the 
measurement methods described above. 
• 
Change in frequency of participants with eye 
symptoms (all, severe, serious) and change 
in mean visual acuity score and frequency of 


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Protocol Gates MRI-TBD03-201 
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Objectives 
Endpoints 
color vision changes from screening to Days 
28 and 42 and from Days 1-15 (combined) to 
Days 28-42 (combined). 
Assess whether there are meaningful changes in 
For each blood/semm and mine parameter: 
safety laborato1y measurement 
• Mean, median, highest and lowest value . 
• Shift tables from screening to Day 3, Day 7, 
Dav 14 and Dav 42. 
Secondarv. PK and PK/PD 
Evaluate the pha1macokinetics ofTBA-7371 
• TBA 73 71 concentration profiles and PK 
monotherapy over the 14-day treatment pedod. 
parameters over the 14-day treatment 
inte1val: Cmax, Tmax, C1as,, T1as1, AUCinf, 
AUC1as1, AUC,au, Cmin, half-life, 
accumulation ratios. 
Identify the lowest exposure to ofTBA-7371 
• Expected concentration associated with 90% 
associated with maximal EBA effect. 
of the maximal TBA-7371 EBA effect 
(EC90) 
3.3. 
Exploratory Objectives 
Details of explorato1y objectives will be included in separate operational and/or analysis plans. 
Results of exploratory objectives may be reported separately from the main clinical study repo1i. 
Explorato1y objectives may include but are not limited to: 
• 
exploration of the con elation between EBA and biomarkers such as mycobacterial cell-
free DNA, ribosomal RNA ratio assay, sputum and/or peripheral blood gene expression 
profiles and sernm cytokines or other proteins, urine LAM, and bacterial genotypic 
evaluations for emergence of resistance; 
• 
testing of susceptibility to TBA-7371 (MIC); 
• 
population PK modeling. 
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4. 
Study Design 
4.1. 
Overall Study Design 
This is an interventional, 5-cohort, 3-step dose escalation clinical trial in adult patients between 
18 to 60 years of age with rifampicin-sensitive pulmonary TB.  
The escalation will occur sequentially in 3 steps: from Cohort I to Cohorts II and III, from 
Cohorts II and III to Cohort IV and from Cohort IV to Cohort V (see below). Within the 2nd 
escalation step, participants will be randomized equally (1:1) to Cohort II or Cohort III, which 
have the same total daily dose (200 mg, see below). Within each cohort, participants will be 
randomized unequally (5:1) to TBA-7371 or HRZE (isoniazid [H] / rifampicin [R] / 
pyrazinamide [Z] / ethambutol [E]) fixed dose combination tablets. Rifafour® e-275 (Sanofi) 
tablets, a commercial presentation of HRZE approved and available in South Africa, will be used 
in this study. 1,2 
Each participant will undergo 3 study phases: up to a 7-day Screening Phase with no TB 
treatment, a 14-day Study Treatment Phase on TBA-7371 or HRZE and a 28-day Follow-up 
Phase on standard of care TB treatment.  
The doses and dose schedules of the 5 TBA-7371 cohorts will be as follows: Cohort I: 100 mg 
QD, Cohort II: 100 mg BID, Cohort III: 200 mg QD, Cohort IV: 100 mg TID, Cohort V: 400 mg 
QD. For HRZE, the dose will be weight-based as per package insert. 1  
An IDMC will make dose escalation recommendations. After the last Cohort I participant 
completing the Study Treatment Phase (Day 14), the IDMC will decide whether Cohort II and 
Cohort III can start enrolment (1st escalation step). The same approach will be taken for the 2nd 
escalation step (from Cohorts II & III to Cohort IV) and for the 3rd escalation step (from Cohort 
IV to Cohort V). For each escalation step, the “go / no-go” decision will be based on 
accumulating safety data. Additional data (e.g. PK) may be provided as supporting evidence.  
Authorized study site personnel will dispense each dose of study drug. 
This study will be open label for study participants, study site personnel, IDMC members, 
laboratory personnel involved in PK measurements and all sponsor and CRO personnel. 
The study will instead be masked (blinded) for personnel involved in the conduct of all other 
laboratory procedures (including those for the primary endpoint).  
Study participants will be hospitalized during the Screening Phase and will remain in hospital 
until the day after the last dose of study drug is dispensed (Day 15). Written informed consent 
must be given before any screening procedure is started. Participants will leave the hospital on 
Day 15 after all procedures scheduled for that day have been completed. Thereafter, participants 
will undergo scheduled visits on Days 28 and 42 (+/- 3 days) as outpatients during the Follow-up 
Phase.  
Candidates will be screened to achieve 90 randomized study participants. Within each dose 
escalation cohort, 18 participants will be randomly assigned in a 5:1 ratio to TBA-7371 (N=15) 
or HRZE (N=3). The total sample size of the HRZE group (all cohorts combined) will be 15, 
assuming all cohorts will be allowed to undergo treatment.  


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Within each cohort, there will be no replacement for the first 2 early withdrawals (drop-outs) 
occurring during the Treatment Phase. Drop-outs from the 3rd onwards will be replaced to ensure 
that the total number of participants completing study treatment in each cohort is at least 16. 
Participants who withdraw prematurely during the Follow-up Phase will not be replaced.  
4.2. 
Scientific Rationale for Study Design 
The dose escalation approach, with go/no-go decision on each escalation step to be taken by the 
IDMC based on the complete safety dataset from lower dose cohort(s), has been chosen to 
maximize the safety of participants, against the background of the safety and tolerability profile 
observed in study TBA-7371-001. As mentioned above, the two most frequent treatment 
emergent adverse events, namely heart rate increase and eye symptoms, had a dose-dependent 
(above 100 mg QD) frequency and were mostly mild and transient.  
The level of masking, in this study, which includes all personnel involved in CFU counts for the 
primary endpoint (see Section 6.3.2), ensures balance of methodological excellence and 
feasibility, and is considered adequate for the stage of development of TBA-7371. 
Whereas the 3 dose escalation steps will be conducted in an open-label manner, within the 2nd 
escalation, participants will be randomized to Cohort II or Cohort III. This approach is justified 
because Cohorts II and III have the same total daily dose of TBA-7371 (200 mg) and strengthens 
the design of the study. 
Within each cohort, participants will be randomized to TBA-7371 or HRZE control with a 5:1 
ratio (15 TBA-7371 vs. 3 HRZE). This unequal randomization is justified by the fact that HRZE 
data from all cohorts will be pooled; hence, if all 5 cohorts will be allowed to enter the trial, the 
target size of the control group (N=15) will be the same as the TBA-7371 groups. 
The target population is adult males and females with untreated, rifampicin-sensitive, 
uncomplicated pulmonary TB. This population is ideal for the assessment of the bactericidal 
activity of a new drug. 
In this trial, QD, BID and TID schedules will be tested. The scientific rationale is that some 
symptoms appear to be associated with Cmax. It is therefore possible that fractionation of the 
daily dose could improve the tolerability profile and the benefit-risk ratio. 
Primary endpoints are: 1) EBA of TBA-7371 as determined by the slope of log CFU count on 
solid media culture from screening though Day 14; and 2) frequency of participants with serious 
and/or severe (≥ Grade 3) AEs throughout the treatment. The value of EBA to predict clinical 
efficacy is outlined in Section 2.2.2. Combined SAEs and severe AEs are considered the best 
indicators of the overall burden and acceptability of the treatment to patients. 
The scientific rationale for secondary endpoints is as follows: 
• EBA as assessed by alternative methods [TTP in MGIT culture and LAM assay]. MGIT 
culture and LAM assay are easier to conduct compared to solid media culture. Hence, 
insight into the suitability of such methods to replace solid media culture will be useful for 
this and other TB drug development programs.  
• Full AE assessment. All AE will be assessed by seriousness, intensity (severity), 
relationship to study drug and expectedness based on the information provided in the 


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Investigator Brochure and summarized by body system and preferred medical term. This 
will allow the full safety and tolerability profiling of TBA-7371. 
• Assessment of heart rate and blood pressure via vital signs and ECG, eye symptoms, visual 
acuity and color vision. These measurements were selected based on the safety profile that 
emerged from animal studies and from phase 1 study TBA7371-001 (see above). Multiple 
assessment methods will be carried out for cardiovascular variables to maximize the 
sensitivity of the study. Eye symptoms will be assessed by non-leading questions delivered 
by trained staff based on a standardized script. Visual acuity and color vision will be 
assessed through standardized procedures. The possibility of decrease (tachyphylaxis) or 
increase over time of these unwanted effects, as well as their persistence or recurrence in 
the month following discontinuation of study drug, will also be assessed: results of study 
TBA7371-001 suggest changes over time during treatment with TBA-7371 of 
cardiovascular (decrease) and eye (increase) adverse events. It should be noted that all eye 
symptoms reported study TBA7371-001 were transient.  
PK profile and relationship between exposure and magnitude of EBA. So far, the PK profile of 
TBA-7371 has been only studied in animals and in healthy volunteers. This study allows the 
confirmation of the PK profile in TB patients. The relationship between exposure and 
bactericidal response will guide the selection of the dose regimen(s) for further development of 
TBA-7371. No active metabolite of TBA-7371 has been identified so far, and no major 
metabolite seen in humans has been detected at more than 10% of parent TBA-7371.  Therefore, 
TBA-7371 metabolism will not be examined further in this study. 
Additional measurements may be added as exploratory endpoints. Exploratory endpoints will be 
the object of separate documents. 
4.3. 
Justification for Dose 
In this study 5 dose regimens of TBA-7371 will be tested over a 14-day treatment period: 100 
mg QD, 100 mg BID, 200 mg QD, 100 mg TID and 400 mg QD. 
From a safety perspective the dose selection is justified by the fact that in study TBA7371-001 
single doses of 100, 200, 400 and 800 mg and multiple doses over 14 days of 100, 200 and 400 
mg QD were tested: doses from 100 to 400 mg/day are considered suitable for further 
development assuming proper mitigation steps are in place (see Section 2.3). See Investigator 
Brochure for more detail. 
From an activity perspective, no human data are available. PK-PD modelling of animal data, 
taken together with human PK data in healthy volunteers, suggest that 200 mg QD or above may 
be necessary to achieve a meaningful bactericidal effect.  
Whereas QD dosing is an important feature of the target product profile for TBA-7371, the 
introduction in the study design of a twice daily (100 mg BID) and a three times daily (100 mg 
TID) regimen will allow assessment of the impact of daily dose fractionation vs. QD dose on the 
bactericidal activity and the safety/tolerability profile of TBA-7371. This information will be 
valuable for further development of this and other investigational drugs with similar mechanism 
of action. 


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4.4. 
End of Study Definition 
A participant is considered to have completed the study if he/she completes the final visit on Day 
42. The end of the study is defined as the date of the last visit of the last participant in the study 
or last scheduled procedure shown in the SoA for the last participant in the trial. 
 
 


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5. 
Study Population 
Prospective approvals of protocol deviations to enrollment criteria, also known as protocol 
waivers or exemptions, are not permitted. 
Recruitment 
Participants will be recruited from communities with known high burden of TB transmission and 
disease. Various methods of recruitment may be used, such as community information sessions, 
advertising, referrals, word-of mouth, or solicitation through participants previously known to 
the clinical site.  
Recruitment materials, if any, will be approved by the appropriate Institutional Review Board/s 
(IRBs) or Independent Ethics Committee/s (IECs). Interested participants will be invited to 
participate in the informed consent process. 
5.1. 
Inclusion Criteria 
Age 
1. 
18 to 60 years of age (inclusive) at the time of signing the informed consent. 
Weight 
2. 
Body weight within 40 and 100 kg (inclusive). 
Disease Characteristics 
3. 
Untreated, rifampicin-sensitive pulmonary TB, as defined by all of the following: 
a. isoniazid urine screen negativity 
b. sputum smear positivity for acid-fast bacilli using fluorescent microscopy, defined as at 
least 1+ on the International Union Against Tuberculosis and Lung Disease 
(IUATLD)/WHO scale 
c. chest X-rays which in the opinion of the investigator is consistent with TB  
d. Mtb positivity on molecular test (GeneXpert®) 
e. rifampicin sensitivity on molecular test (GeneXpert®). 
Sputum Production 
4. 
Participants must be able to produce at least 10 mL of sputum during the screening 
overnight sputum collection (two attempts can be made during Day -7 to -3 to meet the 
volume requirement if the patient is domiciled at the site for both), as assessed by a 
Sponsor-approved central laboratory. 
Childbearing potential 
5. 
Female and male participants should be of non-childbearing potential or using an effective 
method of birth control. 
Non-childbearing potential is defined as follows:                       
a. participant is not heterosexually active or practices sexual abstinence, OR 
b. female participant or sexual partner has undergone bilateral oophorectomy, bilateral tubal 
ligation and/or hysterectomy, OR 


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c. female participant or sexual partner has been postmenopausal with a history of no menses 
for at least 12 consecutive months, OR 
d. male participant or sexual partner has undergone vasectomy or bilateral orchidectomy at 
least three months prior to screening, OR 
e. male participant with pregnant sexual partner (for duration of the study) who does not 
have any other sexual partners. 
An effective method of birth control is defined as follows:   
a. double barrier method, which can include any 2 of the following: a male condom, 
diaphragm, cervical cap, or female condom (male and female condoms should not be used 
together), OR  
b. barrier method (one of the above) combined with hormone-based contraceptives or an 
intra-uterine device for the female participant or partner, AND 
c. participant willing to continue practicing one of the above-mentioned birth control 
methods throughout 14-day Study Treatment Phase and for 4 weeks after the last dose of 
study medication or discontinuation from study medication in case of early withdrawal.  
See Section 10.3 (Appendix 3) for more information on contraceptive guidance and 
collection of pregnancy information 
Informed Consent 
6. 
Participants must be capable of giving signed informed consent as described in Section 10.1 
(Appendix 1), which includes agreeing to compliance with the requirements and restrictions 
listed in the informed consent form (ICF) and in this protocol. 
5.2. 
Exclusion Criteria  
Participants are excluded from the study if any of the following criteria apply.  
Medical Conditions and History 
1. 
Need for immediate effective anti-TB treatment as judged by the investigator.  
2. 
Tested positive for COronaVIrus Disease-19 (COVID-19)/SARS-CoV-2 during the 
Screening Period with a PCR-based assay. 
3. 
Evidence and/or history of extra-thoracic TB (e.g. miliary TB, abdominal TB, urogenital TB, 
osteoarthritic TB, TB meningitis, ocular TB), as judged by the investigator. 
4. 
Evidence and/or history in the last 5 years of one or any combination of the following: 
a. uveitis; 
b. color vision deficiency; 
c. amblyopia; 
d. visual acuity worse than 20/25 after correction in either eye; 
e. any known eye disease or prior eye surgery; 
f. any systemic condition with ocular manifestations (i.e. Marfan, syphilis, diabetes, Beçhet, 
Vogt-Koyanagi-Harada, Lyme, or chronic inflammatory condition such as sarcoidosis, 
rheumatoid arthritis, psoriatic arthritis) 


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5. 
Evidence and/or history in the last 5 years of clinically significant medical condition(s) as 
judged by the investigator, including malignancies and unstable or uncontrolled hypertension. 
6. 
Any current medical, psychiatric, occupational, or substance abuse problems that, in the 
opinion of the investigator, will make it unlikely that the participant will comply with the 
protocol. 
7. 
For HIV infected participants: 
a. CD4+ count <350 cells/µL, OR 
b. AIDS-defining opportunistic infection or malignancies (except pulmonary TB). 
8. 
Seated systolic/diastolic blood pressure assessed as vital sign (i.e. not from ECG) is less than 
95/40 mmHg or greater than 145/95 mmHg at screening. Out-of-range blood pressure may be 
repeated twice with at least 5 minutes intervening. 
9. 
Seated heart rate assessed as vital sign (i.e. not from ECG) is lower than 40 beats per minute 
(bpm) or higher than 110 bpm at screening. Out-of-range heart rate may be repeated twice 
with at least 5 minutes intervening.  
10. A clinically significant ECG abnormality at screening. NOTE: The following can be 
considered not clinically significant:  
a. 
mild first-degree atrio-ventricular block (P-R interval <0.23 sec); 
b. 
right or left axis deviation; 
c. 
incomplete right bundle branch block; 
d. 
isolated left anterior fascicular block (left anterior hemiblock) in young athletic subjects. 
Prior/Concomitant Therapy 
See Section 10.6 (Appendix 6) for a list of commonly used prohibited medications (based on 
exclusion criteria # 11 to # 16). Please note that the list is not comprehensive and other medications 
with the features described below are also prohibited. 
11. Use of medications active against Mtb within 3 months prior to the first dose of study drug.  
12. Use of systemic immunosuppressive medications within 14 days prior to the first dose of 
study drug.  
13. Use of strong inhibitors or strong inducers of cytochrome P450 (CYP) enzymes within 14   
days prior to the first dose of study drug. 
14. Use of inhibitors of phosphodiesterase (PDE) enzymes within 14 days prior to the first dose  
of study drug. 
15. Use of medications known to affect the eye within 3 months prior to the first dose of study 
drug.  
16. For HIV+ patients, use of medications listed in Section 10.6 (Appendix 6) within 3 months 
prior to the first dose of study drug. 
Prior/Concurrent Clinical Study Experience 
17.  Participation in other clinical study(-ies) with investigational agent(s) within 6 months prior 
to trial start. 
Diagnostic Assessments 
18. The following laboratory values from blood collected during the Screening Phase, which 
represent Grade 2 or higher abnormalities per DAIDS Toxicity Table Version 2.1 (see Section 
10.4, Appendix 4), will be cause for exclusion:  
• AST, ALT, alkaline phosphatase (ALP) ≥ 2.5x upper limit of normal (ULN) 


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• Total bilirubin ≥ 1.6x ULN 
• Creatinine ≥ 1.3x ULN 
• Hemoglobin < 10 g/dL (male) or 9.5 g/dL (female) 
• White Blood Cell Count (WBC) < 2,000 / mm3 
• Platelets ≤ 100,000 /mm3 
• INR ≥ 1.5x ULN 
• PTT ≥ 1.66 ULN 
• PT ≥ 1.25x ULN 
      ULN= upper limit of normal for local laboratory values 
Grade 2 or higher abnormalities in other laboratory parameters from blood or urine Grade 1 
abnormalities, or abnormalities from laboratory parameters not included in the DAIDS Toxicity 
Table Version 2.1, may lead to exclusion if the investigator considers them clinically significant.   
Other Exclusion Criteria 
19. History of allergy or hypersensitivity to any of the study drugs or related substances. 
20. Positive urine drug screening for cocaine AND/OR amphetamines AND/OR opiates 
AND/OR methamphetamines. Note: screening will also be conducted for cannabinoids and 
results documented in the CRF; however, a positive test for cannabinoids is not an exclusion 
criterion.  
21. Female participants currently pregnant or lactating/nursing; OR having positive serum 
pregnancy test during the Screening Phase OR planning a pregnancy within the 1 month after 
first dose of study drug. Refer to Section 10.3 (Appendix 3) for more information. 
5.3. 
Lifestyle Considerations 
Avoidance of pregnancy during the study: see Section 5.1. 
5.4. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently randomly assigned to study intervention/entered in the study. A minimal set of 
screen failure information is required to ensure transparent reporting of screen failure 
participants to meet the Consolidated Standards of Reporting Trials (CONSORT) publishing 
requirements and to respond to queries from regulatory authorities. Minimal information 
includes demography, screen failure details (i.e. why eligibility criteria were not met) and any 
SAE. 
Rescreening is not permitted, except in special circumstances. The investigator may review 
rescreening eligibility, on a case-by-case basis, with the Sponsor. 


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6. 
Study Interventions 
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to the 
study protocol. 
6.1. 
Study Interventions Administered  
Two interventions will be used in this study: participants will receive either TBA-7371 oral 
suspension or HRZE, a fixed dose combination of isoniazid [H], rifampicin [R], pyrazinamide 
[Z] and ethambutol [E]) oral tablets, commercially available in South Africa (Rifafour® e-275).1  
6.1.1. 
Composition  
6.1.1.1 
TBA-7371 Oral Suspension 
The drug product is an extemporaneously compounded oral suspension. 
The quantitative composition, function and quality of each ingredient in the drug product 
(TBA-7371 Oral Suspension, 25 mg/mL) is provided in Table 7 below. 
Table 7. 
Composition of the TBA-7371 Oral Suspension, 25 mg/mL 
Ingredient  
Function 
Quality 
Standard 
Quantity 
per dose 
(100 mg )  
Quantity 
per dose 
(200 mg)  
Quantity 
per dose 
(400 mg ) 
TBA-7371 
hydrochloride* 
equivalent to TBA-
7371 
Drug 
substance 
In-house 
100 mg 
200 mg 
400 mg 
Purified water 
Diluent 
Commercially 
available 
0.8 mL 
1.6 mL 
3.2 mL 
Ora-Blend® ** 
Flavored oral 
suspending 
vehicle 
Commercially 
available 
Quantity 
required to 
4 mL 
Quantity 
required to 
8 mL 
Quantity 
required to 
16 mL 
Total volume 
4 mL 
8 mL 
16 mL 
*TBA-7371 hydrochloride salt is calculated using the assay value of free base from the certificate of analysis. 
Quantity of HCl salt (g) = amount of free base equivalent divided by % assay value as free base.  
** Purified water, sucrose, glycerin, sorbitol, flavoring, micro- crystalline cellulose, carboxymethylcellulose 
sodium, xanthan gum, carrageenan, calcium sulfate, trisodium phosphate, citric acid and sodium phosphate as 
buffers, dimethicone antifoam emulsion. Preserved with methylparaben and potassium sorbate. 
6.1.1.2 
HRZE Tablets 
HRZE is a commercially available fixed dose combination of 4 TB drugs: isoniazid (H, 75 mg), 
rifampicin (R, 150 mg), pyrazinamide (Z, 400 mg), and ethambutol (E, 275 mg)  
Rifafour® e-275 (Sanofi) tablets, a commercial presentation of HRZE approved and available in 
South Africa, will be used in this study. 
See package insert 1 (also enclosed in the study specific manual) for information on the 
composition of Rifafour® e-275 tablets. 


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6.1.2. 
Intervention Cohorts 
During the Screening Phase participants will not receive TB treatment. 
Participants who meet all inclusion and none of the exclusion criteria at the end of the Screening 
Phase will be enrolled sequentially in one of 5 cohorts in 3 escalation steps and randomized as 
follows. 
• Cohort I: randomized to TBA-7371 oral suspension 100 mg QD OR HRZE tablets (Rifafour® 
e-275) QD for 14 days.  
• Cohort II and Cohort III:  randomized first to Cohort II OR Cohort III, and subsequently 
o 
Cohort II: randomized to TBA-7371 oral suspension 100 mg BID OR HRZE tablets 
(Rifafour® e-275) QD for 14 days.  
o 
Cohort III: randomized to TBA-7371 oral suspension 200 mg QD OR HRZE tablets 
(Rifafour® e-275) QD for 14 days. 
• Cohort IV: randomized to TBA-7371 oral suspension 100 mg TID OR HRZE tablets 
(Rifafour® e-275) QD for 14 days. 
• Cohort V: randomized to TBA-7371 oral suspension 400 mg QD OR HRZE tablets (Rifafour® 
e-275) QD for 14 days. 
On Day 15 all participants will switch to standard of care TB treatment as determined by the 
National Health System.   
6.1.3. 
Administration  
Study drugs will be prepared and administered in an unmasked (unblinded) fashion based on the 
randomization list by authorized and trained site staff members. 
All doses of study drug will be taken under direct observation of a study staff member. 
TBA-7371 oral suspension will be administered every day from study Day 1 to Day 14 once 
(Cohorts I, II and V), twice (Cohort II) or three times (Cohort III) daily (see Section 6.1.2). 
HRZE tablets (Rifafour® e-275) will be administered every day from study Day 1 to Day 14 QD 
as per Package Insert 1 as follows: 
• 40-54 kg: 3 tablets 
• 55-70 kg: 4 tablets 
• 71 kg and over: 5 tablets. 
If a patient’s weight changes between specified weight bands during the course of the Study 
Treatment period, the investigator will determine which of the measured weights to use for 
dosing.  
The 1st dose of study drug will be administered at the same time each day for the individual 
participant. Subsequent doses will be administered as follows:  
• BID schedules: 12 hours after 1st dose 
• TID schedule: 7 hours and 14 hours after 1st dose.  
Fasting must occur at least 2 hours before dosing and at least 1 hour after dosing. 


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When the dosing timing coincides with the time of other procedures, dosing will occur after 
completion of the procedures. It is important that dosing occurs at the assigned time. Procedures 
should be timed accordingly i.e. start before dosing time as appropriate.  
6.2. 
Preparation/Handling/Storage/Accountability 
6.2.1. 
Preparation 
TBA-7371 will be prepared extemporaneously for 250 mL or 500 mL of a 25 mg/mL 
suspension. Please refer to the study specific manual(s) for preparation details.  
Commercial HRZE tablets (Rifafour® e-275) will be provided.  
6.2.2. 
Handling 
TBA-7371 oral suspension will be transferred and stored in Pyrex glass reagent bottles with a 
polypropylene screw cap without a liner. These bottles will be used for mixing, sampling and 
storage prior to administration. The required doses of the drug product will be dispensed using 
commercially available oral syringes of suitable capacity. The suspension will be dispensed just 
prior to dosing and not stored in the oral syringes. 
6.2.3. 
Storage 
Based upon the supportive stability study data, the recommended storage condition for batches of 
TBA-7371 oral suspension clinical trial material is 2-8°C (36-46°F). A do-not-use-beyond-date 
of 7 days after compounding has been assigned. 
Rifafour® e-275 tablets will be stored in a cool place, below 25°C as per Package Insert.1   
The study pharmacist (or designee) must confirm appropriate temperature conditions have been 
maintained during transit and during site storage for all study drugs received and that any 
discrepancies are reported and resolved before use. Upon receipt of study drug supplies, the 
study pharmacist (or designee) must immediately inspect supplies for damage. Any damage or 
discrepancy from the packing list must be documented and promptly discussed with the sponsor 
or CRO representative to determine the appropriate action. 
6.2.4. 
Accountability 
Only participants enrolled in the study may receive study drug and only authorized site staff may 
supply or administer study drug. All study drug must be stored in a secure, environmentally 
controlled, and monitored (manual or automated) area in accordance with the labeled storage 
conditions with access limited to the investigator and authorized site staff. 
The principal investigator is responsible for study drug accountability, reconciliation, and record 
maintenance (i.e., receipt, reconciliation, and final disposition records). 
Authorization for any unused study drug and supplies to be destroyed is the responsibility of the 
sponsor. Unused supplies will be destroyed according to the facility’s SOPs or per local 
regulations. Any disposal of study drug conducted at the clinical site must be documented in the 
study file.  


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Further guidance and information for the preparation, handling, storage and accountability are 
provided in the study specific manual(s). 
6.3. 
Measures to Minimize Bias: Randomization and Masking 
6.3.1. 
Randomization  
Participants will be enrolled in one of 5 cohorts in 3 sequential escalation steps as follows. 
• Cohort I: TBA-7371 100 mg QD or HRZE (Rifafour® e-275) QD for 14 days.  
➢ First escalation step (from Cohort I to Cohorts II and III). Participants will be randomized to 
Cohort II OR Cohort III. 
• Cohort II: TBA-7371 100 mg BID or HRZE (Rifafour® e-275) QD for 14 days.  
• Cohort III: TBA-7371 200 mg QD for or HRZE (Rifafour® e-275) QD for 14 days. 
➢ Second escalation step (from Cohort II and Cohort III to Cohort IV) 
• Cohort IV: TBA-7371 100 mg TID or HRZE (Rifafour® e-275) QD for 14 days. 
➢ Third escalation step (from Cohort IV to Cohort V) 
• Cohort V: TBA-7371 400 mg 400 QD or HRZE (Rifafour® e-275) QD for 14 days. 
Across Cohorts I, IV, and V, the design is non-randomized and open label, whereas the design is 
randomized with respect to Cohort II and III, which have the same total daily dose (200 mg). 
Within each cohort the design is randomized, active-controlled and open label. Within each 
cohort participants will be randomized unequally in a 5:1 ratio to TBA-7371 (N=15) or HRZE 
(N=3). 
Participants will be randomized on Day -1 or Day 1 based on a randomly-generated sequence of 
participant identification (identifier) numbers (randomization schedule) using a validated 
Interactive Voice/Web Response System (IVRS/IWRS). Before the study is initiated, the 
telephone number and call-in directions for the IVRS and/or the log in information and 
instructions for the IWRS will be provided to the study sites.  
6.3.2. 
Masking (Blinding) 
This study will be open label for study participants, study site personnel, IDMC members, 
laboratory personnel involved in PK measurements and all sponsor and CRO personnel. 
The study will instead be masked (blinded) for personnel involved in the conduct of all other 
laboratory procedures (including those for the primary endpoint).  
6.3.3. 
Masking Break  
Not applicable in this study. 
6.4. 
Study Intervention Compliance 
All doses of study drug will be taken under direct observation of a study staff member. 
Participant compliance with study intervention will be recorded on his/her eCRF. 


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6.5. 
Concomitant Therapy 
No TB drug must be taken during the Screening Phase.  
No TB drug other than study drugs (TBA-7371 and HRZE fixed dose combination) must be 
taken during the Study Treatment Phase (Days 1-14).  
At the start of the Follow-up Phase (Day 15) participants will be switched to standard of care TB 
treatment.  
All treatments listed in the exclusion criteria 11 to 15 are also not allowed throughout the Study 
Treatment Phase and Follow-up Phase (Days 1 through 42).  
No vaccine should be administered during the trial. 
Any allowed prescription medication, anti-inflammatory drug and antipyretic drug that the 
participant receives from enrollment through study Day 42 must be recorded along with reason 
for use, dates of administration including start and end dates and dosage information including 
dose and frequency. 
The medical monitor may be contacted if there are any questions regarding concomitant or prior 
therapy. 
6.6. 
Dose Modification 
No dose modification of study drug is allowed.  
6.7. 
Intervention after the End of the Study 
There is no intervention planned after the end of the study.  


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7. 
Discontinuation of Study Drug and Participant Discontinuation/ 
Withdrawal 
7.1. 
Pausing and Resumption of Study Drug and Recruitment 
If any one of the conditions listed below apply, an investigator and/or the sponsor will pause 
enrollment and study drug administration. If an investigator observes that a pausing rule is met, 
he/she will inform the sponsor as soon as possible and within 24 hours of the event. The sponsor 
will notify all investigators and IDMC of the pause in enrollment as soon as possible and within 
24 hours of the event. The IDMC will then review all relevant safety data in an ad hoc meeting 
and recommend to the sponsor how to proceed. If the IDMC observes that a pausing rule is met, 
the IDMC will inform the sponsor ASAP and within 24 hours of the observation. The IDMC 
charter describes these processes in more detail. 
If any of the below conditions are met, enrollment and administration of study drug will be 
paused: 
• anaphylaxis with or without bronchospasm within 4 hours of study drug intake, indicative of 
an immediate hypersensitivity reaction; 
• 3 or more of participants in the same or different cohorts experience adverse events with Grade 
3 or higher intensity, considered related to study drug and similar to one another, as assessed 
by the investigator and/or the IDMC and/or the sponsor; 
• an AE pattern of concern, as assessed by the investigator and/or the IDMC and/or the sponsor; 
The decision to pause the study will be recorded in a memorandum to the study file and will 
trigger IDMC review. 
IDMC recommendations will be recorded in a memorandum to the study file.  
The IDMC may recommend resumption of study drug administration and enrollment with or 
without changes to the protocol.  
The final decision to resume study activities or amend the protocol will be made by the sponsor.  
The clinical site will be allowed to resume activities upon receipt of written notification from the 
sponsor.  
Upon resumption of study drug administration, participants who will have missed up to 1 
treatment day will continue in the study; participants who will have missed more than 1 
treatment day will be withdrawn from the study and possibly replaced if the enrollment pause 
results in more than 2 early withdrawals (drop-outs) in a cohort.  
7.2. 
Participant Discontinuation/Withdrawal from the Study 
A participant will discontinue study treatment and end in-clinic hospitalization if the participant 
tests positive for COVID-19/SARS-CoV-2 anytime during the study treatment period, and will 
be referred for on-going TB treatment per national guidelines and for further evaluation for 
COVID-19.  If the participant allows and the PI agrees, telephone follow-up may be completed 
in place of onsite visits on Day 28 and Day 42. 
 


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A participant may withdraw from the study at any time or may be withdrawn at any time at the 
discretion of the investigator for safety, behavioral, compliance, or administrative reasons. This 
is expected to be uncommon. The participant will be permanently discontinued both from the 
study intervention and from the study at that time. 
See Section 10.1.5 (Appendix 1) regarding the participants’ right to withdraw. 
Participants who withdraw before Day 14 will be asked to complete the Early Withdrawal Visit 
assessments within 2 days of withdrawal (see Section 8.3.8).  
Participants who complete the Study Treatment Phase, but do not return for the Day 28 visit will 
be asked to return for the Day 42 visit. 
If a participant withdraws from the study, he/she may request destruction of any samples taken 
and not tested, and the investigator must document this in the site study records and the eCRF. 
7.3. 
Lost to Follow-up 
A participant will be considered lost to follow-up if he/she permanently leaves the hospital or 
refuses study procedures during the Study Treatment Phase or fails to return to the Day 28 and/or 
42 visits during the Follow-up Phase.  
In such cases the site must attempt to contact the participant and urge him/her  
• to return to the hospital and resume study procedures if no or 1 treatment day have been missed, 
OR 
• undergo the Early Withdrawal Visit, OR 
• reschedule missed Day 28 or Day 42 visit as soon as possible.  
Before a participant is deemed lost to follow up, the investigator or designee must make at least 3 
attempts to regain contact with the participant (where possible, telephone calls and, if necessary, 
a home visit by a member of the study team). These contact attempts should be documented in 
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8. 
Study Assessments and Procedures 
Study procedures and their timing are summarized in the SoA (Section 1.3, Table 3 and Table 4). 
Protocol waivers or exemptions are not allowed. 
A ± 15-minute time window is allowed for all measurements. 
8.1. 
Screening Assessments and Procedures 
Prior to any study procedure, all eligible participants will be assigned a unique participant 
identifier. This participant identifier will be used throughout the study for participant 
identification.  
Screening procedures will be conducted during the 7-day screening period. Screening 
assessments can be done at any time during this period, except for the written informed consent, 
which must be given before any screening is started, the overnight sputum collection for 
eligibility assessment and the screening sample for COVID-19/SARS-CoV-2, which must be 
completed on or before Day -3, and the overnight sputum collection for EBA assessment, which 
much be done consecutively on Day -2 and Day -1. Participants may be hospitalized for the 
entire screening period at the investigator’s discretion, but must be hospitalized starting on 
Day -3. Eligibility for randomization will be based on the inclusion and exclusion criteria 
described in Sections 5.1 and 5.2. 
Eligibility criteria will be checked during the Screening Phase and prior to study drug 
administration to ensure that each randomized participant meets all the inclusion criteria and 
none of the exclusion criteria. The investigator will also maintain a screening log to record 
details of all participants screened, to confirm eligibility or record reasons for screening failure, 
as applicable. 
To evaluate eligibility criteria, the following assessments / procedures will be conducted: 
• Demography and medical and treatment history  
• Physical examination (PE) 
• Chest x-rays  
• COVID-19/SARS-CoV-2 test 
• Serum HIV test and blood CD4 count 
• Serum pregnancy test in female participants 
• Laboratory safety tests (haematology, chemistry, coagulation, urinalysis) 
• Urine isoniazid and drug screening 
• Overnight sputum for eligibility assessment (sputum volume, acid-fast bacilli, Mtb 
positivity and rifampicin sensitivity). Sputum assessment, including volume, will be 
performed by a Sponsor-approved central laboratory (see laboratory study instruction 
document). 
• Vital signs and weight 
• ECG 
• Eye assessment (visual acuity, color vision, eye symptoms) 


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Details on the assessments and procedures unique to the Screening Phase are provided in this 
section. Details on the assessments and procedures common to the Screening and Treatment 
Phase and/or Follow-up Phase are provided in the sections to follow. 
8.1.1. 
Demography and Medical and Treatment History  
Information on demographic characteristics (age, sex, place of birth, occupation, number of 
children) will be obtained and a medical and treatment history will be conducted during the 
Screening Phase to assess eligibility. All conditions that exist prior to the Screening Phase will 
be recorded in the medical history section of the ICF. Any clinically relevant new condition or 
fluctuation of existing condition observed during the Screening Phase will be recorded as AE. 
Day to day fluctuations in these conditions that do not represent a clinically relevant change in 
the participant’s status should not be reported as AE (see Section 0). 
8.1.2. 
Chest X-Rays 
Good quality Posterior-Anterior (PA) chest X-rays will be accepted to assess eligibility if 
conducted within 1 week prior to the start of the screening period. If not available, PA chest 
X-rays will be conducted during the Screening Phase. 
Chest X-rays consistent with TB in the investigator’s opinion is one of the conditions that must 
be met for the diagnosis of untreated rifampicin-sensitive pulmonary TB (Inclusion Criteria, 
Section 5.1). 
8.1.3. 
COVID-19/SARS-CoV-2 
In accordance with the SAHPRA Policy on Conduct of Clinical Trials of Health Products during 
the Current COVID-19 Pandemic, issued 25 March 2020, this protocol amendment reflects the 
new and modified processes that were implemented in response to COVID-19. This amendment 
accommodates for changes related to the pandemic that are needed to minimize risk of 
transmission of SARS-CoV-2 among participants and staff and builds on strong infection control 
site practices, which are already in place, to reduce risk of TB transmission as an airborne 
infectious disease. 
PCR-based COVID-19/SARS-CoV-2 testing will be conducted by the site and a negative result 
must be confirmed prior to randomization. In case of a positive COVID-19/SARS-CoV-2 test 
during the screening period, the participant will be excluded per the Exclusion Criterion in 
Section 5.2.  
8.1.4. 
HIV Test and CD4 Count 
HIV test with CD4 cell count will be conducted during the Screening Phase to assess eligibility. 
Details on blood/serum collection procedures, and on the laboratory are provided in the study 
specific manual(s). In case of positive HIV test, the participant will be excluded per the 
Exclusion Criteria, Section 5.2. 
8.1.5. 
Urine Isoniazid Screening 
Participants are eligible for this study if they have received no TB treatment for at least 3 months 
prior to Day 1 (Exclusion Criteria, Section 5.2). Urine isoniazid screening will be conducted 


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during the Screening Phase to support no recent TB therapy. Details on urine collection 
procedure, and on the laboratory are provided in the study specific manual(s). 
8.1.6. 
Urine Drug Screening 
Urine screening for cocaine, amphetamines, opiates and methamphetamines will be conducted 
during the Screening Phase to assess eligibility (Exclusion Criteria, Section 5.2). The same urine 
sample will also be screened for cannabinoids and results documented; however, a positive test 
for cannabinoids is not an exclusion criterion. Details on urine collection procedure and on the 
laboratory are provided in the study specific manual(s). 
8.1.7. 
Overnight Sputum for Eligibility Assessment  
Overnight sputum (collected from 3 PM to 7 AM of the following morning) will be collected 
between Day –7 and Day -3 and analyzed to assess eligibility through the sputum volume 
measurement, acid-fast bacilli detection and molecular tests for Mtb positivity and rifampicin 
sensitivity.  If inclusion criteria cannot be met from the 1st overnight sputum collection, a second 
overnight sputum sample may be collected during Day -7 to Day -3 and one or more of the above 
procedures can be repeated. The patient must be domiciled at the site for the overnight sputum 
collection and sputum samples will be analyzed by a Sponsor-approved central laboratory. 
8.1.7.1. 
Overnight Sputum Volume  
Participants must be able to produce at least 10 mL of sputum during the overnight collection 
(Inclusion Criterion, Section 5.1). If this volume is not reached on the sample(s) taken between 
Day -7 and Day -3, the participant will be excluded. All volume assessments will be performed 
by a Sponsor-approved central laboratory (see laboratory study instruction document). 
8.1.7.2. 
Acid-fast bacilli detection  
Acid-fast bacilli will be sought by concentrated smear microscopy on a sputum sample obtained 
from the overnight collection performed between Day -7 and Day -3. In case of suboptimal 1st 
overnight sputum collection, the microscopy can be conducted on a 2nd overnight sputum 
collected between Day -7 and Day -3. 
Details on the acid-fast bacilli detection methods and on the laboratory are provided in the Study 
Laboratory Manual.  
Sputum smear positivity for acid-fast bacilli is defined as at least 1+ on the IUATLD/WHO 
scale. Sputum positivity for acid-fast bacilli is one of the conditions that must be met for the 
diagnosis of untreated rifampicin-sensitive pulmonary TB (Exclusion Criteria, Section 5.2). 
8.1.7.3. 
Molecular tests for Mtb positivity and rifampicin sensitivity 
A commercial molecular test to assess Mtb positivity and rifampicin sensitivity, GeneXpert® 
diagnostic system (Cepheid), will be carried out on a sputum sample obtained from the overnight 
collection taken between Day -7 and Day -3. In case of inconclusive results from the 1st 
overnight sputum sample, the GeneXpert® can be conducted on a 2nd overnight sputum collected 
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Mtb positivity and rifampicin sensitivity are among the conditions that must be met for the 
diagnosis of untreated rifampicin-sensitive pulmonary TB (Exclusion Criteria, Section 5.2). 
Details on procedures for GeneXpert® test are provided in the Study Laboratory Manual. 
8.2. 
Bactericidal Activity Assessment 
8.2.1. 
Overnight Sputum for EBA assessment and Exploratory Measurements 
Overnight sputum will be collected from 3 PM to 7 AM of the following morning.  
The overnight sputum samples collected on Day -2 and Day -1 of the Screening Phase will be 
used to determine baseline EBA. Subsequent overnight sputum samples will be collected every 
day/night (Day 1 to Day 14) to assess changes in bacterial burden during the Study Treatment 
Phase. 
Early bactericidal activity will be assessed on each sputum sample by 3 different methods: 
1) CFU on solid media culture (primary), 2) time to sputum culture positivity (TTP) in MGIT 
culture, 3) LAM assay. Confirmation of Mtb will be performed on solid media and MGIT 
cultures as necessary using available commercial methods. 
A commercial molecular test to assess isoniazid and rifampicin sensitivity, GenoType 
MTBDRplus (HAIN Lifesciences), will be utilized on positive MTB cultures from Day -2 (or, if 
Day -2 unavailable, Day -1) and Day 14 to assess the drug susceptibilities at each visit. In 
addition, MICs of TBA-7371 will be batch tested on positive MTB cultures from Day -2 (or, if 
Day -2 unavailable, Day -1) and Day 14. 
Extra samples from overnight sputum collections, as well as MTB isolates from cultures, will be 
stored for potential assessment of exploratory endpoints (see Section 8.10).  
Details on sputum collection, handling and testing procedures, and on the laboratory are 
provided in the laboratory study instruction document. 
8.2.2  Samples for exploratory endpoints 
Daily urine samples will be collected and stored for exploratory biomarker development that 
may include establishing the kinetics of LAM reduction following treatment. 
Daily spot sputum samples will be collected into RNA preservation media (e.g., GTC-TCEP) 
and stored for measurements of transcriptomic-based biomarkers, which may include 
mycobacterial as well as host transcription markers. The participant should spontaneously 
produce (i.e., not induced) a spot sputum specimen for collection into RNA preservation media at 
each specified visit. If the specimen cannot be collected due to participant inability to produce 
sputum, or due to operational limitations with RNA media collection kits, it is not considered a 
protocol deviation and participants remain eligible for trial participation. 
Serum samples will be stored for potential assessment of the alteration of mycobacterial and host 
proteins following treatment. 
Additional exploratory biomarkers may be evaluated. Details of exploratory objectives will be 
included in separate operational and/or analysis plans. Results of exploratory objectives may be 
reported separately from the main clinical study report.  


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8.3. 
Safety Assessments 
Immediate safety concerns should be discussed with the sponsor and/or CRO immediately upon 
occurrence or awareness.  
d. Adherence to the requirements of the study protocol, including those specified in the SoA 
(Section 1.3, Table 3 and Screening (Days -7 to -1). Screening procedures will be conducted during the 
up to 7-Day screening period. Screening assessments can be done at any time during this period, except for 
the written informed consent, which must be given before any screening is started, the overnight sputum 
collection for eligibility assessment, which must be completed on or before Day -3, and the overnight 
sputum collection for EBA, which must be done consecutively on Day -2 and Day -1. Subjects may be 
hospitalized for the entire screening period at the investigator’s discretion, but must be hospitalized starting 
on Day -3. 
e. Follow-up (Days 15 to 42). Allowed window for Day 28 and Day 42 visits: +/- 3 Days. 
f. Early Withdrawal Visit (EWV) or Unscheduled Visit. Participants who withdraw before Day 14 will be 
asked to complete the EWV assessments within 2 Days of withdrawal. Participants who complete the Study 
Treatment Phase, but do not return for the Day 28 visit will be asked to return for the Day 42 visit. If access 
to sites is limited due to the local status of COVID-19 pandemic, the Day 28 and Day 42 visits could 
potentially be conducted by telephone.  Procedures and assessments conducted during an unscheduled visit 
will be at the discretion of the investigator in consultation with the medical monitor. 
18. Written informed consent will be given before any screening procedure is started. 
19. Hospital admission and discharge. Study participants will be hospitalized by Day -3 of the Screening 
Phase and will remain in hospital until the Day after the last dose of study drug is dispensed (Day 15). 
Discharge from hospital will occur on Day 15 after all procedures planned for that Day are completed. 
Upon discharge, participants will be referred to the national TB treatment program for standard of care 
(SoC) treatment. 
20. Physical examination (PE). Full PE will be conducted during the Screening Phase; focused PE (guided by 
medical history) will be conducted on Days 7, 15, 28, 42. Focused PE will be conducted at EWV if the 
participant discontinues between Day 1 and Day 14. Focused PE may be conducted during an 
unscheduled visit at the discretion of the investigator. 
21. Chest X-rays. Good quality Posterior-Anterior chest X-rays will be accepted if conducted within 1 week 
prior to Day -7. If not available, chest X-rays will be conducted during the Screening Phase. 
22. Blood/serum sample collection for clinical safety laboratory assessment. The Day 3 and 7 sampling will 
occur before the 1st dose of study drug.  
23. Urine sample collection drug screening: cannabinoids, cocaine, amphetamines, opiates, 
methamphetamines. 
24. Overnight sputum collection for eligibility assessment. Sputum assessment, including volume, will be 
performed by a Sponsor-approved central laboratory (see laboratory study instruction document). The 1st of 
the 3 overnight sputum collections (Day -7 to Day -3) conducted during the Screening Period will be used 
to assess eligibility as follows: sputum volume (must be at least 10 mL), acid-fast bacilli detection, 
Mycobacterium tuberculosis (Mtb) positivity and rifampicin sensitivity via the GeneXpert® diagnostic 
system (Cepheid). In case inclusion criteria cannot be met from the 1st overnight sputum collection, one or 
more of the above procedures can be conducted on a 2nd overnight sputum collected during the Day -7 to -3 
screening period if the patient is domiciled at the site for both.  
25. Vital sign and body weight recording. The following 5 vital signs will be recorded: axillary body 
temperature (BT), respiratory rate (RR), heart rate (HR), systolic blood pressure, (SBP), diastolic blood 
pressure (DBP). Body weight (BW) will also be recorded with vital signs. Vital signs and body weight will 
be recorded as follows: 
• Screening Phase: vital signs and BW once in the morning at approximately the same time the 1st daily 
dose study drug will be administered. SBP, DBP and HR can be repeated twice if exclusion criteria are 
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• Study Treatment Phase: vital signs and BW once every morning (Days 1 to 14) before administration of 
the 1st daily dose of study drug; in addition, on Days 1, 4, 7, 10 and 14 vital signs will also collected 2.5h, 
10.5h and 16.5h after the time of 1st daily dose of study drug (see Table 4). 
• Follow-up Phase: vital signs and BW on Day 15 in the morning before 1st daily dose of SoC medication; 
on Days 28 and 42 during the visit. 
• EWV: vital signs and BW if the participant withdraws from the study between Day 1 and 14. 
At each time point BT, RR and BW will be measured once, whereas HR, SBP and DBP will be measured 
twice as follows: after 10 min supine (“manual, supine”) and after 2 (±0.5) min standing (“manual, 2-min 
standing”). When ECG, vital signs and/or blood/serum samples are to be obtained at the same time point, 
the following order must be followed: ECG, vital signs, blood/serum sample, within 5 min of each other. 
26. ECG recording. 12-lead ECG will be recorded once at each time point after at least 10 minutes of supine 
rest as follows: 
• Screening Phase: once in the morning at approximately the same time the 1st daily dose study drug will 
be administered. 
• Study Treatment Phase: on Days 1, 4, 7, 10 and 14 before administration of the 1st daily dose of study 
drug and 2.5h, 10.5h and 16.5h thereafter (see Table 4). 
• Follow-up Phase: on Day 15 in the morning before 1st daily dose of standard of care medication; on Days 
28 and 42 during the visit. 
• EWV: if the participant withdraws from the study between Day 1 and 14. 
27. Eye assessment. A trained staff member will assess:  i) eye symptoms using a standardized script (Section 
10.5, Appendix 5), ii) visual acuity by means of the Rosenbaum Pocket Eye Screener, iii) color vision by 
means of the Waggoner Computerized Color Vision Test and as follows: 
• 
Screening Phase: once in the AM. 
• 
Study Treatment Phase: Days 1, 4, 7, 10, and 14, 2.5h after 1st daily dose of study drug (see Table 4). 
• 
Follow-up Phase: Days 15, 28 and 42 during the visit. 
• 
EWV: if the participant withdraws from the study between Days 1 and 14.  
28. Study drug (IMP) administration. Study drug (TBA-7371 or HRZE) will be administered from Day 1 to 
Day 14 based on the randomization list by an authorized and trained site staff member. The 1st dose of 
study drug will be administered at the same time each Day for the individual participant. Subsequent doses 
will be administered as follows (see Table 4):  
• Twice daily (BID) schedules: 12h after 1st dose 
• Three times (TID) daily schedule: 7h and 14h after 1st dose   
Fasting must occur at least 2 hours before dosing and at least 1 hour after dosing. Study drug administration 
will be followed by 200 mL water. 
29. Overnight sputum collection for EBA assessment and exploratory measurements. Overnight sputum 
will be collected from 3 PM to 7 AM of the following Day (16 hours) on Days -2 and -1 during Screening 
Phase and on 14 consecutive Days during the Study Treatment Phase (Days 1 to 14) for EBA assessment. 
The last collection will finish at 7 AM of Day 15. Drug susceptibility testing for isoniazid and rifampicin, 
and minimum inhibitory concentrations (MIC) of TBA-7371 will be performed on either of Day -2 or Day -
1, and again on Day 14. Aliquots from each sample, as well as MTB isolates from cultures, will be stored 
and may be used for exploratory measurements.  
30. Spot sputum collection for exploratory measurements. The participant should spontaneously produce 
(i.e., not induced) a spot sputum specimen for collection into RNA preservation media. If specimen cannot 
be collected due to participant inability to produce sputum, or due to operational limitations with RNA 
media collection kits, it is not considered a protocol deviation. 
31. Recording of AE, SAE (including serious ADR) and AESI; recording of concomitant treatments. 
Adverse events (AE), serious adverse events (SAE), including serious adverse drug reactions (ADR), 
adverse events of special interest (AESI) and concomitant treatments will be recorded from the time each 
participant has signed the informed consent form (ICF) until he/she has completed the last follow- up visit 
(Day 42) or the Early Withdrawal Visit (EWV). 
32. Blood/serum sample collection for PK measurements. WILL BE CONDUCTED ONLY IN 
PARTICIPANTS RANDOMIZED TO TBA-7371. Timing of sampling will be as follows: 


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• Study Treatment Phase: Days 1, 2, 4, 7 and 14 before administration of the 1st daily dose of study drug; in 
addition, on Days 1, 7 and 14 samples will also collected 30 min (+/- 5 min) and at 1h, 2.5h, 3h, 4h, 6h, 
7h, 10.5h, 12h, 16.5h (+/- 15 min) after 1st daily dose of study drug. (see Table 4).  Patients assigned to 
BID dosing will not have collections at 16.5h, and the 12h sample will be taken prior to the second daily 
dose. Patients assigned to TID dosing will not have collections at 10.5h, 12h and 16.5h, and the 7h 
sample will be taken prior to the second daily dose.  
When timing coincides, samples must always be taken after recording of ECG and vital signs.  
33. Blood/serum/plasma sample collection for exploratory measurements. Timing of sampling will be as 
follows:  
• Study Treatment Phase: Day 1 and 7 before administration of the 1st daily dose of study drug (see Table 
4). 
• Follow-up Phase: Day 15 in the morning at approximately the same time study drug was administered. 
34. Coronavirus Disease (COVID-19) / Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-
2 Testing). COVID-19 testing will be conducted via PCR using a test product authorized by SAHPRA at an 
accredited public or private sector laboratory. A specimen will be collected during the screening period 
between Day-7 to Day -3, and a negative result must be confirmed prior to randomization. For safety 
monitoring purposes, testing will also be performed at Day 7 (±2 Days), on Day 14 OR Day 15 before 
discharge, and/or at any other time that infection is suspected. 
 


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Table 4) is essential and required for study conduct. 
Safety outcomes will include AE and SAE described in Section 8.4 and 
Section 10.2 (Appendix 2). 
8.3.1. 
Physical Examination  
A full PE, including height, will be conducted during the Screening Phase to assess eligibility. 
A focused PE will be performed as directed by medical history on Days 7, 15, 28 and 42. If early 
withdrawal occurs between Day 1 and Day 14, a focused PE should be conducted at the Early 
Withdrawal Visit.  A focused PE may be conducted during an unscheduled visit at the discretion 
of the investigator. 
8.3.2. 
COVID-19/SARS-CoV-2 
PCR-based COVID-19/SARS-CoV-2 testing will be conducted at Day 7 (±2 Days), on Day 14 
OR Day 15 before discharge, and/or at any other time that infection is suspected. In case of 
positive COVID-19/SARS-CoV-2 test during the study treatment period, the participant will 
discontinue study treatment, will end in clinic hospitalization, and will be referred for on-going 
TB treatment per national guidelines and for further evaluation for COVID-19.  In case of a 
positive COVID-19/SARS-CoV-2 test on Day 14 or Day 15 at the end of the study treatment 
period, participants will be referred for on-going TB treatment per national guidelines and for 
further evaluation for COVID-19.  
8.3.3. 
Pregnancy Status Assessment 
A serum beta human chorionic gonadotropin (βHCG) test will be performed during the 
Screening Phase to assess eligibility, on Day 15, (the day after the last dose of study drug) and on 
Day 42 (end of the Follow-up Phase). The test will also be conducted during the Early 
Withdrawal Visit if the participant withdraws from the study between Day 1 and 14. 
Details on serum collection procedures and on the laboratory are provided in the study specific 
manual(s). 
If a pregnancy is reported during the study, the investigator should inform the local medical 
monitor within 24 hours of learning of the pregnancy and should follow the procedures outlined 
in Section 10.3 (Appendix 3). 
If a participant becomes pregnant during the study, she will be withdrawn from study drug and 
from all study procedures going forward. If the pregnancy is discovered during the Treatment 
Phase, the participant will undergo the Early Withdrawal Visit and thereafter be discharged from 
the hospital. However, she will be encouraged to undergo the Day 28 and Day 42 visits. 
Investigators must make an effort to collect outcomes of pregnancies discovered during the study 
and communicate them to the sponsor and/or CRO. 
8.3.4. 
Clinical Safety Laboratory Assessments  
Clinical safety laboratory assessments will be performed during the Screening Phase to assess 
eligibility, during the Treatment Phase on Day 3 and 7, and during the Follow-up Phase on Days 


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15 and 42. If early withdrawal occurs between Day 1 and Day 14, clinical safety laboratory 
assessments should be conducted at the Early Withdrawal Visit. 
Clinical safety laboratory parameters include: 
• haematology: complete blood count (red blood cells, haemoglobin, platelets and white blood 
cells) and differential (absolute counts) including neutrophils, lymphocytes, monocytes, 
eosinophils and basophils; 
• serum chemistry: Alanine aminotransferase (ALT), Aspartate aminotransferase (AST), ALP, 
total bilirubin, creatinine, blood urea nitrogen (BUN), sodium, and potassium;  
• serum coagulation: PT, PTT, INR 
• urinalysis: specific gravity, pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, 
nitrite, leukocyte esterase. 
Details on blood/serum and urine collection procedures and on the laboratory are provided in the 
study specific manual(s). 
Refer to DAIDS Table in Section 10.4 (Appendix 4), pages 25-31, for intensity (severity) 
grading of common laboratory tests. 
Certain clinical safety laboratory values from the samples collected during the Screening Phase, 
i.e. before randomization, that are outside the normal range with intensity (severity) Grade 2 or 
above, will lead to exclusion from study enrollment, as described in Section 5.2. Grade 1 
abnormalities or other Grade 2 and higher abnormalities will not lead to exclusion, unless the 
investigator considers them clinically significant.  
Abnormal results and findings that make the participant ineligible will be discussed with the 
participant and the participant will be referred for follow-up care with their healthcare provider if 
necessary.  
For laboratory values from the samples collected after randomization, the investigator will record 
any clinically significant change in the AE section of the CRF [see Section 10.2.1 (Appendix 2)]. 
DAIDS intensity (severity) grading of common laboratory tests reported in Section 10.4 
(Appendix 4), DAIDS Table, pages 25-31) will help the investigator in deciding whether or not a 
given laboratory finding is clinically significant and therefore qualifies as an AE. However, the 
investigator is not obliged to follow these criteria and his/her medical judgement should prevail.  
Abnormal laboratory findings are associated with an underlying disease are not clinically 
significant, unless judged by the investigator to be more severe than expected for the participant's 
condition [see Section 10.2.1 (Appendix 2)]. 
The laboratory reports must be filed with the source documents. 
Additional tests may be performed at any time during the study as determined necessary by the 
investigator or required by local regulations. 
If laboratory values from non-protocol specified clinical safety laboratory assessments require a 
change in participant management or are considered clinically significant by the investigator 
(e.g., AE or SAE), then the results must be recorded in the eCRF.  


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8.3.5. 
Vital signs and body weight 
The following 5 vital signs will be measured: axillary BT, respiratory rate (RR), HR, SBP, DBP. 
Body weight (BW) will also be measured with vital signs 
g. Vital sign and body weight recording will occur as follows (see Section 1.3, Table 3 and 
Screening (Days -7 to -1). Screening procedures will be conducted during the up to 7-Day screening 
period. Screening assessments can be done at any time during this period, except for the written informed 
consent, which must be given before any screening is started, the overnight sputum collection for eligibility 
assessment, which must be completed on or before Day -3, and the overnight sputum collection for EBA, 
which must be done consecutively on Day -2 and Day -1. Subjects may be hospitalized for the entire 
screening period at the investigator’s discretion, but must be hospitalized starting on Day -3. 
h. Follow-up (Days 15 to 42). Allowed window for Day 28 and Day 42 visits: +/- 3 Days. 
i. Early Withdrawal Visit (EWV) or Unscheduled Visit. Participants who withdraw before Day 14 will be 
asked to complete the EWV assessments within 2 Days of withdrawal. Participants who complete the Study 
Treatment Phase, but do not return for the Day 28 visit will be asked to return for the Day 42 visit. If access 
to sites is limited due to the local status of COVID-19 pandemic, the Day 28 and Day 42 visits could 
potentially be conducted by telephone.  Procedures and assessments conducted during an unscheduled visit 
will be at the discretion of the investigator in consultation with the medical monitor. 
35. Written informed consent will be given before any screening procedure is started. 
36. Hospital admission and discharge. Study participants will be hospitalized by Day -3 of the Screening 
Phase and will remain in hospital until the Day after the last dose of study drug is dispensed (Day 15). 
Discharge from hospital will occur on Day 15 after all procedures planned for that Day are completed. 
Upon discharge, participants will be referred to the national TB treatment program for standard of care 
(SoC) treatment. 
37. Physical examination (PE). Full PE will be conducted during the Screening Phase; focused PE (guided by 
medical history) will be conducted on Days 7, 15, 28, 42. Focused PE will be conducted at EWV if the 
participant discontinues between Day 1 and Day 14. Focused PE may be conducted during an 
unscheduled visit at the discretion of the investigator. 
38. Chest X-rays. Good quality Posterior-Anterior chest X-rays will be accepted if conducted within 1 week 
prior to Day -7. If not available, chest X-rays will be conducted during the Screening Phase. 
39. Blood/serum sample collection for clinical safety laboratory assessment. The Day 3 and 7 sampling will 
occur before the 1st dose of study drug.  
40. Urine sample collection drug screening: cannabinoids, cocaine, amphetamines, opiates, 
methamphetamines. 
41. Overnight sputum collection for eligibility assessment. Sputum assessment, including volume, will be 
performed by a Sponsor-approved central laboratory (see laboratory study instruction document). The 1st of 
the 3 overnight sputum collections (Day -7 to Day -3) conducted during the Screening Period will be used 
to assess eligibility as follows: sputum volume (must be at least 10 mL), acid-fast bacilli detection, 
Mycobacterium tuberculosis (Mtb) positivity and rifampicin sensitivity via the GeneXpert® diagnostic 
system (Cepheid). In case inclusion criteria cannot be met from the 1st overnight sputum collection, one or 
more of the above procedures can be conducted on a 2nd overnight sputum collected during the Day -7 to -3 
screening period if the patient is domiciled at the site for both.  
42. Vital sign and body weight recording. The following 5 vital signs will be recorded: axillary body 
temperature (BT), respiratory rate (RR), heart rate (HR), systolic blood pressure, (SBP), diastolic blood 
pressure (DBP). Body weight (BW) will also be recorded with vital signs. Vital signs and body weight will 
be recorded as follows: 
• Screening Phase: vital signs and BW once in the morning at approximately the same time the 1st daily 
dose study drug will be administered. SBP, DBP and HR can be repeated twice if exclusion criteria are 
met. 
• Study Treatment Phase: vital signs and BW once every morning (Days 1 to 14) before administration of 
the 1st daily dose of study drug; in addition, on Days 1, 4, 7, 10 and 14 vital signs will also collected 2.5h, 
10.5h and 16.5h after the time of 1st daily dose of study drug (see Table 4). 


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• Follow-up Phase: vital signs and BW on Day 15 in the morning before 1st daily dose of SoC medication; 
on Days 28 and 42 during the visit. 
• EWV: vital signs and BW if the participant withdraws from the study between Day 1 and 14. 
At each time point BT, RR and BW will be measured once, whereas HR, SBP and DBP will be measured 
twice as follows: after 10 min supine (“manual, supine”) and after 2 (±0.5) min standing (“manual, 2-min 
standing”). When ECG, vital signs and/or blood/serum samples are to be obtained at the same time point, 
the following order must be followed: ECG, vital signs, blood/serum sample, within 5 min of each other. 
43. ECG recording. 12-lead ECG will be recorded once at each time point after at least 10 minutes of supine 
rest as follows: 
• Screening Phase: once in the morning at approximately the same time the 1st daily dose study drug will 
be administered. 
• Study Treatment Phase: on Days 1, 4, 7, 10 and 14 before administration of the 1st daily dose of study 
drug and 2.5h, 10.5h and 16.5h thereafter (see Table 4). 
• Follow-up Phase: on Day 15 in the morning before 1st daily dose of standard of care medication; on Days 
28 and 42 during the visit. 
• EWV: if the participant withdraws from the study between Day 1 and 14. 
44. Eye assessment. A trained staff member will assess:  i) eye symptoms using a standardized script (Section 
10.5, Appendix 5), ii) visual acuity by means of the Rosenbaum Pocket Eye Screener, iii) color vision by 
means of the Waggoner Computerized Color Vision Test and as follows: 
• 
Screening Phase: once in the AM. 
• 
Study Treatment Phase: Days 1, 4, 7, 10, and 14, 2.5h after 1st daily dose of study drug (see Table 4). 
• 
Follow-up Phase: Days 15, 28 and 42 during the visit. 
• 
EWV: if the participant withdraws from the study between Days 1 and 14.  
45. Study drug (IMP) administration. Study drug (TBA-7371 or HRZE) will be administered from Day 1 to 
Day 14 based on the randomization list by an authorized and trained site staff member. The 1st dose of 
study drug will be administered at the same time each Day for the individual participant. Subsequent doses 
will be administered as follows (see Table 4):  
• Twice daily (BID) schedules: 12h after 1st dose 
• Three times (TID) daily schedule: 7h and 14h after 1st dose   
Fasting must occur at least 2 hours before dosing and at least 1 hour after dosing. Study drug administration 
will be followed by 200 mL water. 
46. Overnight sputum collection for EBA assessment and exploratory measurements. Overnight sputum 
will be collected from 3 PM to 7 AM of the following Day (16 hours) on Days -2 and -1 during Screening 
Phase and on 14 consecutive Days during the Study Treatment Phase (Days 1 to 14) for EBA assessment. 
The last collection will finish at 7 AM of Day 15. Drug susceptibility testing for isoniazid and rifampicin, 
and minimum inhibitory concentrations (MIC) of TBA-7371 will be performed on either of Day -2 or Day -
1, and again on Day 14. 
 
  
47
48. Recording of AE, SAE (including serious ADR) and AESI; recording of concomitant treatments. 
Adverse events (AE), serious adverse events (SAE), including serious adverse drug reactions (ADR), 
adverse events of special interest (AESI) and concomitant treatments will be recorded from the time each 
participant has signed the informed consent form (ICF) until he/she has completed the last follow- up visit 
(Day 42) or the Early Withdrawal Visit (EWV). 
49. Blood/serum sample collection for PK measurements. WILL BE CONDUCTED ONLY IN 
PARTICIPANTS RANDOMIZED TO TBA-7371. Timing of sampling will be as follows: 
• Study Treatment Phase: Days 1, 2, 4, 7 and 14 before administration of the 1st daily dose of study drug; in 
addition, on Days 1, 7 and 14 samples will also collected 30 min (+/- 5 min) and at 1h, 2.5h, 3h, 4h, 6h, 
7h, 10.5h, 12h, 16.5h (+/- 15 min) after 1st daily dose of study drug. (see Table 4).  Patients assigned to 


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BID dosing will not have collections at 16.5h, and the 12h sample will be taken prior to the second daily 
dose. Patients assigned to TID dosing will not have collections at 10.5h, 12h and 16.5h, and the 7h 
sample will be taken prior to the second daily dose.  
When timing coincides, samples must always be taken after recording of ECG and vital signs.  
50.
51. Coronavirus Disease (COVID-19) / Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-
2 Testing). COVID-19 testing will be conducted via PCR using a test product authorized by SAHPRA at an 
accredited public or private sector laboratory. A specimen will be collected during the screening period 
between Day-7 to Day -3, and a negative result must be confirmed prior to randomization. For safety 
monitoring purposes, testing will also be performed at Day 7 (±2 Days), on Day 14 OR Day 15 before 
discharge, and/or at any other time that infection is suspected. 
 


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Table 4). 
Screening Phase 
Vital signs and body weight 1 to 3 times (see below) in the morning at approximately the same 
time the 1st daily dose study drug will be administered. 
SBP, DBP and HR assessed as vital sign (i.e. not from ECG) will be used to assess eligibility 
(Exclusion Criteria, Section 5.2). An out-of-range value may be repeated twice with at least 5 
minutes intervening 
Study Treatment Phase 
Vital signs and body weight every morning (Days 1 to 14) before administration of the 1st daily 
dose of study drug. 
In addition, on Days 1, 4, 7, 10 and 14 vital signs will also be collected 2.5h, 10.5h and 16.5h 
after the time of 1st daily dose of study drug (see Table 5). 
Follow-up Phase 
Vital signs and body weight on Day 15 in the morning before 1st daily dose of standard of care 
medication  
Vital signs and body weight on Days 28 and 42 during the visit. 
Early Withdrawal Visit 
Vital signs and body weight if the participant withdraws from the study between Day 1 and 14. 
At each assigned time point, BT, RR and BW will be measured once, whereas HR, SBP and 
DBP will be measured twice as follows:   
• after at least 10 minutes in supine position (“manual, supine”) 
• after 2  minutes in standing position (“manual, 2-min standing”) 
If the rhythm is regular, manual measurement or automated blood pressure equipment may be 
used for HR and SBP/DBP determination. Pulse oximeter HR data should not be used. If the 
rhythm is irregular, the measurements should be done manually. 
When ECG, vital signs and/or blood/serum samples are to be obtained at the same time point, 
ECG will be recorded first after 10 minutes of supine rest, followed by the vital signs and then 
the blood draw(s) within 5 minutes of each other. 
The investigator must record any clinically significant abnormalities in vital signs occurring 
during the study as AE. DAIDS intensity (severity) grading of adverse events reported in Section 
10.4 (Appendix 4, page 7) may help the investigator in deciding whether or not a given finding is 
clinically significant and therefore qualifies as an AE. However, the investigator is not obliged to 
follow these criteria and his/her medical judgement should prevail.  
A HR, SBP or DBP AE emerging from both vital sign and ECG recording at the same time point 
must be reported only once, with the highest intensity and seriousness grading.  
Participants with vital signs-related AEs classified as ≥ Grade 3 severity and/or serious will 
contribute to the primary safety end-point (see Section 3.1, Table 1).  


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Participants with ≥ 25% increase in HR, and /or ≥ 25 % decrease in SBP and/or ≥ 25% decrease 
in DBP from baseline (Day 0) detected through vital signs measurements will contribute to 
secondary safety end-points (see Section 3.2, Table 2).  
Increases in HR and decreases in SBP and/or DBP from vital signs and/or ECG qualifying as 
AEs ≥ Grade 2 and/or serious are considered adverse events of special interest based on the 
outcomes of the Phase I trial TBA7371-001 [AESI, see Section 10.2.5, (Appendix 2)].  
8.3.6. 
ECG 
Centralized ECG reading will be used. Details on centralized ECG procedures are provided in 
the study specific manual(s).  
One ECG recording will occur at each of the following time points (see Section 1.3, Table 3 and 
Table 4): 
Screening Phase 
Once in the morning at approximately the same time the 1st daily dose study drug will be 
administered. 
This tracing will be used to assess eligibility (Exclusion Criteria, Section 5.2). Study Treatment 
Phase 
On Days 1, 4, 7, 10 and 14 before administration of the 1st daily dose of study drug and 2.5h, 
10.5h and 16.5h after the time of 1st daily dose of study drug (see Table 4). 
Follow-up Phase 
On Day 15 in the morning before 1st daily dose of standard of care medication; On Days 28 and 
42 during the visit. 
Early Withdrawal Visit 
If the participant withdraws from the study between Day 1 and 14. 
When ECG, vital signs and/or blood/serum samples are to be obtained at the same time point, 
ECG will be recorded first after 10 minutes of supine rest, followed by the vital signs and then 
the blood draw(s) within 5 minutes of each other. 
The investigator must record any clinically significant ECG abnormality occurring during the 
study as adverse events (AE). DAIDS intensity (severity) grading of cardiovascular adverse 
events reported in Section 10.4 (Appendix 4, page 7) may help the investigator in deciding 
whether or not a given finding is clinically significant and therefore qualifies as an AE. 
However, the investigator is not obliged to follow these criteria and his/her medical judgement 
should prevail. Important: a HR, SBP or DBP AE emerging from both vital signs and ECG 
recorded at the same time point must be reported only once, with the highest intensity and 
seriousness grading.  
Participants with ECG-related AEs classified as ≥ Grade 3 and/or serious contribute to the 
primary safety end-point (see Section 3.1, Table 5).  
Participants with ≥ 25% increase in HR, and /or ≥ 25 % decrease in SBP and/or ≥ 25% decrease 
in DBP from baseline detected through ECG recordings contribute to secondary safety end-
points (see Section 3.2, Table 6). 


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PR, RR, QRS, QT, QTcF intervals from ECG contribute to secondary safety end-points (see 
Section 3.2, Table 6) 
Increases in HR and decreases in SBP and/or DBP from vital signs and/or ECG qualifying as 
AEs ≥ Grade 2 and/or serious are considered AESI based on the outcomes of the Phase I trial 
TBA7371-001 [AESI, see Section 10.2.5 (Appendix 2)].  
8.3.7. 
Eye Assessment  
On each eye assessment day participants will undergo the following 3 eye assessment procedures 
(always in this order): 
i) Eye symptom assessment using the standardized script provided in Section 10.5 (Appendix 5) 
ii) Visual acuity test by means of the Rosenbaum Pocket Eye Screener on each eye. 
iii) Color vision by means of the Waggoner Computerized Color Vision Test on each eye. 
The visual acuity test and Waggoner Computerized Color Vision Test (updated computerized 
version of the paper-based ColorDX test) will be conducted by staff members trained by an 
ophthalmologist. Whenever possible the same staff member should conduct all eye assessment 
procedures on an individual participant. 
Details on use of the Rosenbaum Pocket Eye Screener and Waggoner Computerized Color 
Vision Test are provided in the study specific manual(s). 
The 3 eye assessment procedures will be conducted on each of the eye assessment days as 
follows:   
Screening Phase 
Once in the AM.  
This assessment will be used to assess eligibility (Exclusion Criteria, Section 5.2). 
Study Treatment Phase 
On Days 1, 4, 7, 10 and 14, 2.5 hours after the 1st daily dose of study drug (see Table 4).  
Follow-up Phase 
On Days 15, 28 and 42 during scheduled visit. 
Early withdrawal visit  
If the participant withdraws from the study between Day 1 and 14. 
Regarding eye symptoms, based on the outcome of study TBA7371-001, special attention will be 
paid to blurred vision, photophobia, altered color vision and increased lacrimation, but any other 
eye symptom will be assessed if it occurs (see Section 10.5, Appendix 5). 
Intensity (severity) grading of eye symptoms reported in Section 10.4 (Appendix 4, page 20) 
may help the investigator. However, the investigator is not obliged to follow these criteria and 
his/her medical judgement should prevail. The visual acuity and color vision tests will 
complement the clinical assessment of eye symptoms in the assessment of AE intensity and 
seriousness. 


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Any eye symptom and/or abnormal visual acuity / color vision test outcome considered clinically 
meaningful by the investigator must be recorded as AE. 
Participants with eye symptom-related AE classified as severe (≥ Grade 3) and/or serious will 
contribute to the primary safety end-point (see Section 3.1, Table 5). 
Participants with any eye symptom will contribute to secondary safety end-points (see 
Section 3.2, Table 6). 
Eye symptoms ≥Grade 2 intensity (severity) and/or severe are considered adverse events of 
special interest based on the outcome of the Phase I trial TBA7371-001 [AESI, see 
Section 10.2.5 (Appendix 2)].  
8.3.8. 
Early Withdrawal Visit 
Participants who withdraw from the study before Day 14 will be asked to complete the Early 
Withdrawal Visit assessments within 2 days of withdrawal. These are as follows (see Table 4): 
• Focused PE (see Section 0) 
• Pregnancy status assessment (see Section 8.3.3) 
• Clinical Safety laboratory assessments (see Section 8.3.4) 
• Vital signs and body weight (see Section 8.3.5) 
• ECG (see Section 0) 
• Eye assessment (see Section 8.3.7) 
• AE and SAE (see Section 0) 
• Concomitant treatments (see Section 8.5). 
Participants who complete the Study Treatment Phase, but do not return for the Day 28 visit will 
be asked to return for the Day 42 visit.  
If a participant withdraws from the study, he/she may request destruction of any samples taken 
and not tested, and the investigator must document this in the site study records and the eCRF. 
If a patient is withdrawn from the study due to a positive COVID-19/SARS-CoV-2 test and 
maintains consent, a telephone follow-up may be documented on Day 28 and Day 42. 
8.3.9. 
Unscheduled Visit 
Procedures and assessments conducted during an unscheduled visit will be at the discretion of 
the investigator in consultation with the medical monitor. 
8.3.10. 
Participant Follow-Up 
During the Follow-Up Phase participants will be instructed to contact by phone a study team 
member to report new or worsening AEs, as well as new diagnoses, and to come to the study 
clinic if medical attention is needed. 


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On Day 15, participants will be transferred to the local TB clinic, following completion of all 
study assessments. Unscheduled assessments may be performed, following transfer, for purposes 
of safety follow-up. 
In exceptional circumstances as assessed by the investigator in consultation with the medical 
monitor (e.g. issues related to COVID-19/SARS-CoV-2, etc.), participants may have telephone 
follow up for Day 28 and Day 42.  
All deviations from protocol procedures, evaluations, and/or visits will be documented.  
8.4. 
Adverse Events and Serious Adverse Events 
The definitions of AEs, SAEs, serious adverse drug reactions (Serious ADRs) and AESI can be 
found in Section 10.2.1, 10.2.2, 10.2.4, and 10.2.5 (Section 10.2, Appendix 2), respectively. 
Study nurses and physicians are responsible for collecting and documenting information and 
events that would potentially meet the definition of an AE. However only the investigator (study 
physician) is responsible for assessment, including assignment of causality seriousness and 
intensity, reporting and management of all AE. The investigator is responsible for following up 
AE that are serious, considered related to the study intervention or study procedures, or that 
caused the participant to discontinue the study (Section 7). 
8.4.1. 
Time Period for Collecting AE Information 
AE, SAE (including Serious ADR) and AESI will be collected from the time each participant has 
signed the ICF until he/she has completed the last follow-up visit (Day 42) or the EWV. 
All SAE (including Serious ADR) and AESI will be reported to the sponsor or designee within 
24 hours, as indicated in Section 10.2.5 (Appendix 2). The investigator will submit any updated 
SAE/AESI data to the sponsor or designee within 24 hours of it being available. 
The investigator is not obligated to actively seek AE or SAE after conclusion of study 
participation. However, if the investigator learns of any SAE, including a death, at any time after 
a participant has been discharged from the study, and he/she considers the event to be related to 
the study intervention or study participation, the investigator must promptly notify the sponsor. 
8.4.2. 
Methods of Detection of AE and SAE 
The methods of detection, recording and follow-up of AE and SAE are provided in detail in 
Section 10.2.5 (Appendix 2), which includes assessments of intensity (severity), causality, 
expectedness and outcome of AEs and SAE.  
8.4.2.1. 
Recording of AE and SAE 
When an AE or SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g. hospital progress notes, laboratory reports, and diagnostics reports) related 
to the event and record all relevant information in the appropriate section of the CRF.  
Care should be taken not to introduce bias when detecting AE and SAE/AESI: open-ended and 
non-leading questions are the preferred method to inquire about AE occurrences.  
Refer to Section 10.2.5 (Appendix 2), Follow-up of AE and SAE/AESI. 


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After the initial AE/SAE/AESI report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAE will be followed until resolution, stabilization, 
or the participant is lost to follow-up (as defined in Section 7.3).  
Refer to Section 10.2.5 (Appendix 2). Assessment of Intensity (Severity) of AE and SAE/AESI. 
Clinical signs and symptoms that constitute AE/SAE/AESI will be classified by the investigator 
as mild (Grade 1), moderate (Grade 2), severe (Grade 3), potentially life threatening (Grade 4), 
death (Grade 5). Refer to Section 10.2 (Appendix 2). 
Grading criteria reported in in the DAIDS Table, Section 10.4 (Appendix 4) may help in the 
assessment of intensity of AEs. Additional grading criteria reported in Section 10.5 (Appendix 5) 
may help in the assessment of intensity of selected eye symptoms. However, the investigator is 
not obliged to follow these criteria and his/her medical judgement should prevail.   
Participants with AE classified as severe (Grade 3 and above) will contribute to the primary 
safety end-point (see Section 3.1, Table 5).  
8.4.2.2. 
Assessment of Causality of AE and SAE 
All AE will be evaluated by the principal investigator (PI) or by a medically qualified designee 
(i.e. investigator, study physician) to assess the relationship between study intervention and each 
occurrence of each AE/SAE/AESI. Careful medical judgement should be exercised to determine 
the level of causal relationship between an AE and the study intervention. The causality 
assessment will be determined using a two-level scale: related or not related.  
The sponsor or designee will have the opportunity to confirm the seriousness and case causality 
based on the clinical judgement of the medical monitor and sponsor designee. If a SAE is 
considered unrelated by the investigator but the sponsor believes that there is a reasonable 
possibility that the event is related, the sponsor will upgrade the case to a ‘related’ status. The 
sponsor or designee will never downgrade a case from serious to non-serious or related to not 
related. 
Refer to Section 10.2.6.4 (Appendix 2). 
8.4.2.3. 
Assessment of AE/SAE Expectedness 
Each SAE will be evaluated by the sponsor. based on applicable product information (e.g. 
Investigator Brochure or Package Insert).  
Refer to Section 10.2.6.5 (Appendix 2).  
8.4.2.4. 
Assessment of SAE Outcome 
The outcome of each SAE must be reported to the sponsor, even if this extends beyond the SAE 
reporting period (i.e., after the final study visit).  
Refer to Section 10.2.6.6 (Appendix 2). 


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8.4.3. 
Reporting Requirements for SAE, Serious ADR, AESI and Other Events 
Prompt notification (within 24 hour) by the investigator to the sponsor of a SAE is essential so 
that legal obligations and ethical responsibilities towards the safety of participants and the safety 
of a study intervention under clinical investigation are met. 
The sponsor has a legal responsibility to notify both the local regulatory authority and potentially 
other regulatory agencies about the safety of the study intervention under clinical investigation. 
The sponsor will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, IRB/ IEC, and investigators. 
All fatal and life-threatening serious unexpected ADR are to be reported to South African Health 
Products Regulatory Authority (SAHPRA) within 7 calendar days after first knowledge with a 
complete report to be submitted within an additional 8 calendar days. Serious, unexpected ADRs 
that are not fatal or life threatening are to be reported to SAHPRA no later than 15 calendar days 
after first knowledge. An investigator who receives a Serious, unexpected ADR report or other 
specific safety information (e.g., summary or listing of SAEs/SADRs) from the sponsor will 
review and file it. A tracker of all such reports received from the CRO will be maintained by the 
site. The PI will notify the IRB/IEC, if appropriate and according to local requirements. IRB/IEC 
submissions will be conducted per the local IRB/IEC SOP.  
Certain events other than SAEs and ADRs require immediate reporting to the Sponsor. These 
include withdrawal of consent, emergency unmasking, protocol violation affecting safety, AE 
thought to be an allergic reaction to study drug, event precluding further administration of study 
drug in the investigator’s opinion, pregnancy. Reporting of these events will be conducted 
through the Immediately Reportable Event Form.  
Refer to Sections 10.2.6.1, 10.2.6.2, and 10.2.6.3 and to the schema in Section 10.2.6.4 
(Appendix 2).  
8.4.4. 
Death Events 
Any untoward medical occurrence resulting in death is reported as SAE. Any event resulting in 
death without identification of medical occurrence must also be reported as SAE; such event will 
be coded as “death NOS” (No Other Specified”) until the medical event is identified.  
8.5. 
Concomitant Treatments 
Concomitant treatments will be recorded during the Screening Period to assess eligibility. Any 
change to concomitant treatments throughout the study from Day -1 (signed ICF) to Day 42 or 
EWV, will be recorded. If a concomitant treatment that would have precluded enrollment (see 
Exclusion criteria in Section 5.2 and Section 10.6, Appendix 6) is deemed necessary during the 
Study Treatment Phase, the participant will be discontinued from the study.  
8.6. 
Treatment of Overdose 
All participants will be hospitalized during the entire Study Treatment Phase. The study drug 
will be administered by trained staff. Hence, overdose is considered unlikely. 
In case of overdose, appropriate medical treatment will be instituted, guided by a full PE. The 
study participant will be discontinued from the study and will remain in hospital until symptoms 


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of overdose have disappeared or in the investigator’s opinion it is safe to discharge the 
participant.  
8.7. 
Pharmacokinetics 
Blood/serum samples for PK measurements WILL BE CONDUCTED ONLY IN 
PARTICIPANTS RANDOMIZED TO TBA-7371. Timing of sampling will be as follows (see 
Section 1.3, Table 3 and Table 4). 
Study Treatment Phase 
• Days 1, 2, 4, 7 and 14 before administration of the 1st daily dose of study drug. 
j. In addition, on Days 1, 7 and 14 samples will also be collected at 30 min, 1h, 2.5h, 3h, 4h, 6h, 7h, 10.5h, 
12h, 16.5h after 1st daily dose of study drug. (see Screening (Days -7 to -1). Screening procedures 
will be conducted during the up to 7-Day screening period. Screening assessments can be done at any time 
during this period, except for the written informed consent, which must be given before any screening is 
started, the overnight sputum collection for eligibility assessment, which must be completed on or before 
Day -3, and the overnight sputum collection for EBA, which must be done consecutively on Day -2 and 
Day -1. Subjects may be hospitalized for the entire screening period at the investigator’s discretion, but 
must be hospitalized starting on Day -3. 
k. Follow-up (Days 15 to 42). Allowed window for Day 28 and Day 42 visits: +/- 3 Days. 
l. Early Withdrawal Visit (EWV) or Unscheduled Visit. Participants who withdraw before Day 14 will be 
asked to complete the EWV assessments within 2 Days of withdrawal. Participants who complete the Study 
Treatment Phase, but do not return for the Day 28 visit will be asked to return for the Day 42 visit. If access 
to sites is limited due to the local status of COVID-19 pandemic, the Day 28 and Day 42 visits could 
potentially be conducted by telephone.  Procedures and assessments conducted during an unscheduled visit 
will be at the discretion of the investigator in consultation with the medical monitor. 
52. Written informed consent will be given before any screening procedure is started. 
53. Hospital admission and discharge. Study participants will be hospitalized by Day -3 of the Screening 
Phase and will remain in hospital until the Day after the last dose of study drug is dispensed (Day 15). 
Discharge from hospital will occur on Day 15 after all procedures planned for that Day are completed. 
Upon discharge, participants will be referred to the national TB treatment program for standard of care 
(SoC) treatment. 
54. Physical examination (PE). Full PE will be conducted during the Screening Phase; focused PE (guided by 
medical history) will be conducted on Days 7, 15, 28, 42. Focused PE will be conducted at EWV if the 
participant discontinues between Day 1 and Day 14. Focused PE may be conducted during an 
unscheduled visit at the discretion of the investigator. 
55. Chest X-rays. Good quality Posterior-Anterior chest X-rays will be accepted if conducted within 1 week 
prior to Day -7. If not available, chest X-rays will be conducted during the Screening Phase. 
56. Blood/serum sample collection for clinical safety laboratory assessment. The Day 3 and 7 sampling will 
occur before the 1st dose of study drug.  
57. Urine sample collection drug screening: cannabinoids, cocaine, amphetamines, opiates, 
methamphetamines. 
58. Overnight sputum collection for eligibility assessment. Sputum assessment, including volume, will be 
performed by a Sponsor-approved central laboratory (see laboratory study instruction document). The 1st of 
the 3 overnight sputum collections (Day -7 to Day -3) conducted during the Screening Period will be used 
to assess eligibility as follows: sputum volume (must be at least 10 mL), acid-fast bacilli detection, 
Mycobacterium tuberculosis (Mtb) positivity and rifampicin sensitivity via the GeneXpert® diagnostic 
system (Cepheid). In case inclusion criteria cannot be met from the 1st overnight sputum collection, one or 
more of the above procedures can be conducted on a 2nd overnight sputum collected during the Day -7 to -3 
screening period if the patient is domiciled at the site for both.  


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59. Vital sign and body weight recording. The following 5 vital signs will be recorded: axillary body 
temperature (BT), respiratory rate (RR), heart rate (HR), systolic blood pressure, (SBP), diastolic blood 
pressure (DBP). Body weight (BW) will also be recorded with vital signs. Vital signs and body weight will 
be recorded as follows: 
• Screening Phase: vital signs and BW once in the morning at approximately the same time the 1st daily 
dose study drug will be administered. SBP, DBP and HR can be repeated twice if exclusion criteria are 
met. 
• Study Treatment Phase: vital signs and BW once every morning (Days 1 to 14) before administration of 
the 1st daily dose of study drug; in addition, on Days 1, 4, 7, 10 and 14 vital signs will also collected 2.5h, 
10.5h and 16.5h after the time of 1st daily dose of study drug (see Table 4). 
• Follow-up Phase: vital signs and BW on Day 15 in the morning before 1st daily dose of SoC medication; 
on Days 28 and 42 during the visit. 
• EWV: vital signs and BW if the participant withdraws from the study between Day 1 and 14. 
At each time point BT, RR and BW will be measured once, whereas HR, SBP and DBP will be measured 
twice as follows: after 10 min supine (“manual, supine”) and after 2 (±0.5) min standing (“manual, 2-min 
standing”). When ECG, vital signs and/or blood/serum samples are to be obtained at the same time point, 
the following order must be followed: ECG, vital signs, blood/serum sample, within 5 min of each other. 
60. ECG recording. 12-lead ECG will be recorded once at each time point after at least 10 minutes of supine 
rest as follows: 
• Screening Phase: once in the morning at approximately the same time the 1st daily dose study drug will 
be administered. 
• Study Treatment Phase: on Days 1, 4, 7, 10 and 14 before administration of the 1st daily dose of study 
drug and 2.5h, 10.5h and 16.5h thereafter (see Table 4). 
• Follow-up Phase: on Day 15 in the morning before 1st daily dose of standard of care medication; on Days 
28 and 42 during the visit. 
• EWV: if the participant withdraws from the study between Day 1 and 14. 
61. Eye assessment. A trained staff member will assess:  i) eye symptoms using a standardized script (Section 
10.5, Appendix 5), ii) visual acuity by means of the Rosenbaum Pocket Eye Screener, iii) color vision by 
means of the Waggoner Computerized Color Vision Test and as follows: 
• 
Screening Phase: once in the AM. 
• 
Study Treatment Phase: Days 1, 4, 7, 10, and 14, 2.5h after 1st daily dose of study drug (see Table 4). 
• 
Follow-up Phase: Days 15, 28 and 42 during the visit. 
• 
EWV: if the participant withdraws from the study between Days 1 and 14.  
62. Study drug (IMP) administration. Study drug (TBA-7371 or HRZE) will be administered from Day 1 to 
Day 14 based on the randomization list by an authorized and trained site staff member. The 1st dose of 
study drug will be administered at the same time each Day for the individual participant. Subsequent doses 
will be administered as follows (see Table 4):  
• Twice daily (BID) schedules: 12h after 1st dose 
• Three times (TID) daily schedule: 7h and 14h after 1st dose   
Fasting must occur at least 2 hours before dosing and at least 1 hour after dosing. Study drug administration 
will be followed by 200 mL water. 
63. Overnight sputum collection for EBA assessment and exploratory measurements. Overnight sputum 
will be collected from 3 PM to 7 AM of the following Day (16 hours) on Days -2 and -1 during Screening 
Phase and on 14 consecutive Days during the Study Treatment Phase (Days 1 to 14) for EBA assessment. 
The last collection will finish at 7 AM of Day 15. Drug susceptibility testing for isoniazid and rifampicin, 
and minimum inhibitory concentrations (MIC) of TBA-7371 will be performed on either of Day -2 or Day -
1, and again on Day 14. 
 
  
64. Spot sputum collection for exploratory measurements. The participant should spontaneously produce 
(i.e., not induced) a spot sputum specimen for collection into RNA preservation media. If specimen cannot 
be collected due to participant inability to produce sputum, or due to operational limitations with RNA 
media collection kits, it is not considered a protocol deviation. 


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65. Recording of AE, SAE (including serious ADR) and AESI; recording of concomitant treatments. 
Adverse events (AE), serious adverse events (SAE), including serious adverse drug reactions (ADR), 
adverse events of special interest (AESI) and concomitant treatments will be recorded from the time each 
participant has signed the informed consent form (ICF) until he/she has completed the last follow- up visit 
(Day 42) or the Early Withdrawal Visit (EWV). 
66. Blood/serum sample collection for PK measurements. WILL BE CONDUCTED ONLY IN 
PARTICIPANTS RANDOMIZED TO TBA-7371. Timing of sampling will be as follows: 
• Study Treatment Phase: Days 1, 2, 4, 7 and 14 before administration of the 1st daily dose of study drug; in 
addition, on Days 1, 7 and 14 samples will also collected 30 min (+/- 5 min) and at 1h, 2.5h, 3h, 4h, 6h, 
7h, 10.5h, 12h, 16.5h (+/- 15 min) after 1st daily dose of study drug. (see Table 4).  Patients assigned to 
BID dosing will not have collections at 16.5h, and the 12h sample will be taken prior to the second daily 
dose. Patients assigned to TID dosing will not have collections at 10.5h, 12h and 16.5h, and the 7h 
sample will be taken prior to the second daily dose.  
When timing coincides, samples must always be taken after recording of ECG and vital signs.  
67. Blood/serum/plasma sample collection for exploratory measurements. Timing of sampling will be as 
follows:  
• Study Treatment Phase: Day 1 and 7 before administration of the 1st daily dose of study drug (see Table 
4). 
• Follow-up Phase: Day 15 in the morning at approximately the same time study drug was administered. 
68. Coronavirus Disease (COVID-19) / Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-
2 Testing). COVID-19 testing will be conducted via PCR using a test product authorized by SAHPRA at an 
accredited public or private sector laboratory. A specimen will be collected during the screening period 
between Day-7 to Day -3, and a negative result must be confirmed prior to randomization. For safety 
monitoring purposes, testing will also be performed at Day 7 (±2 Days), on Day 14 OR Day 15 before 
discharge, and/or at any other time that infection is suspected. 
 


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• Table 4).   
• Patients assigned to BID dosing will not have collections at 16.5h, and the 12h sample will be taken 
prior to the second daily dose. Patients assigned to TID dosing will not have collections at 10.5h, 12h 
and 16.5h, and the 7h sample will be taken prior to the second daily dose.  
Follow-up Phase 
On Day 15 in the morning before 1st daily dose of standard of care medication;  
When ECG, vital signs, or blood/serum samples are to be obtained at the same time point, ECG 
will be done first after 10 minutes of supine rest, followed by the vital signs and then the blood 
draw(s) within 5 minutes of each other. 
Concentrations of TBA7371 will be measured, and the following PK parameters calculated over 
the 14-day treatment interval: Cmax, Tmax, Clast, Tlast, AUCinf, AUClast, AUCtau, Cmin, half-life, 
accumulation ratios.  
Details on serum collection procedures, and on the laboratory are provided in the study specific 
manual(s). 
8.8. 
Pharmacodynamics 
No pharmacodynamic parameter other than those included in the efficacy or safety assessments 
will be evaluated in this EBA study. 
8.9. 
Transcriptomics, Genetics and Epigenetics 
Refer to Section 8.10. 
8.10. 
Biomarkers and Other Exploratory Measurements 
Participants will be explicitly asked to consent for storage and use of biological samples for 
biomarker and other exploratory measurements not included in the present protocol.  
Blood/serum and urine samples for biomarker and other exploratory measurements will be 
collected on Day 1 before administration of the 1st daily dose of study drug and on Day 15 in the 
AM, if the participant gives his/her consent. If not, such samples will not be collected.  
Details on blood/serum and urine collection procedures are provided in the study specific 
manual(s). 
Samples for biomarkers and other exploratory measurements will also be obtained from 
overnight sputum collection (Section 8.2.1).  
A spot sputum collection will also be collected at screening and then daily from Day 1 to Day 15 
for exploratory assessments. Collection procedures are provided in the study specific manual(s). 
Details of exploratory objectives will be included in separate operational and/or analysis plans.  
Results of exploratory objectives may be reported separately from the main clinical study report.  
Exploratory measurements may include but are not limited to:  mycobacterial cell-free DNA, 
ribosomal RNA ratio assay, gene expression profiles, serum cytokines or other proteins, urine 


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LAM, bacterial genotypic evaluations for emergence of resistance; susceptibility testing to 
TBA7371 (MIC); population PK models.  
8.11. 
Health Economics 
Not applicable to this study. 


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9. 
Statistical Considerations 
9.1. 
Statistical Hypotheses 
Primary:  at least one of the TBA-7371 treatment groups has an average log CFU counts per day 
reduction from screening to Day 14 [BACFU(0-14)] that is greater than zero, with an acceptable 
safety profile. 
9.2. 
Sample Size Determination 
Approximately 90 participants will be randomized 5:1 to either intervention arm, totaling N = 15 
for each TBA-7371 treatment and control groups. 
Bactericidal effect 
Based on Diacon et al. (2013) 3, standard deviations associated with BACFU(0-14) were relatively 
consistent across 5 treatment groups, ranging from 0.05 to 0.08. If we assume conservatively that 
the true SD of the BACFU(0-14) measures for the TBA-7371 treatment groups is equal to 0.1, 
then with N=15 per group we have 80% (90%) power to detect a true group mean BACFU(0-14) 
reduction of 0.067 (0.079), using a 1-sided alpha = 5%. For reference, the observed BACFU(0-14) 
reduction in Diacon et al, 2013 3 were 0.040, 0.056, 0.077, 0.104, and 0.112 for Bedaquiline 100 
mg, 200 mg, 300 mg, 400 mg and standard HRZE, respectively. 
Safety 
With N=15 per group, we have approximately 80% (90%) probability to observe at least one AE 
if the true AE rate is 10% (15%). We have only 54% probability to observe at least one AE if the 
true AE rate is 5%. Across the five TBA-7371 treatment groups (N=75), we have 90% 
probability to observe at least one AE if the true AE rate is 3.0%. 
9.3. 
Populations for Analyses 
Analysis populations are shown in Table 8. 


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Table 8 
Populations for Analyses 
Population 
Description 
Modified intention to treat 
(mITT) efficacy population 
All participants randomly assigned to study intervention, who received 
the study intervention. Participants will be analyzed according to the 
intervention they actually received. 
Per Protocol (PP) efficacy 
population 
All participants randomly assigned to study intervention, who received 
the study intervention, and did not substantially deviate from the 
protocol procedures.  
Participants who substantially deviated will be identified prior to 
database lock and unmasking.  
Participants will be analyzed according to the intervention they actually 
received. 
Safety 
All participants randomly assigned to study intervention and who 
received the study intervention. Participants will be analyzed according 
to the intervention they actually received.  
PK population 
All participants who received at least one dose of TBA7371 and have at 
one blood sample with measurable concentrations 
9.4. 
Statistical Analyses 
A detailed statistical analysis plan (SAP) centered on primary and secondary endpoints will be 
developed and finalized prior to initiation of enrollment and will further describe the participant 
populations to be included in each analysis, details of the statistical methods, including 
procedures for accounting for missing, unused, and spurious data. Primary and secondary 
analyses are summarized in Table 9. 
Exploratory endpoint analyses will be described in a separate exploratory scientific SAP(s) 
(exploratory SSAP). Specific objectives and hypotheses related to exploratory biomarker 
analyses will be documented in this exploratory SSAP prior to full data unmasking and analysis.  
Results from the exploratory analyses may be reported in a separate results memo and included 
as an addendum to the clinical study report (CSR).   
 
 


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Table 9. 
Summary of Primary and Secondary Endpoints and Analyses 
Endpoint 
Statistical Analysis  
Primary Bactericidal Effect 
Slope i.e. average change per day from 
screening (“0”) to Day 14 [BACFU(0-14)] of the 
log CFU counts. 
For each patient, linear and bilinear regression 
models will be fit, and the better fit model based on 
lower AIC will be used to estimate [BACFU(0-14)] of 
log CFU counts from screening to Day 14. The log 
CFU screening measurement used in the model will 
be the average of the two individual screening 
measurements. An ANCOVA model will be used to 
quantify the evidence that each of the treatment 
group mean BACFU(0-14) is less than 0 (i.e., that the 
treatment group mean has a negative slope on 
average). Multiplicity will be handled by means of a 
step-down sequential approach. The study will be 
declared a success if at least one of the TBA-7371 
treatment groups achieves a statistically significant 1-
sided p-value and demonstrates an acceptable safety 
profile. 
Primary Safety 
Frequency of study participants who 
experienced one or more severe AEs and/or 
SAEs 
The frequency of patients who experienced one or 
more severe and/or serious AE will be summarized 
by treatment group. 
Secondary Bactericidal Effect 
Slope i.e. average change per day from 
screening (“0”) to Day 2 [BACFU (0-2)] and 
from Day 2 to Day 14 [BACFU (2-14)] of the 
log CFU counts. 
For each patient, linear and bilinear regression 
models will be fit, and the better fit model based on 
lower AIC will be used to estimate BACFU(0-2) and 
BACFU(2-14) of log CFU counts from screening to 
Day 2 and Day 2 to Day 14, respectively. An 
ANCOVA model will be used to quantify the 
evidence that the each of the treatment group means 
BACFU(0-2) and BACFU(2-14) is less than 0. 
Slope of the time to sputum culture positivity 
(TTP) in the MGIT system from screening to 
Day 14 [BATTP (0-14)], from screening to Day 
2 [BATTP (0-2)], and from Day 2 to Day 14 
[BATTP (2-14)]. 
For each patient, linear and bilinear regression 
models will be fit, and the better fit model based on 
lower AIC will be used to estimate BATTP(0-14), 
BATTP(0-2) and BATTP(2-14) of TTP from screening 
to Day 14, screening to Day 2 and Day 2 to Day 14, 
respectively. An ANCOVA model will be used to 
quantify the evidence that the each of the treatment 
group means BATTP(0-14), BATTP(0-2) and BATTP(2-
14) is less than 0. 
 


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Endpoint 
Statistical Analysis  
Slope of the log concentration of sputum LAM 
from screening to Day 14 [BALAM (0-14)], 
from screening to Day 2 [BALAM(0-2)], and 
from Day 2 to Day 14 [BALAM (2-14)]. 
For each patient, linear and bilinear regression 
models will be fit, and the better fit model based on 
lower AIC will be used to estimate BALAM(0-14), 
BALAM(0-2) and BALAM(2-14) of log concentration of 
sputum LAM from screening to Day 14, screening to 
Day 2 and Day 2 to Day 14, respectively. An 
ANCOVA model will be used to quantify the 
evidence that the each of the treatment group means 
BALAM(0-14), BALAM(0-2) and BALAM(2-14) is less 
than 0. 
Secondary Safety 
Frequency of participants with adverse events 
(AEs) and frequency of AEs: overall, by 
seriousness, severity, body system, preferred 
term and relatedness to study drug. 
The frequency of participants with and frequency of 
AEs will be summarized by treatment group. The 
incidence of AEs by seriousness, severity, body 
system, preferred term and relatedness to study drug 
will be summarized by treatment group.  
• 
Frequency of participants with any new 
(vs. baseline) eye symptom in one or both 
eyes. 
• 
Mean and frequency distribution of 
duration (hours) of each eye symptom. 
• 
Mean and frequency distribution of 
percentage of days with any eye symptom 
and each of the eye symptoms. 
The incidence of new eye symptoms, mean and 
frequency distribution of duration of each eye 
symptom, and mean and frequency distribution of 
percentage of days with any eye symptom and each 
of the eye symptoms will be summarized by 
treatment group. 
• 
Mean/median change in visual acuity from 
screening (s) to lowest score during Days 
1-15. 
• 
Frequency of participants with any new 
color vision abnormalities (tritan, protan, 
deutan) in one or both eyes and degree of 
severity (mild, moderate, severe) 
Mean and median changes in visual acuity from 
screening to lowest score will be summarized by 
treatment group. 
Frequency of participants with any new color vision 
abnormalities, as well as the specific type of 
abnormality (tritan, protan, deutan) will be 
summarized by the number of eyes the abnormality 
occurs in (one or both), severity (mild, moderate, 
severe) and treatment group. 
• 
Mean and frequency distribution of 
changes from Day 1 to 15 in HR, systolic 
blood pressure (SBP) and DBP as 
measured by the following 2 (BP) or 3 
(HR) methods: 
▪ 
manual (vital signs), after at least 10 
minutes in supine position (“manual, 
supine”); 
▪ 
manual, after 2 (±0.5) minutes in 
standing position (“manual, 2-min 
standing”); 
▪ 
HR from ECG, supine position 
(“ECG, supine”) 
• 
Frequency of participants with ≥ 25 % 
increase in HR, decrease in SBP, decrease 
Mean and frequency distribution of changes from 
Day 1 through Day 15 in HR, SBP and DBP will be 
provided by treatment group and by each method 
measured. 
The frequency of participants with ≥ 25 % increase in 
HR, decrease in SBP, decrease in DBP vs. baseline as 
measured with any of the methods will be provided 
by treatment group. 
The mean and frequency distribution of percentage of 
days with ≥ 25% increase in HR, decrease in SBP, 
decrease in DBP vs. baseline will be provided by 
treatment group. 
The mean and median RR, QRS, QT, QTcF values 
from ECG will be provided by treatment group. 
 


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Endpoint 
Statistical Analysis  
in DBP vs. baseline as measured with any 
of the methods described above. 
• 
Mean and frequency distribution of 
percentage of days with ≥ 25% increase in 
HR, decrease in SBP, decrease in DBP vs. 
baseline.  
• 
Mean/median RR, QRS, QT, QTcF values 
from ECG 
• 
Mean change in HR, SBP and DBP from 
Day 1 to Days 4, 7, 10, 14 and 15 for each 
of the measurement methods described 
above. 
• 
Change in frequency of participants with 
eye symptoms (all, severe, serious) and 
change in mean visual acuity score and 
frequency of color vision abnormalities 
(tritan, protan, deutan) in one or both eyes 
and degree of severity (mild, moderate, 
and severe) from Day 1 to Days 4, 7, 10, 
14 and 15. 
The mean change in HR, SBP and DBP from Day 1 
to Days 4, 7, 10, 14 and 15 will be provided by 
treatment group and by each method measured. 
 
Frequency of participants with any new color vision 
abnormalities, as well as the specific type of 
abnormality (tritan, protan, deutan) will be 
summarized by the number of eyes the abnormality 
occurs in (one or both), severity (mild, moderate, 
severe) and treatment group. 
• 
Mean change in HR, SBP and DBP from 
baseline (Day 0) to Days 28 and 42 and 
from Day 14 to Day 28 and 42 for each of 
the measurement methods described 
above. 
• 
Change in frequency of participants with 
eye symptoms (all, severe, serious) and 
change in frequency of participants with 
any new color vision abnormalities (tritan, 
protan, deutan) in one or both eyes and 
degree of severity (mild, moderate, severe) 
from baseline (Day 0) to Days 28 and 42 
and from Days 1-15 (combined) to Days 
28-42 (combined). 
The mean change in HR, SBP and DBP from 
baseline (Day 0) to Days 28 and 42, and from Day 14 
to Days 28 and 42 will be provided by treatment 
group and by each method measured. 
 
Frequency of participants with any new color vision 
abnormalities, as well as the specific type of 
abnormality (tritan, protan, deutan) will be 
summarized by the number of eyes the abnormality 
occurs in (one or both), severity (mild, moderate, 
severe) and treatment group. 
• 
Mean, median and range of each 
blood/serum and urine safety parameter at 
screening, Day 3, Day 7, Day 14, and Day 
42 
• 
Mean, median and range of the changes in 
each blood/serum and urine safety 
parameter from screening to Day 3, Day 7, 
Day 14 and Day 42.  
The mean, median and range of each blood/serum 
and urine safety parameter at screening, Day 3, Day 
7, Day 14 and Day 42 will be provided by treatment 
group. 
The mean, median and range of the changes in each 
blood/serum and urine safety parameter from 
screening to Day 3, Day 7, Day 14 and Day 42 will 
be provided by treatment group. Changes may be 
assessed on the raw (difference) or log (fold change) 
scale, depending on which scale the distribution of 
the measure is more appropriately described by a 
normal distribution. 


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Endpoint 
Statistical Analysis  
Secondary PK and PK/PD 
TBA7371 concentration profiles and PK 
parameters over the 14-day treatment interval: 
Cmax, Tmax, Clast, Tlast, AUCinf, AUClast, AUCtau, 
Cmin, half-life, accumulation ratios. 
Individual values will be listed for each PK 
parameter by treatment group, and the following 
(non-model-based) descriptive statistics will be 
provided: N, arithmetic mean, standard deviation, 
arithmetic percent CV, median, minimum, maximum, 
geometric mean, and geometric percent CV. 
Correlation between TBA-7371 AUC, Cmax, 
T>MIC and CFU counts on solid media 
culture. 
Spearman correlations, simple linear regressions and 
graphical visualizations will be used to summarize 
correlations. 
Expected concentration associated with 90% 
of the maximal TBA-7371 EBA effect (EC90) 
EC90 will be estimated from exposure-response Emax 
model fits.  
9.4.1. Bactericidal Activity Analyses 
9.4.1.1. 
Primary Bactericidal Activity Analyses 
The primary endpoint will be the slope of the log CFU counts from screening to Day 14 
[BACFU(0-14)], i.e., average change in log CFU count per day over 14 days, where sputum is 
collected twice during the screening phase and daily thereafter. The log10 CFU counts vs. time 
profiles over 14 days of treatment may be biphasic, i.e. the rate of change in log10 CFU changes 
over time. A simple solution 3 is to characterize the subject-specific log10 CFU count vs. time 
profiles using a bilinear regression model, which has been proved to fit the data of many TB 
bactericidal agents quite well, especially over the time interval of 14 days. However, it is also 
likely that the some of the subject-specific log10 CFU count vs. time profiles will be better 
characterized using a simple linear regression model. 
The average slope can be estimated for each subject, i, as the mean of the slopes over each day, 
i.e., 
𝐵𝐴𝐶𝐹𝑈(0 −14)𝑖= ∑
𝛽̂𝑖𝑡/14
14
𝑡=1
,  
where 𝛽̂𝑖𝑡 is the estimated slope for subject i at time t. For each subject, slopes will be estimated 
using both bilinear and simple linear regression models, and the better fit model (based on lower 
AIC) will be selected for that subject. The log CFU screening measurement used in the model 
will be the average of the two individual screening measurements. If the bilinear regression 
model is selected, the average change in log10 CFU per day over 14 days will be estimated by: 
 𝐵𝐴𝐶𝐹𝑈(0 −14)𝑖= ∑
[𝛽̂1𝑖𝐼(𝑡≤𝜅̂𝑖) + 𝛽̂2𝑖𝐼(𝑡> 𝜅̂𝑖)]/14
14
𝑡=1
, 
where 𝛽̂1𝑖 is the estimated slope prior to the estimated inflection point 𝜅̂𝑖, and 𝛽̂2𝑖 is the estimated 
slope after the estimated inflection point 𝜅̂𝑖. The parameters of main interest include the slopes 
𝛽̂1𝑖 and 𝛽̂2𝑖, and the inflection points, 𝜅̂𝑖, and can be readily estimated using least squares.  If the 
linear regression model is selected, the average change in log10 CFU count per day over 14 days 
will be estimated by the constant linear regression slope estimate, 𝛽̂𝑖. BACFU(0-14) will be 
calculated for each patient within a treatment group individually, and then used as the response 
variable in an ANCOVA model, with a fixed effect for treatment group and screening log10 CFU 
count as a covariate. Treatment group means from the ANCOVA model will be used to quantify 


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the evidence that each of the treatment group mean BACFU(0-14) is less than 0 (i.e., that the 
treatment group mean has a negative slope on average). The mITT population will be used for 
the primary efficacy analysis. 
Multiplicity will be handled by means of a step-down sequential approach. The five TBA-7371 
treatment regimens will be divided into 3 testing groups:  Group 1 = Cohort V (400 mg QD) and 
Cohort IV (100 TID); Group 2 = Cohort III (200 mg QD) and Cohort II (100 BID); and Group 3 
= Cohort 1 (100 QD). Group 1, or the group with the highest cohort allowed by the IDMC will 
be tested first using a Hochberg multiplicity adjustment: if the maximum and minimum one-
sided p-values are ≥ 0.05 and ≥ 0.025, respectively, formal testing will be stopped and all cohorts 
below will be declared a failure; if the maximum and minimum one-sided p-values are ≥ 0.05 
and <0.025,  formal testing will be stopped but the regimen with p-value < 0.025 will be declared 
a success; if the maximum and minimum one-sided p-values are < 0.05 and <0.025,  both cohorts 
will be declared a success and testing will proceed to Group 2 regimens with the same step-down 
approach to continue until a failed cohort is observed.  
The study will be declared a success if at least one of the TBA-7371 treatment groups achieves a 
statistically significant 1-sided p-value and demonstrates and acceptable safety profile.  
9.4.1.2. 
Secondary Bactericidal Activity Analyses 
EBA measures (BACFU(0-2) and BACFU(2-14)) will be calculated from the regression models and 
assessed similarly as described above for BACFU(0-14). MGIT TPP and concentrations of LAM 
will also be assessed similarly. For all secondary EBA measurements there will be no adjustment 
for multiple comparisons and no formal success criteria. 
All efficacy analyses will be performed in the mITT population, with sensitivity analyses 
performed in the per-protocol population to assess the robustness of results. 
One of the limitations of the primary analysis method is that each individual subject must have 
enough data to fit a bilinear regression model in order to be included in the primary analysis. 
More sophisticated statistical models, such as a Bayesian nonlinear mixed-effects regression 
model 13 do not have this same limitation, and will therefore be examined through sensitivity 
analyses to assess the robustness of the primary model fits. The Bayesian model jointly fits the 
data from all patients and treatment groups and comprises the joint bilinear regression model as a 
special case. In addition, similar bilinear and linear regressions will also be fit directly to the 
change from screening response variable to further assess the robustness of the results. 
9.4.2. 
Safety Analyses 
9.4.2.1. 
Primary Safety Analyses 
The frequency of patients who experienced one or more severe AEs and/or SAEs will be 
summarized by treatment group with 95% CIs. The proportion of patients with this endpoint 
within each of the TBA-7371 treatment groups will not be formally compared to the control arm 
given limitations due to small sample sizes. The primary safety analysis will be performed in the 
Safety population.  


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9.4.2.2. 
Secondary Safety Analyses 
Individual safety parameters of interest, e.g., mean HR over time, mean SBP and DBP over time, 
and incidence of and frequency of eye symptoms and other adverse events will be summarized 
by treatment group. The incidence of AEs by seriousness, severity, body system, preferred term 
and relatedness to study drug will be summarized by treatment group. 
Mean and frequency distribution of changes from baseline through Day 15 in HR, SBP and DBP 
will be provided by treatment group and by each method measured. The frequency of 
participants with ≥ 25 % increase in HR, decrease in SBP, decrease in DBP vs. baseline as 
measured with any of the methods will be provided by treatment group. The mean and frequency 
distribution of percentage of days with ≥ 25% increase in HR, decrease in SBP, decrease in DBP 
vs. baseline will be provided by treatment group. The mean and median RR, QRS, QT, QTcF 
values from ECG will be provided by treatment group. 
The mean change in HR, SBP and DBP from Day 1 to Days 4, 7, 10, 14 and 15 will be provided 
by treatment group and by each method measured. The change in frequency of participants with 
eye symptoms (all, severe, serious) and abnormal visual acuity and abnormal color vision scores 
from Day 1 to Days 4, 7, 10, 14 and 15 will be provided by treatment group. The mean change in 
HR, SBP and DBP from screening to Days 28 and 42, and from Day 14 to Days 28 and 42 will 
be provided by treatment group and by each method measured. The change in frequency and 
duration of eye symptoms (all, severe, serious) and/or abnormal visual acuity and/or abnormal 
color vision scores from screening to Days 28 and 42, and from Days 1-14 (combined) to Days 
28-42 (combined) will be provided by treatment group. 
The mean, median and range of each blood/serum and urine safety parameter at screening, Day 
3, Day 7, Day 14 and Day 42 will be provided by treatment group. The mean, median and range 
of the changes in each blood/serum and urine safety parameter from screening to Day 3, Day 7, 
Day 14 and Day 42 will be provided by treatment group. Changes may be assessed on the raw 
(difference) or log (fold change) scale, depending on the whether the distribution of the measure 
is more appropriately described by a normal or lognormal distribution, respectively. 
Bayesian linear and nonlinear mixed effects models will be utilized to characterize the profile of 
continuous variables (e.g., heart rate, blood pressure) over time, and the proportion of patients in 
the population reaching clinically relevant thresholds will be estimated. From these models, the 
likelihood of tachyphylaxis can be characterized by the posterior probability that the mean heart 
rate decreases from Day 1 to Day 14, the posterior probability that the mean blood pressure on 
decreases from Day 1 to Day 14, and the posterior probability that the frequency of patients with 
eye symptoms (all, severe, serious) decreases from Day 1 to Day 14. 
9.5. 
PK Analyses 
Concentration data will be summarized by treatment group using nominal time points. Individual 
and mean concentration versus nominal time plots will be presented by treatment groups. PK 
parameters will be summarized by treatment group.  
The relationship of each TBA7371 PK parameter (AUC, Cmax, T>MIC) and CFU counts (e.g. 
BACFU(0-14), CFU change) will be explored graphically for the treatment groups combined. The 
PK and CFU data used in the correlations will also be presented in tabular format. If a correlation 


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is observed, further analysis may be performed to identify exposure targets for response. Details 
of such analysis will be provided in the analysis plan.  
9.6. 
Demographic and Compliance Analyses 
Demographic parameters (age, sex, and race/ethnicity) and other baseline characteristics will be 
summarized by treatment group for all participants in the safety population.  
Listings of randomized participants with protocol deviations (to be defined in the SAP) will be 
presented by treatment group. 
9.7. 
Interim Analyses  
No formal interim analysis is planned in this trial.  
Unmasked safety and (if available) PK data on each cohort will be provided to the IDMC.  
9.7.1. 
Independent Data Monitoring Committee (IDMC) 
The independent IDMC will be established to oversee the safety of this study and to make a go / 
no-go decision at each dose escalation step. 
The IDMC will operate according to a charter. The IDMC structure, participants and other 
details will be provided in the charter. The charter will be available prior to study start. 
The IDMC will review unmasked safety and, if available, PK data during regular scheduled 
safety review meetings. The IDMC may request additional information, or a pause in recruitment 
and study treatment, while safety data are being evaluated.  
During active enrollment, the IDMC will meet at least once before each of the 3 dose escalation 
steps, unless a decision is made to stop recruitment earlier. The IDMC reviews will include vital 
signs, ECG and eye symptoms / visual acuity and color vision tests, and safety laboratory tests as 
well as solicited and unsolicited AE and SAE. All procedures associated with these reviews, 
including objectives, data handling, elements included for review, and recommendations will be 
documented.  
The IDMC will make a formal recommendation on the continued enrolment into the trial after 
each safety review. 
The IDMC charter will provide meeting information and other details.  
If study drug administration is paused by the local medical monitor or the principal investigator, 
the IDMC will convene on an ad hoc basis.  
The recommendation of the IDMC, along with the sponsor’s decision, will be communicated to 
the investigators and the IRB/IEC and the national regulatory authorities as required. The 
sponsor or its designee agrees to abide to any directives issued by the national regulatory 
authority of the IRB. 


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10. 
Supporting Documentation and Operational Considerations 
10.1. 
Appendix 1. Regulatory, Ethical, and Study Oversight 
Considerations 
10.1.1. 
Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and with the following: 
• Consensus ethical principles derived from international guidelines including the Declaration 
of Helsinki and Council for International Organizations of Medical Sciences (CIOMS) 
International Ethical Guidelines 
• Applicable International Council for Harmonization of Technical Requirements for 
Pharmaceuticals for Human Use (ICH) Good Clinical Practice (GCP) Guidelines 
• Applicable laws and regulations 
• The protocol, protocol amendments, ICF, and other relevant documents (e.g., diary cards) 
must be submitted to an IRB/IEC by the investigator and reviewed and approved by the 
IRB/IEC before the study is initiated. 
• Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants. 
10.1.2. 
Study Oversight 
The study sponsor, the IRB/IEC, the institution through which the research is performed, and all 
members of the principal investigator’s clinical team and the national regulatory authority share 
responsibility for ensuring the safety of participants in this trial. 
The principal investigator will be responsible for the following: 
• Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently, in accordance with the requirements, policies, and procedures established by the 
IRB/IEC 
• Notifying the IRB/IEC of SAEs or other significant safety findings as required by IRB/IEC 
procedures 
• Providing oversight of the conduct of the study at the site and adherence to requirements of 
ICH and GCP guidelines, SAHPRA Regulations the IRB/IEC, and all other applicable country 
and local regulations. 
• Closely monitoring study participants and taking whatever measures necessary to ensure their 
safety. The principal investigator may delay an individual’s study drug administration or pause 
study drug administration altogether if the investigator is concerned that the study drug might 
place a participant or participants at significant risk. Where specified, the responsibilities of 
the principal investigator may be delegated to a medically qualified team member (designee). 
The investigator determines severity and causality with respect to the study drug for each AE. 


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The sponsor has an institutional responsibility to ensure participant safety and is ultimately 
accountable for safety oversight. Local medical monitors and the IDMC play an important role in 
this regard and support the sponsor. 
The local medical monitor is the sponsor’s representative and is a physician or surgeon in their 
country of residence. The local medical monitor: 
• reviews the safety of the product for protocols in a specific region and, in conjunction with the 
sponsor, determines expectedness of AEs.  
• Is responsible for safety oversight in-country and plays an important role in the reporting of 
SAEs, ADRs and pregnancies, as described in the protocol 
• in consultation with the sponsor, may assess the severity and causality for AEs and may upgrade 
the degree of severity and causality determined by the principal investigator or designee 
The IRB or EC has institutional responsibility for the safety of research participants. The IRB or 
EC has the authority to terminate, suspend or require changes to a clinical trial. 
The national regulatory authority, SAHPRA, has the authority to terminate, suspend or require 
changes to a clinical trial. 
10.1.3. 
Financial Disclosure 
Include text related to financial disclosure if not included in another document. 
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study. 
10.1.4. 
Informed Consent Process 
Written informed consent will be obtained prior to conducting any study-related procedures.  
Participants must be informed that their participation is voluntary. The principal investigator or 
designee will explain the study to the participant or his/her legally authorized representative and 
answer all questions regarding the study. The principal investigator or designee will conduct the 
consent discussions on an individual basis with each participant Adequate time will be allowed 
for all questions to be addressed. Potential participants will be interviewed to ensure that they 
meet all entry criteria relating to history. 
10.1.5. 
Informed Consent Forms 
Informed consent for study participation  
Participants will be required to sign a statement of informed consent that meets the requirements 
of 21 Code of Federal Regulations (CFR) 50, local regulations, ICH guidelines, Health Insurance 
Portability and Accountability Act (HIPAA) requirements, where applicable, and the IRB/IEC or 
study center. The informed consent will be obtained by the use of a written consent form 
approved by the IRB or IEC.  
Consent for HIV testing will also be obtained prior to enrollment. 


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Other consents will be presented to the participant which are optional and if not signed, would 
not exclude the participant from the study: 
• consent to collect, store and testing of samples for research not described in the protocol; 
• consent to allow any remaining specimens originally taken for mandatory testing to be used 
for research not described in the protocol 
• consent to genetic testing. 
Sample testing will be in line with the consent of the participant. 
A copy of the signed consent forms shall be given to the participant prior to conducting any 
study-related procedures. 
The medical record must include a statement that written informed consent was obtained before 
the participant was enrolled in the study and the date the written consent was obtained. The 
authorized person obtaining the informed consent must also sign the ICF. 
If there is a change to the ICF during the conduct of the study, participants must be re-consented 
to the most current version of the ICF. 
Any withdrawal of consent for sample testing will be documented in the eCRF. 
Laboratory assays for primary and secondary endpoints will be carried out in South Africa. 
Participants will be informed that some of the assays for exploratory endpoints may be carried 
out in laboratories outside South Africa. If participants will be asked to consent to optional 
exploratory research using the remainder of mandatory samples, include text that addresses the 
use of remaining mandatory samples for optional exploratory research. 
Participants will be told that they are free to refuse to participate and may withdraw their consent 
at any time and for any reason during the storage period.  
10.1.6. 
Data Protection 
Participants will be assigned a unique identifier by the sponsor. Any participant record or dataset 
that is transferred to the sponsor will contain the identifier only; participant names or any 
information which would make the participant identifiable will not be transferred to the sponsor. 
The participant must be informed that his/her study-related data will be used by the sponsor in 
accordance with local data protection law. The level of data disclosure must also be explained to 
the participant. 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
10.1.7. 
Dissemination of Clinical Study Data 
Study information from this protocol will be posted on publicly available clinical trials registers 
(clinicaltrials.gov and the South African registry) before enrolment of participants begins. 
The final study report will include all available safety data, clinical assessments, and 
concomitant medications through the final study visit. The database will be locked prior to 
unmasking and preparation of the final study report when all of the above data have been 


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entered, reviewed, and all queries related to the data have been addressed. Modifications or 
additions to the analyses will be included in the relevant SAP. Any decisions to deviate from the 
planned analyses described in the protocol and in the SAP will be described in detail in the final 
study report.  
The final clinical study report will be reviewed and approved by the sponsor signatory and the 
principal investigator.  
Summaries of the results of the study will also be posted on the same websites. 
10.1.8. 
Data Quality Assurance 
All participant data relating to the study will be recorded on printed or electronic CRF using an 
Electronic Data Capture (EDC) system, unless transmitted to the sponsor or designee 
electronically (e.g., laboratory data). The investigator is responsible for verifying that data entries 
are accurate and correct by physically or electronically signing the CRF. 
The investigator must maintain accurate documentation (Appendix 1, Section 10.1.9) that 
supports the information entered in the CRF. 
The study will be monitored regularly by the sponsor or its designee throughout the study period. 
The investigator must permit study-related monitoring, audits, IRB/IEC review, and regulatory 
agency inspections and provide direct access to source data documents. 
Monitoring details describing strategy (e.g., risk-based initiatives in operations and quality such 
as Risk Management and Mitigation Strategies and Analytical Risk-Based Monitoring), methods, 
responsibilities and requirements, including handling of noncompliance issues and monitoring 
techniques (central, remote, or on-site monitoring) are provided in the Monitoring Plan. 
The sponsor or designee is responsible for the data management of this study including quality 
checking of the data. 
The sponsor assumes accountability for actions delegated to other individuals (e.g., Contract 
Research Organizations). 
Study monitors will perform ongoing source data verification to confirm that data entered into 
the CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements. 
Records and documents, including signed ICFs, pertaining to the conduct of this study must be 
retained by the investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during the 
retention period without the written approval of the sponsor. No records may be transferred to 
another location or party without written notification to the sponsor. 
 


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10.1.9. 
Source Documents 
Source documentation consists of existing medical records and/or study records developed and 
maintained by the investigator. Source documents provide evidence for the existence of the 
participant and substantiate the integrity of the data collected. 
Data recorded on source documents will be transcribed onto case report forms (CRFs) or entered 
using electronic case report forms (eCRFs) using an EDC system. 
Data entered in the eCRF that are transcribed from source documents must be consistent with the 
source documents or the discrepancies must be explained. The investigator may need to request 
previous medical records or transfer records, depending on the study.  
For the purpose of monitoring and auditing the study, source documentation will consist of 
existing medical records and/or study records developed and maintained by the investigator. 
10.1.10. 
Study and Site Closure 
The sponsor designee reserves the right to close the study site(s) or terminate the study at any 
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to: 
• Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC or 
local health authorities, the sponsor's procedures, or GCP guidelines 
• Inadequate recruitment of participants by the investigator 
• Discontinuation of further study intervention development 
At the discretion of the sponsor, all materials and supplies provided to the investigator will be 
returned or disposed of in compliance with local regulatory requirements upon authorization 
from the sponsor, upon study completion. The investigator or designated clinical site staff will 
notify the IRB/IEC when the study has been completed. 
10.1.11. 
Publication Policy 
The results of this study may be published or presented at scientific meetings. If this is foreseen, 
the investigator agrees to submit all manuscripts or abstracts to the sponsor before submission. 
This allows the sponsor to protect proprietary information and to provide comments. 
The sponsor will comply with the requirements for publication of study results. In accordance 
with standard editorial and ethical practice, the sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International Committee of 
Medical Journal Editors authorship requirements. 


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10.2. 
Appendix 2. Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting 
10.2.1. 
Definition of AE 
AE Definition 
• An AE is any untoward medical occurrence in a patient or clinical study participant, 
temporally associated with the use of study intervention, whether or not considered 
related to the study intervention. 
• An AE 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 study intervention. 
 
Events Meeting the AE Definition 
• Any abnormal laboratory test results (e.g. hematology, clinical chemistry, or urinalysis) 
or other safety assessments (e.g. ECG, radiological scans, vital signs measurements, eye 
symptom or findings), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator. 
• Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
• New conditions detected or diagnosed after study start even though it may have been 
present before the start of the study. 
• Signs, symptoms, or the clinical sequelae of a suspected DDI. 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-harming 
intent. Such overdoses should be reported regardless of sequelae. 
Lack of efficacy per se will not be reported as an AE or SAE. Such instances will be captured 
in the efficacy assessments. 
 


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Events NOT Meeting the AE Definition 
• Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is the AE. 
• Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen. 
10.2.2. 
Definition of ADR 
• “Adverse drug reaction” or “adverse reaction” means a response to a medicine in humans 
which is noxious and unintended and which occurs at any dose and which can also result 
from overdose, misuse or abuse of a medicine. The phrase "responses to a medicinal 
product" means that a causal relationship between a medicinal product and an adverse 
event is at least a reasonable possibility, i.e., the relationship cannot be ruled out. 
 
 


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10.2.3. 
Definition of SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met. 
A SAE is defined as any untoward medical occurrence that, at any dose: 
a. Results in death 
b. Is life-threatening 
The term 'life-threatening' in the definition of 'serious' refers to an 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. 
c. 
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. 
d. Results in persistent 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. 
e. 
Is a congenital anomaly/birth defect 
f. 
Is a medically significant / important event or reaction: 
• Medical or scientific judgment should be exercised in deciding whether SAE reporting 
is appropriate in other situations such as important medical events 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 other 
outcomes listed in the above definition. These events should usually be considered 
serious. 
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency or 
drug abuse. 
10.2.4. 
Definition of Serious Adverse Drug Reaction (Serious ADR) 
When an adverse event is judged to be serious and related (see Section 10.2.6.4) to an 
investigational product, it is referred to as Serious ADR and is subject to expedited reporting (see 
Section ). 


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10.2.5. 
Definition of AESI 
Adverse events of special interest (AESIs) are adverse events that the sponsor wants to monitor 
carefully and which are subject to expedited reporting (within 24 hours) from the investigator to 
the Sponsor or representative following the same process and timelines than the SAEs.   
In this trial the following AEs will be collected and reported as AESI: 
• Anaphylactic reaction 
• ≥Grade 2 intensity (severity) and/or serious AE related to increase of heart rate (HR); 
• ≥Grade 2 intensity (severity) and/or serious AE related to decrease of SBP; 
• ≥Grade 2 intensity (severity) and/or serious AE related to decrease of DBP; 
• ≥Grade 2 intensity (severity) and/or serious eye symptom-related AE.  
 


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10.2.6. 
Recording and Follow-up of AEs and SAEs 
10.2.6.1. AE and SAE Recording  
• Care will be taken not to introduce bias when detecting AE and SAE. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences. 
• When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory reports, and diagnostics reports) 
related to the event. 
• The investigator will then record all relevant AE/SAE information in the CRF.  
• AE will be reported on the AE CRF using a recognized medical term or diagnosis that 
accurately reflects the event.  
• AE evaluations will be reviewed by the principal investigator or a medically qualified 
delegate. AE CRF pages are to be completed by members of the study team designated in 
writing by the principal investigator. The onset and resolution dates of an AE and action 
taken in response to the AE will be documented.  
• After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAE and non-serious AESI will be followed 
until resolution, stabilization, the event is otherwise explained, or the participant is lost to 
follow-up.  
• It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the sponsor in lieu of completion of the AE/SAE CRF page. 
• There may be instances when copies of medical records for certain cases are requested by 
the medical monitor, the IDMC or the sponsor. In this case, all participant identifiers, with 
the exception of the participant number, will be redacted on the copies of the medical records 
before submission. 
• The investigator will attempt to establish a diagnosis of the event based on signs, symptoms, 
and/or other clinical information. Whenever possible, the diagnosis (not the individual 
signs/symptoms) will be documented as the AE/SAE. 
• SAE will be assessed for severity and causal relationship to the study investigational 
medicinal product. 
 


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10.2.6.2.  Follow-up of AEs and SAEs and Resolution 
• The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated 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. 
• If a participant dies during participation in the study or during a recognized follow-up period, 
the investigator will provide the sponsor with a copy of any post-mortem findings including 
histopathology, if available. 
• New or updated information will be recorded in the CRF. 
• The investigator will submit any updated SAE data to the sponsor within 24 hours of receipt 
of the information. 
• The onset and resolution dates of the event and medical care taken in response to the event 
will be documented.  
• AEs will be considered resolved when the condition returns to normal or returns to the 
participant’s baseline status as established during the Screening Phase, or when the condition 
has stabilized with the expectation that it will remain chronic 
• If the event has not resolved by the final study visit, it will be documented as “ongoing” on 
the eCRF, however, follow-up of the SAE must continue until resolved or the condition has 
stabilized. Information recorded on the CRF must be substantiated in the source documents. 
• The resolution date to be recorded on the CRF is the last date on which the participant 
experienced the AE.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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10.2.6.3. Assessment of AE/SAE Intensity 
The investigator will assess intensity (severity) for each AE and SAE reported during the study 
and assign 1 of 5 grades:  
• Grade 1: Mild 
• Grade 2: Moderate 
• Grade 3: Severe 
• Grade 4: Potentially life-threatening 
• Grade 5: Death (where applicable) 
It is recommended that definitions provided in the Division of AIDS (DAIDS) Table for Grading 
the Severity of Adult and Pediatric Adverse Events, Version 2.1 of July 2017 (reported in 
Section 10.4, Appendix 4) be followed. The DAIDS Table provides definitions of intensity 
grades 1 to 4 for numerous major clinical conditions and laboratory parameters, organized by 
body system. Furthermore, for conditions and parameters not specifically identified, the DAIDS  
It should be noted that the investigator is not obliged to use the definitions reported in Appendix 
4 and medical judgement should prevail. 
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes as described 
in the definition of an SAE (see Section 10.2.2), not when it is rated as severe. 
10.2.6.4.  Assessment of AE/SAE Causality (Relatedness) 
• The investigator is obligated to assess the relationship between study intervention and each 
occurrence of each AE/SAE. 
• The causality assessment will be determined using a two-level scale: related or not related.  
• An AE/SAE is considered related to study intervention if there is a reasonable possibility 
that the study intervention contributed to the AE. 
• Not-related means there is no reasonable possibility that the AE is causally related to 
administration of the study intervention. There are other more likely causes for the AE.  
• The investigator will use clinical judgement to determine the relationship. 
• Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention administration 
will be considered and investigated. 
• 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. However, it is very important that the 
investigator always assess causality for every event before the initial transmission of 
the SAE data. 


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• The investigator may change his/her opinion of causality in light of follow-up information 
and send a SAE follow-up report with the updated causality assessment. 
• The causality assessment is one of the criteria used when determining regulatory reporting 
requirements (see Section 10.2.6). 
10.2.6.5. Assessment of AE/SAE Expectedness 
Expected adverse events are adverse events consistent with the applicable product information 
provided by the sponsor (investigator brochure for TBA-7371 and package insert for 
Rifafour® e-275 HRZE).  
10.2.6.6.  Assessment of SAE Outcome 
The outcome of each SAE must be reported to the sponsor, even if this extends beyond the 
SAE reporting period (i.e. after the final study visit). 
For analysis purposes, the outcome for SAE will be determined on the final study visit.  
Outcome of all AE will be classified as one of the following:  
• Resolved   
• Resolved with sequelae  
• Ongoing  
• Death 
10.2.7. 
Reporting of SAE, Serious ADR, AESI and Other Events 
10.2.7.1. 
Reporting to Sponsor Delegate’s (CRO Safety Team) Via the Electronic Data 
Collection Tool 
• The primary mechanism for reporting an SAE by the investigator to the sponsor or 
delegate (e.g. CRO safety team) will be the electronic data collection tool.  
• The site will enter the SAE data into the electronic system as soon as it is identified. 
• All SAE (related and unrelated) and AESI must be reported to the sponsor or delegate 
throughout the study.  
• Serious ADRs are reported to the sponsor or delegate even after the trial is over, if the 
sponsor, Medical Monitor or PI become aware of them. 
• The investigator must not wait to collect additional information to fully document the 
event before notifying the CRO Safety team of an SAE. The initial notification should 
include at least the following:   
o Protocol number and name and contact number of the investigator 
o Participant ID number (and initials and date of birth, if available)  


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o Date participant received study investigational medicinal product. 
o SAE and date of event onset  
o Current status of participant  
NOTE: the reporting must be done anyway even if one or more of the above items 
are missing 
• The investigator is responsible for applicable expedited safety report submission to the 
sponsor or delegate and the sponsor or delegate reports to SAHPRA within specific 
time periods of being notified of the event. Therefore, it is important that the 
investigator submit additional information requested as soon as it becomes available.  
• All fatal and life-threatening Suspected Unexpected Serious Adverse Reactions 
(SUSARs) are to be reported to SAHPRA with 7 calendar days after first knowledge 
with a complete report to be submitted within an additional 8 calendar days. Non-fatal 
and life-threatening SUSARs need to be reported to SAHPRA no later than 15 calendar 
days after first knowledge. The same timelines apply to follow-up information received 
for the SUSARs. 
• The sponsor will notify the IDMC of all SUSARs within the same timelines the report 
is send to investigators, health authorities, IEC and other relevant parties. Any follow-
up report will be sent with the same timelines.  
• If the electronic system is unavailable, the site may use the paper SAE data collection 
tool (see Section 10.2.6.2) instead of the electronic data collection tool, in order to 
report the event within 24 hours of becoming aware. 
• After the study is completed at a given site, if used, the electronic data collection tool 
will be taken off-line to prevent the entry of new data or changes to existing data. 
• If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form (see 
Section 10.2.6.2). 
• Contacts for SAE reporting and for all safety personnel are contained in the Team 
Contact List which will be maintained by the study sponsor. 
• 
Refer to Section 10.2.6.4 for the reporting schema. 
10.2.7.2. 
SAE  Reporting via paper CRF  
• If the CRF cannot be completed, the Supplemental SAE Report (paper form) should be 
completed by the PI or his/her designee, and scanned and emailed, or faxed to the CRO 
Safety Team. The investigator is responsible for ensuring an adequate transmission of 
the fax and will store the distribution confirmation in the study file. 


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• In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE report form sent by overnight mail or 
courier service. 
• Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames. 
10.2.7.3. 
Other Events Requiring Immediate Reporting  
• The investigator must report the following events by scanning and emailing, or faxing the 
appropriate form to the local medical monitor within 24 hours of becoming aware of the 
event:    
o Withdrawal of consent during the study for medical reasons (Immediately Reportable 
Event Form)  
o Emergency unmasking (unblinding) (Immediately Reportable Event Form) (not 
applicable for this trial) 
o Protocol violation affecting the safety of a participant (Immediately Reportable Event 
Form) 
o Any event that, in the opinion of the investigator, precludes further administration of 
the study drug (Immediately Reportable Event Form, unless meets SAE criteria)   
o Pregnancy (Immediately Reportable Event Form, and Pregnancy Notification Form) 
 
 
 
 
 
 
 
 


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10.3. 
Appendix 3. Contraceptive Guidance and Collection of Pregnancy 
Information 
Definitions: 
Female of Childbearing Potential (FOCBP) 
A female is considered fertile following menarche. If fertility is uncertain (e.g. amenorrhea in 
adolescents) and a menstrual cycle cannot be confirmed before first dose of study intervention, 
additional evaluation should be considered. If in doubt, the participant should be considered 
fertile. 
Women in the following categories are not considered FOCBP 
1. Premenarchal 
2. Documented hysterectomy, bilateral salpingectomy or bilateral oophorectomy 
o For individuals with permanent infertility due to an alternate medical cause other than 
the above, (e.g. mullerian agenesis, androgen insensitivity), investigator discretion 
should be applied to determining study entry. 
Note: Documentation can come from the site personnel’s: review of the participant’s medical 
records, medical examination, or medical history interview. 
Contraception Guidance: 
Women physically capable of pregnancy must agree to use an acceptable method of avoiding 
pregnancy for 1 month after the last dose of study medication.  
Male participants of childbearing potential must agree to use an acceptable method of 
contraception for 3 months after the last dose of the study medication and must also refrain from 
sperm donation through 3 months after receiving the last dose of study medication.  
Acceptable methods of avoiding pregnancy include:  
• sexual abstinence (not engaging in sexual intercourse)  
• a confirmed sterile partner 
Or at least 2 of the below contraceptive methods 
• hormonal contraceptives (oral, injection, transdermal patch, or implant) 
• Intra Uterine Device (IUD) 
• male or female condom  
• diaphragm  
Collection and Reporting Pregnancy Information 
Male and female participants will be provided with information on acceptable methods of 
contraception as part of the informed consent process and will be asked to sign the ICF stating 
that they understand the requirements for avoidance of pregnancy.  


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In the event of a pregnancy by a female participant or pregnancy by a sexual partner of a male 
participant, the processes outlined below must be followed.  
• The investigator will collect pregnancy information on any female participant who becomes 
pregnant while participating in this study. Information will be recorded on the appropriate form 
and submitted to the sponsor within 24 hours of learning of a participant's pregnancy.  
• Investigators must make an effort to collect outcomes of pregnancies discovered during the 
study and communicate them to the sponsor and/or CRO. The health status of the mother and 
child, the date of delivery, and the child’s sex, birth weight and multiparity should be recorded 
and be reported to the medical monitor after delivery. If delivery occurs before the last 
scheduled study visit, the participant should continue to be followed to determine the outcome 
of the pregnancy, and for SAEs through the final study visit unless withdrawal of consent has 
occurred. If delivery occurs after the final study visit, the investigator should attempt to 
maintain contact with the participant to obtain information after delivery. 
• The investigator will collect follow-up information on the participant and the neonate, and the 
information will be forwarded to the sponsor. Generally, follow-up will not be required for 
longer than 6 weeks beyond the estimated delivery date. Any termination of pregnancy will be 
reported, regardless of fetal status (presence or absence of anomalies) or indication for the 
procedure. 
• While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy will be reported as an AE or SAE. Abnormal pregnancy 
outcomes (e.g. spontaneous abortion, fetal death, stillbirth, congenital anomalies, ectopic 
pregnancy) are considered SAEs.  
• Any post-study pregnancy-related SAE considered related to the study intervention by the 
investigator will be reported to the sponsor. While the investigator is not obligated to actively 
seek this information in former study participants, he or she may learn of an SAE through 
spontaneous reporting.  
 


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10.4. 
Appendix 4. Division of AIDS (DAIDS) Table for Grading Intensity 
(Severity) of Adverse Events  
 
D1v·1s1,on of AIDS (DAIDS) Table for 
Grading the Severity of Adult and 
Pediatric .Adverse Even s 
or 
ct d 
r on 2.1 
ul 2017 
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ati o a] In :titut 
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t of 
a]th ,n 
· u . 1'Vi 


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Table of Contents 
,Glossaicy and Acronyms ....................................................................................................................... 1 
Introduction ............................................................................................................................................... 3 
Instructions for Use .............................................................................................................................. 4 
Major Clinic.al Conditions ..................................................................................................................... 7 
Cardiovascular ................................................................................................................................ 7 
Dermatologic ........................................................................................................................................ 9 
Endocrine and Metabolic ................................................................................................................. 10 
Gastro.tntestinal ............................................................................................................................. 12 
Musculoskeleta! .................................................................................................................................. 14 
Neurologic ..................................................................................................................................... 15 
Pregnancy, Puerperium, and Perinatal .......................................................................................... 1 7 
Psychiatric ..................................................................................................................................... 18 
Respiratory .......................................................................................................................................... 19 
Sensory .......................................................................................................................................... 20 
Systelllic ............................................................................................................................................. 21 
Urinary .......................................................................................................................................... 23 
Site Reactions to Injections and Infusions ........................................................................................ 24 
Laboratory \ alues .............................................................................................................................. 25 
Chemistries ....................................................................................................................................... 25 
Hematology ................................................................................................................................... 29 
Urinalysis ............................................................................................................................................ 31 
Appendix. A Total Bilirubin Table for Term and Preterm Neonates ............................................. 32 


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ary and 
AE 
Al.T(SOPl) 
ANC 
i\Sl(SOOT) 
AV 
Bas;ic Self-care Functi,0.1:isl 
BMDz-soore 
BPAP 
Chemical Pregnancy 
CNS 
CPAP 
DAER:S 
Disability 
ECG 
eGFR 
Ho:•pital'.izatio.n 
INR 
,cronym 
Ad'lfme e 'fflt; Any unfa :arable and unintended si!ll (includmg .an 
abnornm laboratory finding), syq>tom, or dise-.uetemporally 
associated Vi.iith die use ofa medical treat:ment or procedure regardless 
of"'hether :it is ooruiden!d related to the medical treatment or 
procedure.. 
Alanine aroinotramferase (smmr g/utam.ic pyruvic trmzsaminme) 
Absolute nemrophitl cotml: 
Aspartate aminotransferase {serom glutamlc..c:mloo.ceti.C tronswninase) 
Atrio·ventr:icular 
Adult 
Acti ,iities such as batru:iJ& dressing. toileting, tramfet or movement, 
continence, and reeding. 
YqungJ:;,hiidren 
Acthiiti.es that are age arid ooJmrally appropriate, such as feeding one's, 
s,elfv.'.itb culturally appropriate ,eating implements. 
Body oms index z. soore; A body t,eferene-e norm SpeciticaUy, the 
tmrnber of standard de,;,.iations a participant's B:Ml differs: from the 
.average B1vll for their age, sex, and ethrucity. 
Bo11e mineral density t-soot,e; Tue 011unbet of sitandard deir"iallo115 abO\i1! 
ot be.low the mean bone mineral dens~ty of a healthy 30 year old adult 
of the same s:ex .am! ethruc:ity as the part:icipam .. 
Bone mineraJ density zas:core; The number of standlatd devi,ations a 
participant's BJ!vID difrer:s, ftom the aurage BivID for their age, sex, and 
ethnicity. 
Bilm;-el positi \it! airway pressure; A mode us.ed ooring no.run raisiive 
positi\it! pres.sure -sentilation. 
A pre?,Daucv in ,,..hich a positi've pre_epaucy test is followed by a 
negati re pregn.ancy test 1thout. evide:rme of a clinical pregnancy loss. 
Central nenous sysrem 
Contiinoous posi.th'e airv.ia pressure 
D.i\IDS Adverse Experieuce Reportm,; System; An intemet;ba!red 
system deve]oped for clinical resean:h. s:i.tes to 1,eport Expedit,ed 
Ad ~e Events (E.A.Es) to DllliDS. it facilitates: timel , E.i\E report 
submission and serves as: a centrali21e:d 1ocation for accessin.,; and 
processing EAE imonn.tt:io:o for reporting purposes. 
A substantial disruption of a pe£Son' s abili.ty to oo.nduct nonnal life 
fullctions.. 
Electrocardi.ogram 
Estimated glomef'Ular filtration rate 
Does not include the fo11owing hospi.ral admissions: under 24 .hOl!lrS, 
unrelated to an advel'se e\"e11t (e.g., fur labor and deli\'ecy, cosmetic 
surg,ecy,, social or ad:rumisttati ve for temporary pla.cel:llellt [for la.ck of a 
place to sleep}), protoc:ol-speci:fied, and for diagnosis or therapy of a 
condition that existed before the receipt of a srudj' al].ent and tim:iclthas: 
not increased irt se\mty or frequency. 
mtemM::ional normalized ratio 
DAJDS AE GrallmgT1ble Comm,i · e•rsio.112.1-1\Jly 201 
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a y and Acrony1n 
Intervention 
IV 
lv10 
LDL 
LLN 
Life.,threatenin,11; AB 
NA 
Participant. ID 
PRJntm 
PT 
PIT 
QTc 'Interval 
RBC 
S:I 
uu 
M ical, 51Jlcgica1, or odter procedures reoommen d or ,provid 
I by a, 
healthcare professional fo the treatment of an 
verse even · 
Intmveno 
Intravenous imm 
globulin 
Low derultty lipoprotein 
Lo i.-er limit of normal 
Anv advme event that: places th participant, in the,; 'ew of the 
inves 'ptor, at immedi te risk of de th from the reaction \i,hen. it 
occurred i. 
.i does not includ a reaction that would have caused 
death ifit had oocumd in more mrere form). 
Nat applicable 
The identification number assigned to a study participant \i,hich i!. used 
to track study-related document tion, including any reported AE1. 
The .int«\'ll bet1 un the beginning of the P , ,re and th beginrung of 
the QRS complex of an electrocardiogram that repmient! the time 
betv.Hn the beg:irul:in.g of the c traction of the tria a:nd the begiwtlng 
of the contraction of the ,l'ffltrides. 
Prothrombin time 
Partial thromboplastin time1 
The me ure of time bet we-en the owet of ventricular depolarization 
and completion of ventricular repolarization corrected for ventricular 
r.ate. 
Red blood ceU 
Standard international unit 
Upper limit of normal 
U1ual Social & Functional Acth 'ties 
Acth~ties \,Atleh .aduJts and children perform o a routine buis and 
those \lhlch are pa:rt of re"-1Jlar acti ,~tles of daily 1i, ·n~ fb example: 
WBC 
\VHO 
Vi/NL 
Ad.ap h-e t b ,and dmirable acti ~ties, 1uch u g,oing o \vodc, 
shoppi~g. cooking. 
e of transport tion, er p 
:uing a hobby, 
YQun1Gltildoo 
Acth!ities 1h t are a~ and cuUuraUv appropri..ate, such as social 
interactiom, play acti \!ities, or !earning ub. 
White blood oeU 
W, I Health Organization 
Wi'lhin normal limits 
D.AlDS AB Qr1d1t.11 T1bll CfflKttd V1n:to111 2.1- JuJr 2-<117 
p 
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Introduction 
The Division of AIDS (DAIDS) ov,ersees more than 300 clinical trials domestically and 
.intemationaUy, which evaluate the safety and efficacy of therapeuti:c products, vaccines, and 
other pr-eventive moda ities:. Advef'Se event (AE) data. collected during these clinical trials form 
the basis for suooeque.nt safety and efficacy analyses of pha!maceutical products and medica, 
devices. Incorrect and inconsistent AE severity grading can lead to inaccura1te data a,nalyses and 
interpretation, which in tum can impact the safety and well being ofdmical trial participants. and 
future patients using pharmaceutical products. 
Over the years, DA.IDS scientific kno1,vledge and experietl!ce have expanded, necessitating 
r-evisions of the DAIDS grading table ,vhich serves as a guide for assessing the severity of AEs 
(including dinical and laboratory abnonnalit.ies) in participants emailed in DAIDS-sponso11ed 
and 7 supported dinical triaJs. The Division qf AIDS (DAIDS) Table/or Grading the Severity of 
Adult and Pediatric Adverse Events, Corrected Version 2.1 (July 2017) updates and replaces 
version 2.1 (M:arch 017). 
DAIDS is grateful to the DAIDS Gradi11!g Table, Working Group, numerous govermnent and 
non-government affiliated medical subject matter e,xperts and reviewers who ·wer-e instrumental 
.in the reviston of the DAIDS grading tc,1,ble. 
DAWS .!U! Gr.34i11,g Ta!Yle Correc e4 v~~iQ1I ~-l •11.lly ~o 17 
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Instructions for U e 
Ge:neJ"al Considerations 
The Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pedtatric Adverse 
Events, Version 2.1 consists of parameters, or AEs, with severity grading guidance that are to be 
used in DAIDS clinical trials for safety data reporting to maintain accuracy and consistency in 
the e\ aluation of AEs. The term «severe" is not the same as the term =serious" in dassifying 
AEs. The severity ofa specific event describes its intensity, and it is the intensity which is 
graded Seriousness, which is not graded, relates to an out.come of an AE and is a regulatory 
definition. 
Clinical sites are encouraged to r,eport parameters in the DAIDS grading table as they are written 
to maintain data consistency across clinical trials. However, since some parameters can be 
reported with more specificity, clinical sites are encouraged to report parameters that convey 
additional clinical information. For example, diarrhea could be reported as neonatal diarrhea; 
seizures, as febrile seizures; and pain, as jaw pain. 
The DAIDS gra.ding table provides an AE severity grading scale ranging from grades 1 to 5 with 
de.scrrptions for e-a.ch AE based on the foUowing general guidelines: 
• 
Grade 1 indica,tes a mild event 
• 
Grade 2 indicates a modernt.e event 
• 
Grade 3 indica,tes a se, ere event 
• 
Grade 4 indica,tes a potentially life-threatening event 
• 
Grade S indicates death (Note: This grade is not specificaUy listed on each page of the 
grading table). 
0th.er points to consider include: 
• 
Use age and sex values as applicable. 
• 
Unless noted, laboratory values are for term neonates. Pr,eterm neonates should be assessed 
using local laboratory normal ranges. 
• 
Where applicable, Standard International (SI) units are included in italics. 
Selecting and Reporting a Primary AE Term 
"\Vhen selecting a primary AE term to report, sites should 5,elect the term that best describes what 
occurred to the participant. For example, a participant may present with itching, urticaria, 
flushing, angioedema of the fa.ce, and dyspnea. Iftlie underlying diagnosis is determined to be 
an acute allergic re-action, sites should report "Acute Allergic Reaction" as the primary AE term. 
Primary AE terms should be reported using the DAIDS Am erse Experience Reporting System 
(DA.ERS) only if they meet expedited reportitng criteria. Ho.,rever, all primary AE terms should 
be reported using protocoJ-specific case report forms (CRFs). Because the rnported information 
is stored in different. data1hases (i.e., safety and clinical), sites should report primary AE terms 
using the same terminology for data consistency. 
DAIDS AE Gtad.ingTable Carremd ~rsion2.1-July 2.01 
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"\\Then reporting ustng DAERS, other clinicaUy significant events associated 'With a primacy AE 
term that more fully describe t.he nature, severity, or complications of the primary AE te.m 
.should be entered in the "Other Events" section. However, the s,everity grade for these e ·ents 
must be low·er than or equal to the severity grade of the primary AE term. In the example above, 
dy:spnea, and angioedem.a of the face may be entered in. the "Other Events'' section. because they 
are more descriptive and provide additiona.J information on the &everity of the acute aUergic 
reaction. However, their severity grades must be lower than or equal to the severity grade of the 
primary AE term of"Acute Allergic Reaction". 
Differences exist in the r,eporting and recording of information (e.g .• signs and symptoms, 
clinicaUy significant events) in DAERS and CRFs. Therefore, sites should refer to their 
protocols and CRF requirements for further instructions. 
Grading Adult and Pediatric AEs 
\Vb.en a single parameter is not appropriate for grading an AE in both adult and pediatric 
populations, separa..te parameters with specified age ranges are provided. If no distinction 
between adult and pechatric populations has been DIB.de, the listed parameter should be used for 
grading an AE in both populations. 
Reporting Pregnancy Outco 011.t~ 
In the Pregnanc.~ , Puerperium, and Perinatal section, all para.meters are pregnancy outcomes 
and should be reported using the mother's participant ID. If an infant is not enrolled in the same 
study as the mother, any identified birth defects should be repo.rted using the mother's participant 
ID. However, if an mfant is e.nrolled in. the same study as the mother or in another study; any 
identified birth defects should be reported using the inf.mt' s participant IO. Sites should refe. to 
the applicable network standards for report.ing abnormal pregnancy outcomes on the CRFs. 
Determining S1.werity Gt·ade for Parameters beh,'een Grades 
If the .se ·erity of an AE could fuU in either one of two grades (i.e., these ·erity ofan AE could be 
either grade 2 or grade 3 ), sites should select the higher of the two grades. 
Labon,tory aloes 
General. An asymptoma.tic. abnormal laboratory finding without an accompanying AE should 
not be reported to DAIDS in an expedited timeframe unless it. meets protocol-specific reporting 
r,equirements. Sites should refer to the applicable n.etwork standards for reporting abnormal 
laboratory fmdtngi; on the cJinica.l case report forms. 
Values befow Grade 1. Any laboratory value that is bet, reen the ULN and grade l (for high 
values) or the LLN and grade 1 (for low values) should not be graded or reported as an AE. 
Sites should consult th.e Manual for Expedited Reporting of Adverse Events to DAIDS, Version 
2.0 and their protocol when making an as&essment of the need to report an AE. 
Overlap of Local Laboratory Normal Values with Grading Table Ranges. W'hen local laboratory 
no.rma.l values fall ,vith.in grading table laboratory ranges, the :severity grading is based on the 
r.anges in the grading table unless there is a protocol-specific grading criterion for the laboratory 
DAfDS AE Oradi11g Table Com.cted Verruin 2.1- illly 201. 
Pa;__?.e5 


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value. For example, •• 
agn sium, Lov r" has a grade 1 range of 1.2 to < 1.4 mEq/L. 'Ii rhile a 
particular la,b atory's normal range fo magnesium may be 1.3 to 2.8 mEq/L. Ef a study 
participant's ma.gnesium laboratory value is 1.3 mEq/L, the aborat 
value shou db grad d as 
grade l . 
. pp nd 
Append· 
prio ity oYer the main grading table in all assessments of to · 1 bilirubin fur 
te m n 
n onates . 
. ,dd od 1- : Gr din • 
bl 
din Mi robl id 
tudi 
In protocoJ s involving topical applkation of p oducts to the :female and male genital , cts or 
rectum. strong consideration should be given to using ddenda 1-3 (se bel.o,;) acS the p ·mary 
grading tables for these areas. Although th se grading tabl s are used spedfically in microbicide 
studi s, they may be used in othe protocols as adjuncts to tl'l:e mai grading table i.e .• the 
D fslon of AIDS (AIDS) Table/or Gracltng the Severity of Adult and PedlaMc Adverse Events, 
Vimton 2.0). It should be de ly stated in a protocol hich ad endum is being used acS the 
primary g ding table (and thus takes p ecedence over the main grading table) a• d which 
a.ddendum is being used in a complementary fashion. 
• Addendum 1. - Female Genital Grading Tab]e fo Us in Mi obicide Studies-
http://r.sc.tech-re.s.co1nlcltntcal-research-sites/.sqfety-reporttng/cla!cls-grad!11g-tables 
• Addendum 2- Ivble Genital Grading Table or Use in Mic obicide Studi s -
http:/lr.sc.tech-re.s.co1nlcltntcal-research-sites/.sqfety-reporttnglclatcls-gradtng-tables 
• Addendum 3 - Rectal Grading T ble fo 
se in Microbicide Studi s -
http:llr.sc.tech-re.s.co1nlcltntcal-research-sttes!.sqfety-reporttnglclatds-grad!ng-tables 
1 
tim tin 
e it 
d for P 
m t r 
ot ld n m d In h 
r: din T bl 
The . nctional table below should be used to grade the severity o an AE that is not spedficall r 
tdentified in th grading table. In addition, all deaths related to an AE are to be dassifi d as 
grade 5. 
p 
·~·IEIER 
lln c.l advtlH 
1wn.tW2,I 
idmtifild 
1!J1whu1 in th1 
pdinJ tabl1 
Mild 1ympiom1 
U.IISllllll.O or 
minimal 
int1rftr1nc1 ·ilh 
u.ual ,oc:ial & 
:functional lclivLti11 
vLtb in11r.rention 
not indlc:atld 
Modm.til l)'mptom.s 
c1111in1 Ft:lttr tbm 
minllll.&l mtlrftrtnc1 
with un11I 10ml • 
!i.mcttonal :1etNil.1H 
with it,,tll",'tl:ltl>OD 
inclicattd 
GRAD 3 
S 
RE 
S.v1r. 1ympto:m1 
cw1m1 .ma.bill · to 
p1rform u,111] soc11I & 
ftmcttonal activitlH 
1vilh int1Net1>0n or 
hotpitalwtion 
incite ttd 
D.A.IDS AB Orld Ill 'Flblt Con'tctfld Vtnla,11 2.1- Jwr 2017 
Plp~ 
L 
G 
Potetwly lif1-thnrt1ninJ 
1y:mpto:m1 c1111in1 iiu.biU · 
to perform ban: Hlf-can 
functions wttb intffl'mtion 
indicittd to prtvmt 
ptnnmrw: impaimunt, 
penatet diu.bili ~·, or duth 


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Major linical Condition 
Cardiovascular 
PARAJ.\,fETI.R 
Arr!iythmi:a 
(l;>y ?CG c;,r plw•ical 
e'xamitta.tion) 
Specffi, typs, if 
applicable 
Blood Pruou:l'e: 
Abnonu alitin 1 
,ffyp.STt4,uio,i (,,<•irh 
the lQws.>( Yf!adintf 
ta·~n qjhr r-q,~a.r 
t1;1,1#11g duri"l: a ,.,;..ir) 
18 Y WY3 q/ '18·6 
.HypQuntwn 
Cud.iae J:.d,~mi.a or· 
l.n{arctioo 
RepoFt 0 1:1{\, on.r 
Jhart f ailnr~ 
GRADE i 
Mll,D 
Nc;,~yinptc;,m$AND 
Ne;, i!itav~tio!l-
indi<:lli~ 
140 ti;,<: 160 mmHg 
$}'•to.lie 
OR 
ifofo <: 100 m!l)!i,!l 
dia,tolie 
NA 
No S,}'Jtlplc;,IJ!$ A!::lJ2 
Lal;,,;,n,tory Qr 
cudiac i!nagi.u,!l 
ab1>c;,rma!iti!:$ 
GRADE l 
IODERATE 
No 5}'11\l*'m:tl AND 
No)).-wegent 
intervention 
ind~ted 
160to<: 1!10 
ll'lll'lH g ,yJtl>lie 
OR. 
>100to< 110 
;;,mH,1;~tc;,ti,; 
:'.'.9:'it!oto< 991" 
perc utile 
5 mmHg 
~ j~.,d for •ll-•, 
heigM, and. gender 
(~ntolie an or 
dia,tQli<;) 
Symptom., corrected 
wiili. oral flnid 
replacement 
NA 
,Sy~t=• with 111ild 
tQ mc;,de1a1e a,;:tivily 
or exerli,;,n 
GRADE 3 
SEVERE 
Nc;,n.J:ife-threat,,ni!i,g 
!!)'mpt= AND 
Non-urg.,nt 
inte.nrent ion indiot~ 
? 180 m~Jl •yJto!:ic 
OR 
~no~,nHg 
,.fo,tolic 
1!:: 99"' pen;enti½ 
3 mm!¼ adjl,lsted 
for 
hei~t, ""d 
g~der ($}'$Ioli<: 
and/i;,r diartor ) 
Sy~ptom$ AND I 
fluidi indicated 
New syntptom,i; with 
i!chemia (sb ble 
angina) Q! New 
~mg cons;i!lent 
with i!chemia 
$y~ptom$ at re,t or 
,vitt! mi,i.im;il a,;:tivity 
or e·xertion (e .. g., 
i!)'l!OJ\emi1-) ()~ 
!nt~ ·entio11 
indit;~d (e.g., 
,;,~gen) 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Li~-thre~nin,g 
a,rd1yth:mi.i OR Urgent 
intl!rvention indicated 
Li~•threllienin,g 
CQnieque11c~ in • 
p~iPant not 
previouly d.i,Jgn,;,ml 
with h)'P~en..:ion (~g., 
m ,!il;i.gna.nt hypert~!rion) 
OR Hc;,ipitak ~tion 
i:iidicJted 
L.i~-threllieni.n,g 
CQ!1$e(!Uence,i; i.n a 
~ipant 11.c;,I 
prei.,-i.Qu,ly d:i>l.gn,;,sed 
,,.,th hypertens;ion (e.g., 
m aligna.nt l,ypert~
·n) 
OR ttQ~pitalizJl:ion 
indi~Jted 
Shock requiring u$e of 
vuopre5$0M 01 
m ethaniul M1i?;!ance to 
matnt.ain blood premire 
Unstable an,irna O~ 
Acute myocardial 
infarction 
l,i~-~t@I!~,!; 
og~eq1,1enc~ OR 
Urgll.!lt int~;;:tiQn 
indi~•ted (e.g., 
'"''oacti~ meil.ic,d:iim:., 
ventfi<:u.li!, n:i:in device, 
h~ 
tt'!.llJpla,,t) 
I Blood pre$,u.re no,rms for ehildren <: 1 S years of ai:e can be found in: Expert Panel ,on Int~grated Guideline$ for Cardiova,cubr 
Heilth and Risk Reducfam in Children and Adole,c..1145. Pediatri~. 2011;128;S213; originiUy pubfohed c;,nline November 14, 
011; DOI: 10.154 peds.2-00!l-2107C. 
DAfDS Al! Gr.adJni Tab-le Corree~ V~~io11 2. I -July 2017 
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Cardiovascular 
PAR.UffiTER 
GRADEi 
GRADE2 
GRADE3 
MILD 
MODE.RATE 
SE.VERE 
Hanorrhage 
NA 
Symptom; M-U) No 
Symptoms AND 
(with sig,i.ificant acute 
blood loss) 
Prolo~ed PR loten•al 
or A"\ B.locl< 
Report on!,; o»e 
> 16:.,;sars efage 
s 16 year.; of ags 
Prolo~ed QTc 
htten•al2 
Thromho•is or 
Embolism 
Report on!,; o»e 
2 -~ p€>r Ba.zetl' • formula. 
transmrion indicated 
Tnmfmion of .S: 2 
units p ac:lred RBC, 
indicated 
PR inte,:,,;,al 0.21 t.o 
PR inter.al~ 0.25 
Type Il 2m degree 
< 0 .25 seco·nd• 
seconds OR Type I 
AVbloek OR 
l"" degree AVb ck 
Ventricular pause~ 
3.0 sec•o•nds 
1 <t degree AV block 
Type I 2...i degree 
Type TI 2l>l degree 
(PR interval 
AV block 
AVbloekOR 
> normal for ~ge 
Ventricular pause~ 
aod ra~) 
3.0 seco,nds 
0.45 to 0.47 seconds 
> 0. 47 to• 0.50 
> 0.50 !<eoonds OR 
seconds 
;:: 0.06 seoonds above 
ba~e 
NA 
Sympfom; .l!}{"]) No 
Symptoms AND 
intervencl:ioll 
lnterrentroo 
indie.ated 
indicated 
D."JDS AE Grading Tab _ Corrected el'.tion l .1- Jilly 201 
Page S 
GRADE 4 
POTE_i'flIALL Y 
LIFE-
IllREATE.!""-iNG 
Life-thre,a,~ning 
hypotensioo OR 
Tram fusion of> 21llllls 
pachd RBC, (for 
chil.d:ren, pacl:ed RBC, 
> lO tt/kg) illldic~ted 
Complete. AV Mode 
Complet>: AV bloc!k 
Life-thr.,ate-ning 
consequences (e.g., 
ToBade de pointes, 
other associated serious 
venmcul:ar 
dy:;rhythmia) 
Life-thr.,ate-ning 
embo1ic .,i;ent (e.g., 
pulm~ 
embofam, 
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Dennatologic 
PARAMETER 
Aloped:a (,i,calp only) 
Bruuiog 
C!!llul'iri.!: 
II)11oplgw,l!JltatiOJ1. 
Pn1.ritu,.3 
(without skin .!,,3ion,) 
Ruh 
Spec@ zype. if 
appli~ab~ 
GRADE I 
MILD 
De!ttob.ble by ,tudy 
partKipwt, 
cue giver, o.r 
phy1icim ANO 
Ca1u,ingnO· or 
minimal 
interference with 
1nual ,ocral & 
fimctional ac=tivitia 
Local~i>d to o,11e 
ue:, 
NA 
Slight o. localized 
ca.ugmg no or 
minimal 
inieifetencl!! with 
11;.ual ,ooial & 
fimdional '1<lltiviti'e:3 
Slight ot localized 
causing no or 
minimal 
inteiferenee with 
11,ual social & 
fim<>tional i!Ctivities 
Localized to one 
area 
Itching cam<ing no, 
or m:ioimal 
intemrellQI!! with 
usual social & 
GRADEl 
MODERATE 
Ob,-i.ovu om vi.ma.I 
inspectio11 AND 
CaU!ing gr,eater than 
minimal in:terferen<>e 
n<ith usual a,0cial & 
function:.I activities, 
Loealizi!d to m,cre 
Illa.none atea 
• on-parenteral 
heatment indicated. 
(e.g., oral .mtibiotic,, 
mtifung;ili., 
mtiviral9.) 
Markedot 
generalized c:..using 
greater tn:m minima.I 
interfetene,e \vith 
11,ual .social & 
functional activities 
Marked or 
generalized c.aus:ing 
greater tn:m minimal 
intorfereni:,e with 
tu\lal sodal & 
function:.I ;a.ctivil:ie5 
Localized to more 
1hm one area 
ltclung eauomg 
greater than minimal 
intorfl!!rene,e ,vith 
11011al ,ocial & 
fimctional a,:,tivitiec, 
functional activili.e, 
Localized r:ub 
Diffw:e mh 08. 
Target lea:j,;01 
NA 
GRADE3 
SEVERE 
Generalized 
IV tre;a.tment 
indLC;a.ted (e.g., IV 
antihwtics, 
mtifuogah, 
mtivinl9.) 
NA 
NA 
lkhmg C;a.11,ing 
inability to pm onn 
usual soeia.l& 
functional ;a.etiliitie;; 
Diffuse rash 8N:Q 
eiic:,.. or limiled 
n= bet ofbulb.i! or 
mperfu;ial 
11l~eratio;,5 of 
mucOu5 membrme 
limited to one , iii! 
GRADE4 
POTENTIALLY 
LIFE-
teru:ATENING 
NA 
NA 
Life-threatening 
con,equl!llC.e!I (e.g., 
•ep-iis, tissu.e .nec:roa;i!;) 
NA 
NA 
NA 
NA 
Eltlen,ive ot generaliz,e,ci 
bullou~ les ic,n, QR 
UJc;eraliO•n of mucous 
membrane involving 
t\vo c.t 1110.l'i! di.tinct 
muco,al ,.iti!s OR 
Sti!vi!lls•folm,011 
syndro:liie Qlt Toxic: 
epidermal lil!ctol}••i. 
l Fotprurihl• assocra-!ed with injections or infu,ions, •i!e the Site &acriom to htiiretfon,; and Illfl,sions section (p~ge, 23). 
DAIDS AE Giadillg Talilo Ccu:rect~d Ver.ion 2.1 · ul}' 20 I 
Pilgl! 9 


CONFIDENTIAL 
Protocol Gates MRI-TBD03-201  
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Gates Medical Research Institute 
107 
 
 
nd rir e and Metaboli 
Diab tu :\:l1llilu1 
G)iu co11111tl1 
Jl,'J?olbyroidil m 
lpo1tropb 4· 
RAD l 
flLD 
Controlltcl without 
mtclication 
D t.ctabll by 1tud>· 
panic.ipm~, 
car1.1 twr, or 
physician Alil2 
C111ill1 no• or 
millim,il 
illtuh11111c1 with 
111u,il 1oci.1l & 
funct1.011al utiviti.1 
No l)'.mptom1 &::r.12 
Abnormal 
labontol'"J,' valu1 
No 1ymptom1 
Abnorma.1 
labontol'"J,' valu1 
D t.ctabll by 1tudy 
partic.ipmt, 
car11twr, or 
physician Alil2 
C111in,1no,or 
millim,il 
illt1rh11111c1 wilh 
111u,il1ocial & 
fuuct1.0nal u tivi 111 
Co111Iol11d with 
m1clic.J.tic11 .Qi 
Modiflcalic11 of 
c11m11t mtclication 
HJlnllll 
Obvio111 on vm11I 
ill1p1ction 
C IU_IUIJP,iln ·Ith 
11ul1r thm millim,il 
illtm11m01 with 
1111111 IOCW 
fun.ctio.nal a.clr,i.li.11 
Symptom, c1,111ill1 
11ul11 thm millim,il 
illtwrm01 with 
11111al1ocia.l & 
fun.ctional a.clr,ili.11 
QE Th)'roicl 
1uppnnio:n ih.uapy 
illclical.td 
Symptom• c ,111-ill1 
l,'l'Hlu thm millim.J.l 
illtwrm01 with 
11111al1ocia.l • 
fim.ctional ctr,iliu 
Q.&.Thyroicl 
raplac1m111t fumpy 
inclic:11.td 
Obvio111 o.n vuual 
ill1p1ction 
C1u1illJ Jr 1t 11 th:an 
mintmal int.rfu1nc1 
with u1111I ,ocial • 
fun.ctional aetr .. ili11 
U11oc111trolltd dupit1 
i:11tme11t 
modlfic1tio11 Q.& 
Ho1pitali:1t[o11 for 
imm1d1.1t6 1luco11 
con·trol mdic1t1d 
Dil£iiurill1 chan111 
81:mSymptoms 
n,quirin1 int1N1ntio11 
or ca,111m1 inability to 
puf.onn 111111! ·1oc11.I 
ilnctional 
a.ctivitiu 
S>·mptom1 c.1111m1 
inability to pmo:rm 
11111:al 1ocial 
fundicnal a.ctr.•i liH 
QR Uncontrolltcl 
d11pil1 trutmmt 
modlfic1tion 
S ·mptom1 uu1m1 
illabilitr to pmo:rm 
11111.al 1oci1I 
flmctto111l a.ctr,,ibH 
QR Unco11troll1d 
d11pil1 trutm I 
modif!!!ation 
Dil£iiurill1 chan111 
Dtfmibon: A -cltt:ordu char ct111:1d by &t lou in th• face, 1Xll'lmi1i111 1.11d buttocb. 
DAIDS AE Or (ljlll Tlbll Commd V1nloit 2.1-July 2011 
Pap 10 
GRAD 4 
POT NTL,U.LY 
LIFE-
Lif1-thrut111m1 
COIIIIQ.UtllHI (1,1,, 
lltt0Ki.:101a, 
byp 101mow 011-
ll,.to-bc coma, 111d orim 
fi1hmi) 
NA 
Li£ -thrute11m1 
COllltqUtnHI (1,1,, 
diyroid 1tonn) 
Li£ -thrut1nm1 
QOllltqUtllCtl (1,1, 
myudtma coma) 
NA 


CONFIDENTIAL 
Protocol Gates MRI-TBD03-201  
[Version 4, 07 Jul 2020 
 
Gates Medical Research Institute 
108 
 
 
ndocrine and 
etabolic 
PARAMETER 
L ipohype.rlrophy 5 
GRADE i 
GRADEl 
GR.ADE3 
ULD 
l.lQDERI\TE 
SEVERE 
Detectable hy study 
Qbt,-i.olU on visual 
Di'l,fi!lllrin!l ehan!les 
parf ip~t, 
mspeclion AND 
c::aregi\rer. o·r 
Cau,mg gr-eater than 
phy; icirui AND 
mmilnitl {,,~m:rente 
CalJ,!~~:no ,;,r 
u,ith ~1;1al 
& 
minim.al 
functional activilies 
iniemr~1>ce with 
u~ual !ocial & 
f\J.n,;:tiQ11al .activit ·e• 
DAmS AB O.adi~g Tab . Con:-o,qed \ei,;i.111, J.l• J1,Lly 1017 
~ge 11 
GRADE 4 
POTENil,U,LY 
LIFE-
THRl.ATENlNG 
NA 


CONFIDENTIAL 
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[Version 4, 07 Jul 2020 
 
Gates Medical Research Institute 
109 
 
 
 
Gastrointestinal 
PARAMETER 
Alloru:ia 
Ascites 
Bl..,,t±ng: or Dis tension 
Report on{~ o»" 
Cbolecystitis 
Con• tipation 
Diarrhea 
2 1 .,eflT ef age 
<= 1., .. ar ofag" 
Dy•pb"',gja or 
Odlynoph._i::iia 
Report on{~ o,i., a.,rd 
specify k,.c.alior, 
Go.trainte• tin.I 
Bleeding 
GR.\.DEl 
GR.\.DE2 
GRADE3 
MILD 
MODERATE 
SEVERE 
Loss of appetite 
Loss ofappetite 
Loss of appetitE! 
w;ithout decrBa:Sed 
a3"oc:iatecl with 
associated ,viii, 
oral inta,k:e 
decreased oral inta,k:e 
significomt we.i~ht 
without ,jgnillcam 
loss 
wei_gi.ht loss 
ro ~
ptoms 
S·ymptoms .l!J{l) 
Symptoms recur or 
Intervemio-n 
per.sis! despite 
indicated (e.g., 
intervention 
di.metres, therapeutic 
p=acentesis) 
Symptoms cansing 
Symptoms causing: 
Symptoms causing 
n o or minima.I 
greiater &m m inimal 
inability to perfunn 
interference with 
interference wil!h 
usual social & 
usualsoc:ial & 
usnal rocial & 
fundional .icti.--iti-es 
functional activities 
functional activities 
T_A 
Symptoms A [I) 
Radiologic, 
Medical intervention 
endoscopic,. oY 
indicated 
oper.iti,;e 
intervention indicated 
TA 
Persistent 
Ob!rlip;ition with 
c:on!rlip.ition 
manual e,·acu.ition 
requiring regular u.se 
indi<:;sled 
ofd.iewy 
modmcalions,. 
laxati,,;:es, or emie·mas 
Transiemor 
Persistent episodes 
lnc:rease of 
7 
intermill:ent 
of unformed to 
stools pE>r 24-hour 
epise>des o-f 
watery stools OR 
per.rod OR I fluid 
unformed stoo1s OR 
fucreiase of 4 to 6 
repla.c.ement 
Increase c,f :,'.; 3 
·;tools <>ver ba.cl>lme 
indicated 
etaols o-,.,- b.iseline 
per 24-hour period 
per 24-hom period 
Liquid stc,c,h,; (more 
Liquid stools wiili 
Liquid stools with 
unformed than 
in.creased number of 
moder.ate dehydration 
usual) but u,,-u.al 
stools OR Mild 
number of ~fools 
dE>hydr.ati<>n 
Symptoms but able 
Symptoms causing 
Symptoms c.iusing 
to e.it usu.il diaot 
a.l!Eored d.~bry inta,k:e 
se>'l!rely .iltered 
with no mterventio.n 
dietary mtake with 
indicated 
intervention indicated 
Tot reqnR:ing 
Endm cop•re 
Trans fusion indicated 
intervention oilier 
mien'l!ntion 
than iran 
indicated 
supplement 
DAIDS AE Gtading Table CarreC!Ed Version 2. l -fuly 2.0-1 
Page 12 
GR..\.DE 4 
POTEL\''IlALLY 
LIFE-
THREATENING 
Life-threatening 
c.on,equences OR 
Aggres~r"'-e interventi.o:n 
indicated (e.g., tube 
feeding, total p2<renteral 
nutrition) 
Life-threat.enocg 
co·ng.eq11ence 
NA 
Life-threatening 
c.ong.eq11ence (e.g.-= 
sepsis, p erfaration) 
Life-threatening 
co.ns.equences (e.g.:i 
obstruction) 
Life-threatening 
c.onsequences (e.g., 
hypotensive ,hoclk) 
Life-threatening 
c.onsequences (e.g., 
liquid 
res.ulting in 
se>'l!re dehydration, 
hypotensive shoclk) 
Life-threatening 
reduction in or"1 intake 
Life-threatening 
c.on,equences (e.g., 
hypotensive ,hoclk) 


CONFIDENTIAL 
Protocol Gates MRI-TBD03-201  
[Version 4, 07 Jul 2020 
 
Gates Medical Research Institute 
110 
 
 
Gastrointestinal 
P~JETER 
Muco.oiti, or Stom atifu 
Rspon on(\J onB and 
•P"~W' location 
an1e1 
P ancrH!itb 
Perl'oration 
(oolon orreclum) 
Pro<:IHia 
Rectal Discba,·g• 
, omiting 
GRIDE I 
GRJ\DE2 
CRADE3 
MILD 
IODER.ATE 
SEVERE 
Mu«>••I e1y them.. 
Patchy 
Confl111mt 
p,eudcnneml>.r.i.ne, or 
p, eudomembr.me• o.r 
uk:er.a.tions 
uli>eratiou, OR 
Muco,al bleeding 
with minor trawna 
Tran•ient ( < 24 
Per.istent nausea 
Penrnent uau.ea 
nour!) or 
re,ulting in 
resulling .in mmim:al 
intermittent A ~D 
d,,uea,ed oral intm 
oral iDtdoe for :,, 48 
oormwimal 
for 24 to 48 houn 
hours OR 
int•riereuc-e n,ith 
Rehydration 
oru intake 
ind.-:at.!d (e.,g., IV 
fluid,) 
A 
Symptom, with 
Symptoms " ~lh 
ho,pilalinti.m not 
ho:;pital.ization 
indicated 
indicated 
A 
NA 
Int...-vention 
ind.-:at.!d 
Redal discomfort 
Symptom, causing. 
Symptom, cau,ing 
with ll0 intervention 
gr..ater than minimal 
inability to perform 
indi<,ated 
inteoo ... ce with 
u•ual social & 
u.ual rocial & 
functional activities 
functional activities 
OR.Operative 
ORMed""'-1 
inl.ef\'ention indicated 
intenrention 
indicated 
· isible discharge 
D,,charge requiring 
NA 
the u,e of pad, 
Tran•ient or 
Frequent epioode• 
Penrnent vomiting 
intMmiltent A "D 
wnhnoormilil 
resulling in 
o or minimal 
d.ehyd.ralion 
orthosbtic: 
intmerenc-e n,ith 
hypoh!mion OR. 
oruintm 
AggreHi,-. 
rehyd~tion indicated 
(e.g., 11, fluid.) 
])AIDS AE Or.ading Tobie Comded Venfon 2.1- July 2017 
Pog,, B 
G-RADE4 
PO'In,"IL'\LLY 
LIFE-
THREATENING 
Life4hreatening 
C.0D9"'!Ue!lC1!9 (e.g., 
.,.p,iration, ohol:ing) OR 
Tissue necrmis OB. 
D·iffiue spoubneou. 
m11c05al bleeding 
Life-th.reatening 
con~uencs (e.g., 
hypoteruive •hocl:) 
Life-th.realenin;g 
con•,equenc,eg (e.g., 
circulatory l'a.i[ure, 
hemorrhage, ,ep•io) 
Life-threatening 
C:.0D!<!qUellC.'1!!1 
Life•threatenillg 
c.on•,equencu (e.g., 
perforation) 
NA 
Life-threatening 
c.on,,equencs (e.g., 
hypo~eruive •hocl:) 


CONFIDENTIAL 
Protocol Gates MRI-TBD03-201  
[Version 4, 07 Jul 2020 
 
Gates Medical Research Institute 
111 
u ulo eletaJ 
p 
l· TER 
RAD l 
GRAD :2 
RAD 
GRAD 4 
MILD 
~IOD RA, 
,, 
POI ·NTIALL 
LIFE-
TBREA:11:.,1:uriG 
· rtbral1i1 
Jo int pa.ill c1111iri1 
Joml p~ CW.lmJ 
J.oint p1.w c1u1in1 
Dinblin1joint paw 
noo mm:ioul 
lfllhr th:m minimil 
inability to p1rfo:rm 
Cll.lllUII 1n1bih ' to 
interftrenc, with 
intmHIIICII with 
111ual 1oci1l & 
puform b IC 1t.J:f'-can 
111u.al1ocia.l & 
11111al1ocil.l 
fimctio111I a.ctr.•' LU 
ftmctiona 
fiIKhona.l u tivit1u 
fum:tiona.l a.ctr;itit1 
• rtb id1 
Stdmu1 or joint 
Stifln111 or joint 
StifflltH ar joint 
Diu blin1 joint 1ttlln111 
1 ·1llin1cw1inJ 110 
aw 11w, uu1w1 
l,,·1llinJ ClUIDlJ 
or nn!H11,1 c1111in1 
or mlnim.al 
lfHhr th;m minim.al 
inability to p1rfo:rm 
inabilitr to perf'cnm 
int1rftre11c1 with 
intm1r111c.,,, with 
111ual 1ocial & 
b11:ic 11lf.cir1 ~t110n1 
111u.al 1ocia.l & 
11111al1ocil.l& 
fimctio111l a.ctillitiu 
fuKt110na.l u tivitiu 
fum:tiona.l a.ctr;ili.11 
~f)•.11111 (p11m!i%1d) 
M111dtpllll 
M111cl.1 p1in ciuiin,1 
M111cll p•llD cau1inJ 
Diu blin1 m111dt pain 
ca.u1in1 no or 
lfHbir th;m minim . .ll 
inability to ptrfo:rm 
c1.111in1 inability to 
minim.a.I 
intmHIIIC:,I with 
111ual 1oci1I 
perform butc 11J.f-can 
int1rftre11c1 with 
11111al1ocil.l 
fimctio111l a.ctr.•iliu 
ftmction1 
111u.al 1ocia.l & 
fum:tiona.l a.ctr;it'it1 
fuKt110na.l u tivitiu 
0.1 ttO:llltl'OI b 
NA 
o 1ymptO"m1 but 
Bon, pllD with 
Diu blin1 bo111 pain 
with r.icliol,fl,phic 
r1clioF1phrc fi.DclinJa 
w.ilb r,a.cl io1r.1phrc 
f1.11clinJ1 
No 
QEOptntiVI 
rm.clinp c:a.11,iq 
optra.ti,... 
inttr\' tio:n incl1eatH 
inabtlit)· to perform 
inhrvmtion 
b11:ic Hlf.cir-1 ~t110n1 
ind.ic1t1cl 
0 1 teop1nb • 
:i: JI) ~um qf a,• 
BMD t-1co11 
"A. 
NA 
NA 
-2.Sto -1 
< J()J}l/11'& o/a,t 
BMD z.•IOOfl 
lA. 
NA 
NA 
-2 to -1 
0.1t1oporo il 
:i: JI) ~um qf a,• 
NA 
BMD l'•ICOH < -2.S 
Pi tholopc fr.Idun 
PJ.tholopc fra.cturt 
(1,1,, compr111io11 
Clllllinl 1:if'l-tlrrntlnin1 
fh.ctun c,1.u11a11 lo11 
COllll4Utn.Ctl 
of vlriabral h•i,1111) 
< 50 J!HI'& Qf'a,r, 
NA 
BMD Z•IC.OU < -2 
htholopc fra.cturt 
PJ.tholopc fra.ct11r 
(1.1., compr11,io11 
c:t111in1 li£'1-thrutlnin1 
fi".ictuu c,1.usm1 Ion 
co1111qutn.ct1 
of vw:bnl hti,lhl) 
' B:MD t mcl z 1cO"rts cm b1 i'oimcl m: K:mu JA 011 b Juli' of th.1 \Vo Id HHlth Olpll m.tio11. Sci111tific Group (2007). Au nm.t:llt 
of 01lloporos 
,1.t tht, p.rimlll)' b1a.lfu-ca.n llv, r,ch11ic1l R.tport. \V orlcl Hu.Ith Orim wtio11 Colaboratw1 C1ntr-1 for 
M ubolic. Bone D1111111, Uni.v·mity ofS.h1ffltlicl, UK. 2007: PrmtH II}• the Unmnt · ofSh1ffi1ld. 
DAIDS AB Or1(ljn, Ta'tllt Commd. V:1nio~ 2.1-July 2017 
~pl4 


CONFIDENTIAL 
Protocol Gates MRI-TBD03-201  
[Version 4, 07 Jul 2020 
 
Gates Medical Research Institute 
112 
 
 
urologic 
PARAMETER 
Altorocl h•Ie:ntal Status 
(for 0 11:mentia, ,,ee 
Cog,,i.th'6, Beha,,ioraL or 
Alt81ltio""1 I)iotuYban~• 
belo"') 
Atuia 
Co.gnitive B,e:liavior.al, 
l)r AtiontionaJ 
])iolurl;, one• {incllldi,, 
,lementia and attentiQn 
defu;.it d~order) 
Sper:roi ,yp.., tJ applicahls: 
Devol.opmentaJ ]).,Jay 
.c l 8 Jl""" qf.~• 
Hudacbe 
NA 
GRADEi 
1JLD 
Change.: c.au~i,,g no 
Qrmi,,imal 
intl!rf,e.~nee with 
lll'll•l$OCi;Jl & 
nmctio-n.al activilie, 
Symptom, c.-u,ing 
no 01 minim.al 
· 
inierferen.ee with 
u,;11al W<:lil! & 
NA 
GRADE:? 
IODERATE 
Mild !ethrgi.• or 
$Ollll!Ol1>11~ ca11,ing 
greater than minimal 
inl<1rfi1r<1n~e "'~ 
IJ$11a.l ,oeial &. 
fimctional .acti\riti"' 
Sy1nptom~ camini:; 
greater than m.inimal 
interference with 
11~,ocial&. 
functia,n.al activilie, 
functional .u:.ti\ritiie< 
OR No ,ym.ptom,. 
with ataxia detected 
on eit:>mination 
Oi,ability cauiing 
no ot minim.al 
interie.renee with 
ll:<ulJoci.al& 
fun,:lion.al activilie, 
OR Specialized 
re:;ource, not 
indic<>tod 
Mild dovelc:,pmentil 
d.ehy, 
or ,c,o.~rtlveJ a!!, 
detiermin..d by 
compari<on ,vi.th • 
de,•elopmental 
,cre1>11mg tool 
appropr~te for the 
setting 
$ympto.m, c.,u,ing 
no or minim.al 
interfe.ren.ce with 
U$11al Joe.ml & 
ninctio•nal activitie, 
Dinbitity ~a11sJ!l11 
~eater than m.inimal 
inte~r41nce "'ith 
1J$11al 1ocial &. 
functional .ac.ti\riti~ 
OR Specializod 
re,our,e•• on p,µt-
time lm~ iJ!d~atod 
Moder.a.to 
developmental dela,y, 
eilher motor or 
cognitive~ .J. !!l 
determined by 
comparison wilh a 
developmental 
scr,eening to<>I 
appropriah! for the 
sett~g. 
Symptom,< cau,ing 
greater llm1 minimal 
interference with 
1Jmit 1ocial & 
fiimctional .adnriti~ 
GRADE3 
SE\'ERI. 
Tran · nt i!.~m:i,c 
attack 
Con.fu,ion, mi,mory 
imp,ainnent, lethargy, 
or ,omno~niee 
ean,ing inability le:, 
pe!f<>rm. 1,1~al ~<>~I 
& functional 
activities 
Synwtom• cau:.ing 
inab llity to perf<>rm 
u,ual ,ocial & 
functional activities 
D~ability cau,ing 
inability tc:, porf<>rm 
1111,1al •oci.a.l & 
functional •~tivitie$ 
OR Sp,ecia.~ 
ro,ome~ 011 • ftill-
fune b~i, indi<:ated 
s.,\·er• 
develop,menta.l dohy, 
either motm o·r 
co~ibve:1 as 
determined by 
comparison with a 
developm1>11tal 
screening tool 
a,pprop~e for the 
s,ettm.ii 
Symptoms cau~ing 
m,a.bility le:, perform 
119ual,ocial & 
functional a.~tivil.ie$ 
DAIDS -'i.ll G!.a.d.in:g Tal>I• Corretll!d V:trsio11 2.1-Jufy 2017 
Page 15 
GRA.DE4 
POTENTh\LLY 
LIFE--
IHREATENING 
C&ebral v••cular 
•tci~nt (,e.g., ,;trQh 
,vi!h neurok,gical 
deficit) 
l)el:iriumOR 
Obnmda.tionOR 
Coma 
Dis.abli'lg sympt<:>m, 
caming inability to 
pemmn basic ,.,Jf.care 
function, 
Dui.ability eau,ing 
inability to porform 
ba,ii: ,elf~re function, 
OR In1titutic:,naliz:.tiQn 
indica!<!d 
DevelopmenW 
re~e,,-inn1 etther 
O'f cogn.iti,.et .a.s 
determined by 
co·mpa:rison with .a 
developm1>11tal 
!!ueenlllg tool 
appropri;te for the 
2iettin~ 
Sympt<>m• causing 
inability to perform 
ba,ii: ,elf-ea.re fundiQns, 
OR Hoapilaliµtion 
indicated 9~ Headache 
tvi!h ,i~fi=t 
impau:ment of alertn.ee$• 
Qr other n~urql,ogii: 
function 


CONFIDENTIAL 
Protocol Gates MRI-TBD03-201  
[Version 4, 07 Jul 2020 
 
Gates Medical Research Institute 
113 
 
 
 
eurologic 
PARAMETER 
Neu.romwcula.r 
WeakoesB (includes 
myopathy ad 
1!1e1!1Iopathy) 
Specj_(j; t,ype, if applicable 
Neu.rosemoey 
Afteratio.o ( inelud.es 
pare;the!-ia and painful 
nel'.IIopathy) 
Specj_(j; t,ype, if applicable 
Sazury 
New O,uet SeizJITe 
;,: 18 yeaYS of age 
< I 8 J,"B'{H'S ofa;ge 
(includes new or pre-
;;xistingfebri.le 
seiEures) 
Prs-existina S e~ure 
Syncop~ 
GRADE I 
GR.ADE2 
GRADE3 
MILD 
MODERATE 
SEVERE 
l\.fuiim:al muscle 
Muscle ·u,reakne;g; 
Mnscle weakness 
wea,knes:; causing 
cau!ring greater tfom 
cansing inability ro 
no or minimal 
minimal intezferellce 
perform u!!Ual $ocia.l 
in~rle.re,nce with 
with usual :;oeL1J.I & 
& functiollal 
u:;nal s;aci:al & 
functional aeti,rities 
activities 
fimctirm:al aetivities 
OR ·o symptoms 
with decreased 
atrengj!I, ,an 
,ex;ammalian 
lll1inim:al p;ues.thesia 
S en:;ory alteration or 
Semory alte-r.rlion or 
causmgoo or 
paresth,esia cansing 
pareslhesia ,eau:;ing 
mmimal 
greater Ihm mmimal 
inability to pezform 
int,,s.rl'e.re,nce w:it!h 
interference wifh 
us.uahocial & 
u:;nal s;aci:al & 
U$Uil social & 
funetional activities 
functional activities 
functional aetivities 
OR ·o symptoms 
with s;en:;ory 
alteratio11 011 
,i,.'Qmmalion 
NA 
NA 
1 to 3 se.izure5 
Seizure lasting < 5 
Seizure mli:ng 5 to< 
Seizme lasting?: 20-
mmutes with < 24 
20 minutes wiili 
minutes OR > 24 
hourg poSilicbl state 
< 24 homs pos.ticl::al 
how:s postictal state 
51ate 
NA 
Increased frequency 
Change in seizure 
from pre,;.-ious level 
charaete.r eifher in 
of eoDatro.l wilholilt 
dm-ation or ,quality 
chmge in seizure 
(e.g., severity or 
character 
foc:ality) 
Ne..- syn.cope 
Loss of 
Loss of 
without loss. of 
c.oo~cionsness \:with 
conscioum~s AND, 
eor,sciouSllesg (e.g., 
n.o in.ter11·entio:n 
Hospitilizatio11 or 
pre-syncope) 
indtc:a.ted 
intencention required 
D.o\DS AE Gt-ading. Tab . Corrected Verno,n 2.1- Jnly 201 
Page 16 
GRADE4 
POIT.NI'IALLY 
LIFE-
lHREATENING 
Di2bling ml!lscle 
weakness cansing 
inability to pezform 
basic self-care funetio m,s 
OR Re,a;pi,:;,tory mllscle 
weakness impa:i,:ing 
ventilatio,. 
Di2bling sensory 
alt.eration oY pare.5thesia 
causing inability to 
perform basic self-eaoe 
funetions 
Prolonged md repetitive 
seizures (e.g, :;tatus 
epilepticus) OR 
Difficult to control (e.g., 
refract.ory epilepsy) 
Prolonged md repetitive 
seizures (e.g_,, :;tatus 
epilepticus) OR 
Difficult to eontrol (e.g., 
refractory epilepsy) 
Prolonged md repetitive 
seizures (e.g.,. :;tatus 
epileptrous) OR 
Difficult to eontrol (e.g.,. 
refractory epjlepsy) 
A 


CONFIDENTIAL 
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Pregnancy, Puerperium~ and Perinatal 
PARA.'1ETER 
GRADEi 
GRAD:E:l 
GRADE 3 
GRADE 4 
MILD 
MODERATE 
S:EVERE 
POTENTIALLY 
LIFE-
THRI.ATENING 
Stillbirth (report u•inl! 
NA 
"A 
Fetal dnth occurring 
NA 
mother' i participmt ID) 
al?; 20 weeb: 
RepoYt ,ml~ Olli< 
g.,.lation 
Pre,term Birth (report 
Live birth .it 34 to 
Live birth .it :lS to 
Live birth .it 24 to 
Live birth .it < 24 ween 
ug.mg molher' g. 
< 37 weeks 
< 34 weeb: 
<28 weeb 
ge,lationll a,ge 
parttc.,p.ant ID) 
gi!:slation:.I a,ge 
gE!almn,1.l age 
gl!:51ation:.I .ig• 
SponhmH111 Abo:rti1111. 
Chi,m"""1. 
Dncomplie,ated 
Cc,mpiiic.a.ted 
NA 
or Mi,urriag• (report 
pregnancy 
spontmeo,,u abortion 
g.pontaneous aborlio,n 
usmg mother'!-
o.r miscmi;.ge 
or miscmiage 
pmte,pant ID) 
RepoYt o,i{~ t,,i;, 
7 Def'mition: A pregnancy lo n occurring ,31 ,,. 2:0 weeb ges:btion:.I age. 
DAfDS AE Oracling Table Co.ttec.te<I 'enion2.l-July Wl? 
P~ge 1 


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115 
 
 
P ycl iatric 
p 
fEIER 
l omni• 
P1yclli1trie Dllorde 
(wctud11 an:,;i t)·, 
d1prti1ion, mania, l.lld 
P•>·cho1i1) 
S'JmW, d/1,0rd11 
S lcldal Id lion or 
• Ut pt 
R,pon 011/y o • 
Mild clifficul · 
fallin1 nit p, 
lt1)'1111 ulttp, or 
wakin1 up 1uly 
ca,111.i.n1 no or 
minim.al 
intufer111c1 with 
11111,al 1ocial & 
~
tional &etivit1111 
Symptomt 
Lth 
irit11'\11ntion not 
iridw:attd.Q& 
134h ~·io c1u1iri1 
noo mm:imal 
intuf1r111c1 with 
11111l.11ocial& 
~tional &etivit1111 
P:rtoccupttd ·ith 
lhoUJhh of death 
~Nowi1bto 
kill OM 11£ 
GRAD 2 
. IODERAIE 
Modtnlt dtffiau.lty 
fallm,a 11le1p, 
1hi)·in1 aslup, or 
wakin.J up early 
c11111iri1 mort, lh111 
minimal ininftrlDCI 
with \ljUal J()dal • 
functional actr.·ili11 
Symptom, wilh 
intffll'mtion 
indlc1l1d.Q& 
B1h1vior cau1in.J 
11u11r thm miriim.al 
intfflHIDct, With 
111ual 1ocu.l & 
functional actr.·ilit1 
Pr1o=ipied wtth 
lhouptl of iluth 
~Wilh tokill 
0.111111£ with no 
1p1eific plan or 
intmt 
Slr\'m,difficul · 
tilliq 11lt1p, 1iayin1 
ulup, or akin.J up 
early cm1in1 
iriability to pufo:nn 
11111:al 1oci1I • 
functtonal a.cti,.,itN'I 
r quirinl mlll'\IIDlion 
or ho1pit1lwtio11 
S ·m9tom1 with 
bo1p1talmtiim 
inclicattd QI, 
B havio c1u1in.J 
iriabil' · to pm'o:nn 
11111.al 1ocilll & 
functtonal a.cti\oitNt: 
Tho11p I ofk:illin1 
on11tlfwilh putta.1 
or complll1 pl1111 but 
no 1ttunpt to do 10 
Q&.Ho1pil1lwtion 
inclic:attd 
OAmS AE OucUq:T1bl1 C0'1'1'1Cltd Vmlo.112.l• ul),· 201? 
Papll 
GRAD 4 
POT NI'IALLY 
LIFE-
THREAI 
NA 
Thru11n1 h1nn to 111£ 
or oth111 QR A£utl 
p1)•cho1il QE BthJ.vior 
cm1in1 mabiil · to 
perform buw: Hlf-can 
functtoDI 
Suicid1 a.tttmpttd 


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Re piratory 
PARA .. \1ETI.R 
Dy1poea or Ru pintoey 
Di.tfres1 
Repol'l on(y one 
GRADEi 
AULD 
Forsed ~xi;>i.!';itory 
vg,lume in. I ~•cond 
or peak flow 
reduc~to 
> 70 to .s:: SO% OR 
Mild 'Yll\P!Q!!'5 -
,vil!, inten1entioi, 
noti!,di,;~ed 
Dyspnea on 
exertion with no -or 
minim.al 
int~rference with 
uiu;il •ocial & 
functional ac:.tr..-ities 
Q_~ \\lhe~-~ p~ 
Minimal ii>crea,e in 
re,pi.!';i.tory P!i:!! £01 
~e 
GRADI2 
MODERATE 
f on,ed e1<pmitory 
voh:!.me i.n I ~econd 
or peali; flo•w ·o tQ 
<: 70% OR Sympto1nJ 
"~th inti,,:ve.nti:on 
!lll:l:icat,id OR 
SymptomJ causin,!! 
!f]'eater than min~ 
lll!w'°eren~e ,..,jth 
11,11al ,o,;id & 
fimctiqnal <1-CtiviJ-ie:! 
D~••pnea on exertion 
can;ing greater than 
minimal-interfarenee 
"~ u:rual •ocial & 
ftuictiQnal a.i:;tivitie,i; 
Na$al flaring OR 
!ut~o,tal T•etractig,ns 
Q~ PiJ.IJ;e oximeb)· 
90 to< 9~% 
GRADE3 
SEVERE 
Fon;~ e;,;:pinitor}' 
vo~me in l second 
or peak :t,g,w :.l:5 to 
«:50% OR 
SymJJ!om, Cl!.ll!lin;!): 
inability lo ptrform 
1m1al $OC~ & 
fun.ctional acl:i~•itie~ 
Dy!pnea at rest 
CllU9ll\j!: in:obility to 
penoTm u,nal $Dcia.l 
& fundi<)nal 
activilie, OR P'1he 
g,ximen;• .s::90% 
DAIDS . .m Gtadin~ Table CorrectEd V:er~ion 2 .. l .Juty 2011 
.~ge l9 
GRADE4 
POTENil,i\LLY 
LIFE-
TIDtEATENING 
Porced ~xi;>iratory 
volume .ii! l ~eeg,nd ,;,r 
peal: flow < 5% OR 
Life.threatening 
re•pi{;itory or 
hemodyn;=:ic 
compromi,e OR 
Int,,,.l,,iJ.!ron 
--- -
Re•piratory f.ailn,e with 
1,e.ntihtor ,upped 
indicated (e.g., CPAP, 
BPAP, mtub~tion) 


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Sensory 
PARAl1ETER 
H•oring Lo,s 
;e: 12 ye,us of ag.e 
-s:: 12 ye,zrs of,.g• 
(&as.a,;/ on a I, 1, 3, 4, 
15 and 8 k& 
audiogram) 
Tin11,tu• 
UveLtb 
,emgo 
Visuol Change~ 
(assessed from baseline) 
GRADEi 
GRADE2 
GRADE3 
!\,OLD 
YODERATE 
SE.VERE 
NA 
Hearing aid or 
He-aring aii.d or 
inten.ention n.ot 
intep;,ention indicat!!d 
indicated 
,,_ 20 dB !tea.ring 
,,_ 20 dB hBaring loss 
,,_ 20 dB hea.ring oss 
loss at 
4 kHz 
at:::, 4 kHz 
at 
3 kHz in one ear 
tv:ilh additional 
s.psecli lang,uge 
reh t!!d serviioes 
ind.icat..d ( wh..re 
availabl\a) OR 
Hearing loss 
~..nt to indiioate 
fue,apeutic 
intervention,. 
ind\iding hearing 
aids 
Symptoms causing 
Symptom• cauring 
Symptoms c.aus.ing 
no or minima.I 
greater than minimal 
in•hili:ty to perform 
interference with 
interference ,vith 
usual social & 
usual social & 
nsual ·social & 
functional adi:vit,,ae; 
functional adiseiti;>; 
funcilionaJ activities 
with intervention 
M!h inten.ention 
not indiioated 
indicated 
No symptoms AND 
Anl:E!rror ui.eim with 
Posterior or pan-
D"teotable on 
symptoms OR 
uv..itis OR Opera.tis"' 
examinatton 
Medt=I inten;ention 
intep;,ention indicat!!d 
indicated 
V<!rligo causing 110 
Vertigo cmsing 
Vertigo causing 
ormmimal 
greater than minimal 
inability to perform 
interference with 
interference with 
usual social & 
usual social & 
usual .social & 
functional ac.ti:viti<!s. 
functional ac.tivit,~ 
fimcilionaJ activities 
Visual changes 
Visual changes 
Visual clianges 
causing n_o or 
ca:nsing grn:a,ter than 
causing inability to 
minimal 
minimal mterferenee 
perform uruaJ soe:iial 
interference with 
M!h =•I rocial & 
& functional 
usual social & 
fimetionaJ activities 
activities 
functroi,aJ ac,tis,it,~ 
DAIDS AE Gtadin:g Ta'!Jle Correcred Vusion2.1-Jruly 2.01 
Pa.ge 2-0 
GRADE4 
POTENTIALLY 
LIFE-
THREATENING 
Profound biht!!ral 
b.earing !os.s (> 8.0 dB •t 
2 kHz and abov<!) OR 
Non-_;en'll:e>b le bearing 
(i.e., > 50 dB audiogram 
and -s::50% speech 
discrimination) 
Audiologic indiioation 
for coehlear implam and 
additional speech-
languag" related 
serviioes indicat!!d 
(wher" °';ailab _) 
NA 
Di..o.i.blillg visual loss in 
affeot!!d eye(s) 
Dis;ablillg vertigo 
causing inability to 
perform bas.re self-ca.r<! 
functiions 
Di..o.i.blillg ,eisual loss in 
affed!!d e}'e(s) 


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Syste:rnic 
PARAMET£R 
A.~ule All,ri::ic 
Readfoo 
Chills 
Cytokioe Rell!aa Ii! 
Syodrome 6 
F aligu,e o.r i!\fi11u e 
Repon 011(); 011s 
F enr (non•a.x:ilhry 
lemperature9 only) 
Pain~ (no,t associaled 
with stud,• agent 
inj ectLOD$ and not 
,peci£1ed ehev,ihere) 
Specif.j; foc(JJ_icm 
GRADE I 
j\ffl.,I) 
Loca!Ul!!d urticaria 
(wh•ab:) with no 
medico-al inler,~,ti.on 
indicated 
Symptoms caus.ing 110 
or minim..i.l 
interferenc,e with 
umal social & 
fimdion~I activilie,. 
Mild ,igi,5 and 
symptom, AND 
Therapy (i•e., 
mll'body infusion) 
intemiption. not 
indicated 
S)"mptoms ~11,.illg 110 
o.t minim.al 
interferene:e \vith 
u,ual social & 
fimdional activ:il:ies 
3s.o to s:: J.S.6·c or 
100.4 to< lOU'F 
Pain e:.auzin,g no or 
mininial mterfexencl! 
wilh usnal eoocia.l • 
functional activil.in 
GRAD[l 
MODER.\TE 
Localized urtic3!l"ia 
willi interventiou 
indicated QB Mild 
angioedema with 
n.o .intervention 
indicate.<! 
Symploim; c:aUJ<ing 
greater Ihm 
minimal 
inlerfe,renc,a wiln 
u,ru;al social & 
functional activitie! 
TheraJI}' (ie., 
an:tibody infiuiM>.) 
inteituption 
indicated AND 
Ra,pond,. promptly 
to ,ymptomati.: 
trealment OE. 
Proph)'lactic 
m.edicatiom 
indicated for ~ 24 
ho1m 
Symp!Oiil.!i Call~m,g 
graaterthan 
minimal 
interference with 
usu.al social & 
functrooal adivities 
e:: Ju to..: 39_3•c 
or,;: IOU to 
< 102.T'f 
Pa.in causing 
grster lban 
minimal 
interference ·it!, 
11rual social & 
functional ac,tn'1tie3 
CRADE.3 
SEVERE 
Genl!r.llized urticaria 
QR Angioedema with 
ia.tmren.tiou indicated 
OR S:,mpfom:!i of 
mild hronciho sp.i.!Jll 
Symptoms causing 
mbility to perform 
ll!ual~Ollial& 
functiona.l activitie, 
Ptolooged se,\ci!re 
signi :ind ,ympfoms 
OR Retwte:nc,• of 
,ymp,tomic following 
initial improvement 
Symptoms. cau,:ing 
inability to p,erform 
usual!Ollial& 
functional activities 
'.!1: 39.3 to< 40.o~c or 
=: l0-.2.7to < 104.t'.l""F 
Pam cau~ing inability 
to perform usual 
,ocioil ,&, functional 
activities 
GRADE 4 
POTENTIALLY 
LIFE-
TIIRIATENING 
Ac:ut• anaphylaici3 OR. 
li.fe•threatening 
broncllospam!. OR 
LiU)'li.geoil i!dem.a 
NA 
life-threatenin,~ 
<!<Ji,.saqtlenlle'3 (e.,g., 
requiring ptes..or or 
ventibt.or support) 
Illcap.ititating symplDm• 
of f.a.tigue or m:ih.i.e 
causm;g in;abilify to, 
pmorm b.a!ie self•caf• 
functions 
Dia;ablmg pain caming: 
inability to perform basic 
self•cllre function• OR. 
H ospitalization indicated 
• Defmition : A d isorder .:ih.tr.acte,:ized by nausea, beada~e, lachycatdia, hypoleruion,, ~""h, an or ,bortneu ofbrealh. 
For p.tin as,.oci.ated wiili wje,ction;; or infusion,, ••e the Site Rea.ct! ant to l,rjecti(m~ a11d l'lfi,!.lon.r section (pago 23). 
D.AIDS AE GtamngTlibli! Cotrec td exsion.2.J.July Wl? 
P'.11,ge 21 


CONFIDENTIAL 
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Gates Medical Research Institute 
119 
 
 
y t m1c 
s ' 
Sic 
UllO 
Mild. sisnt m.d 
l>.-foder1t1 111111 md 
S1v-.r1 1ip.1 :md 
Lif1-thrta:t111iq 
1)1mptom1 
lyrll9tolnl Ali)2 
1y~tom1&:m 
COllHCflllllCIII (1.J., 
Intervention 
HiJher lave! 
rt(fUirin1 pms-or o 
ind.1u!H (1.1-, 
mtmr.ntion indicaltd 
v111tibtor 1uppori) 
anlihiltunin11) 
(1,1,, 1t1r0id1 or IV 
iluicl1) 
ad1m1l1bt11 
:,. j 10 J9y,ano/ 
\VHO BM! Z•tcOII 
WHO BMI Z•ICO:rtl 
\VHO BMI Z-IC.011 
WHO BMI :t-lC0II 
a.,, 
<•l to -2 
< ·21.o .3 
< .3 
< -3 with lift-lhrHtmin1 
COIIHCfllll\CIII 
2 ro 5 ,v,an q/a,, 
\VHO \V iiht-for-
WHO \V 111ht-for-
\VHO W1ipt-for• 
WHO W1isbt-for-b1i,ht 
b1iJbt Z•liCOII 
btipt Z-IC0:rtl 
ntiJht z-1c.or1 < .3 
Mcon < -3 wil:h lifi • 
<•l to -2 
< •2t.o .3 
thrta:luiq c1mu qu111c11 
< J y,art ef q• 
\VHO \V i,sht-for-
WHO \V 111ht.£or-
\VHO Wtipt-for-
WHO \V1iJht-for-ltnJth 
lqlh.z.tieort 
111111:b :-SCOH 
lfnJtn Z-IC0II < .3 
~Jeon < -3 with lifi • 
<-l to -.2 
< -2 to -3 
thrtattniq conn qu111c11 
11:I tt111io1111I 
NA 
5 to < 9"/4 1011 ill 
:!: ~i.0 <20'¼ !ou Ill 
ii!: 20% Ion in bod)• 
, '1l1btl-o, 
body w1isbt lrom 
body w i,ht from 
,tpt fro.m baHlin1 .QE, 
(txcl11d.11 po 1qiutum 
bu1tlin1 
b111lm1 
A11r1uiv1 intm·mtw,n 
1nish,t lou} 
indicattd (1.1., t11b1 
ft1dm,, total parmtml 
nutrition) 
IO D1£J.nili.o11: A d.ilordlll' chanc:tuind. by &\·11, arl:br1l11.1, mr 1lJ:ia, 1km 1n1piion1, lymphad1110p1iliy, marlctd dtJcomfon, ancllor 
dysp1111. 
11 WHO Hlirmc1 tablas m.ay b1 acc1111d by cw:kin1 th.1 d11irld 111 wip or by 1cc111m1 th1 fo llowm1 URL1: 
http ://w1 rw. who.intlpowthrt• who2007 _bmi,_for_111/1 for p&rticipmh > S to 19 y1m of 111 and 
http ://www. who.intlchil.cla;ro, 
1"iand11d1/chart_c W.01111/111/ for thost S )'Hrl of q1. 
DAIDS AB Oradi~I T1blt CfflKttd V1n.la11 2.1- Jill)' 2017 
P•p22 


CONFIDENTIAL 
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Gates Medical Research Institute 
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Urinary 
PARAMETER 
rum·ytu ;i;f 
Obs truclioo 
NA 
GRADE i 
l\.ULD 
GRADi l 
MODERATE 
$~$ or 5ym.,ptomi 
of urinary tract 
ob,lnl~ti.Qn without 
hydr,oWll)hro!i! o:r 
re.na.1 dp fwl.cti.Qn 
GRADE3 
SEVERE 
Si!W'~ or ~ymp 11m,i; of 
11ri:1my tract 
ol>,!ruc:ti<ln with 
bydron,i:pliro!i! or 
renal dr,funetion 
DAIDS .i\E Qr,adin~Tabl.e Carrette<l V:ers!O)) 2.J.J1,lly 20·1"1 
Plli:;elJ 
GRADE 4 
POTENU.I\L-LY 
LIFE~ 
THREATENING 
O'bJtn!ction c;au~ ~l: 
life.tmeat~Dll\i!' 
con,~u•~n~<:! 


CONFIDENTIAL 
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PARMIETER 
GRADE I 
GRADE2 
GRADE3 
GRADE4 
:MILD 
MODERATE 
SEVERE, 
POTENTIALLY 
LIFE-
THREATENING 
lnjedion Site Pain or 
Pain or tendeml!'.!:~ 
Pm or tendeme-ss 
Pain or tademe;~ 
Pain or udeme;~ 
T1>ndoroe.s 
caiusmg no or 
causing greater than 
causing inability to 
earning mabilil:y to 
Repc~t on(y one 
minimal limitation 
minimal lim.itation of 
pmorm usu.al social 
pmarm basic: self-care 
ofuse of limb 
use of limb 
&.fimdional 
fuoctiauOR 
J::::tii.,ities 
Ho spilalization 
indic:ated 
lnjedion Site Erythema 
or Redn••• 12 
Repcn on(y orie 
2.5 to -c 5 cm in 
:?: 5 to-c 10 cm in 
:?: IO cm in diameter 
Potentially life-
::, H year,; of age 
,d:iame,t<>r OR 6.25 to 
diameter OR::, 25 to 
OR:::: 100cm2 
threa,!<>ning 
-c 25 ,c:m- filiface 
-c 10 0 cm2 snri'ace 
·mmce area OR 
con,,;equences (e.g,, 
areaA}.:i[) 
.uea. OR Symptoms 
Ub!ration OR 
abscess, exfoliative 
Symptom, ca:nsing 
caus;ing greater than 
Secondary infection 
derma:lrtis, ne,crn, is 
no o:r minimal 
minimal interference 
OR Phlebitis OR 
mvolving ilerai.is or 
in.terfe:rence with 
with n,ual social & 
Stai _ abscess OR 
deeper tssue) 
usual social & 
functional aeti\,itil!'.!: 
Drainage OR 
fundional activities 
Symptoms c:rusing 
inability to perform 
m nal socia9. & 
fu!!lcuo•nal activities 
15 years of age 
S2.5 cm in 
::, 2.5 cm in diameter 
:.:C 500/o :surface area 
Potentially life-
,d:iame,ter 
with< 50·' mrf.ace 
ofilie ex,tremily 
thre-ate.ning 
.uea ofilie extremity 
segment invoh--ed 
con,,;equences (e.g., 
segm<>nl involved 
(e.g., 11pper J.m1 o:r 
abscess, exfoliative 
(e.g., upper arm or 
thigh) OR Ulceration 
derma:lrtis, necrosis 
thigh) 
OR Seconi!;ny 
involvmg ilerai.is or 
infection OR 
deeper tssue) 
Ph!,.bits OR Sterile 
abscess OR Drmiage 
lnjedion Site 
Sa,me a:s for 
Same as fur 
Sa,me as for 
S:a,me as for lojed±oo 
lodu.ratioo or Suell.ing 
ln.jee'tion Site 
Io,jec,tioo Site 
loj..ctioo Site 
Site Erylhema or 
Repcn on(y orie 
Ery-i:h1>ma ,or 
Eryth.1>ma or 
Eryt],.ema or 
Redo•.,.,::, 15 J,'<lars of 
::, 15yeanofage 
Redo . .,,,,,::, 15 
Redoeu, ::, 15 years 
Redoes,, ,::, 15 years 
age 
y ean of age 
of age 
of age 
:£ 15 years of age 
S:a,me as for 
Same as fur 
Sa,me as for 
S:a:me as for Iojectioo 
Site 
Iojtt,tioo Site 
Ioj..ctioo Site 
Site Erylhema or 
Ery-i:he,ma or 
Eryth.•ma. or 
Eryt.b.emaor 
Redoe.,., l5year.s of 
Redo . .,,,,,~ I .5 .ve,u~ 
Redoeu, 15 years 
Redoe.,., 15 .-.ears 
age 
of age 
of age 
of age 
Injection Site Proritm 
Itching localized to 
Itching beyond ihe 
Generalized itchmg 
NA 
the injeclion rit.e 
injection site that is; 
causing inability to 
that is relieved 
n.ot ga.eraliz:ed OR 
p<!rl'orm usu.al social 
spo11bnBously or in 
]tching localized to 
&. fimctional 
-c 48 hours of 
the inj ectio11 ~t" 
a-:::tii.,ities 
treabn"1Lt 
requiring~ 48 hours 
trealment 
" mjeclion Site Erythema or Rednes:s ehcmld be e;.ca.lnated ancl graded nsing 
e greatl!St single diameter or measnred ,m:fa.ce a:rl!'.a. 
DAIDS AE Giadmg Table Canernd Version 2. -July 20 1 
Psge 24 


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Laboratory Value 
Chemistries 
* 
PARAMETER 
Aci.do1u 
Mbuwiin, 1 °''' 
(g/ dL; g/L) 
Alltalme Pho.,phatH@, 
ffigb 
Alltaloiit 
NA 
GRADil 
m...o 
3.0to< .LLN 
J() to <LlN 
l..25 to <2.5 
xULN 
NA 
GRADE2 
IODERATE 
::; 2.0 to < 3.0 
2 W to -1.: JO 
l ..S to< $.0 x ul.N 
GRADE3 
SEVERE 
pH < 7.3 widioat life• 
thre:il.enm.g 
con~equm ces 
5.0to< 10.0x it.N 
pH > 7.5 widioot life• 
threah!nin,g 
~on:i:eq11.enc,a 
GRADE4 
POT£NTh\LLY 
LIFE-
THREATENING 
pH c 7.3 wilh lif~ 
thre:il.ellm.g 
com>eq11mc,.. 
NA 
,::IO.Ox UL . 
pH 7.5 with Ji£~ 
thremnin,g 
COli9'i!qllellC>a 
ALT or SC.PT, 11:iib 
Report o>il:v olie 
us to <2.5 
X tJLN 
2.S to< 5.0 x ULN 
5.0 to< 10.0 d
.il.N 
10.0 x UL -
An,Jtue (PUJ.ei,eati~) or 
U lo..: U x ULN 
U to< 3.0 x tll.N 
An,Jiaa (Total), Hlib 
Rep.on 011{\l om; 
AST 0 1· SCOT, High 
Report 01i{ll 01ie 
B.ica.rbouate, L ow 
(ml!q/L; mm:oM.) 
B.ilhubio 
Direct Biliru.bin11, 
High 
;;,. 18 d.:i.i;s of age 
Tota.lBilfrubin, Higlt. 
> 18 d.:i.}'!i of age 
US to <2.5 
xULN 
16.0 to-= LL . 
16.0ro..: LLN 
NA 
ULN to " l m~'dl. 
1.1 to < 1.6 ,dJL • 
See Appendix A. 
Total Biluubin for 
Tettn ,and Pretellll 
Neonate:.5 
2.S to<:: S.O x UI.N 
n.o to< 16.0 
11.a to < 16.0 
NA 
> l to .: U mg/dL 
l .6 to< 2.6 x ut.N 
See Appendix A. 
Total Bilirubin for 
Term :md Preterm 
Neonate$ 
J.0 to..: 5.0" ULN 
S.O to-:; 10.0 it ul.N 
B.O to<:: ll.O 
8.0 to< 11.0 
:;, Ul.N with oilier 
,ago• anil S)'mptom• 
ofhepatotoxi'iC::il.y. 
::,, U to" 2mg/dL 
H to< S.Ox UL' 
See Append.ix A. 
Total B ilirubin for 
Term and Pretenn 
Neonate$ 
S.Ox utN 
JO.Ox UL. 
:;, Ul.N with life-
thre:iteoin,g 
cone.eq11e:nca (e.J!., 
,igns. and symptoms of 
Li ·er failure) 
::,, 2 m.g/dL 
2: 5.0x trLN 
See Append.ix A . Total 
Bil.irubm for Temi and 
Pretenn N eon.a.tl!.5 
*Reminder; Pm a,ymp-tcmatic .abnormal labomoiy findin,~ without m accompanying Al!. Bhouid n.ot be reported to DAIDS .i.n m 
expedited time liame unleH it meel3 prot~ol••pe<:ific. reporting requirements. 
u Direct hilirubin > U m ell i.n a participant< 28 d31)'5 o:l'a,ge ,hould be ~aded a! grade 2, it< IO% of the-total bilirubm. 
DAIDS All Grliding'Ttl>l.e Correcte.d \lenio.tl'.U•J\JIJ, Wl 
P.a.~25 


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hemi trie , 
p.i.n,.,..rT R 
GRAD l 
RAD 2 
RAD 3 
RAD 
MILD 
MOD RATE 
,, 
POT NI1ALLY 
LIFE-
TllRE,. ' - ·~ 
-
., ____ ,_ -
al lu ,Hirh 
(mf'dL; 110110V.C.) 
:i: 7 dtzy: of t11• 
)0,6 to < 11.5 
lU to < 12.5 
12.S lo< 13.5 
13.5 
.2.65 to < 1.88 
:J.88 to< J.J J 
S.H to< J.S8 
5..98 
< 7 d((VS of°''' 
]l.S to < 12.4 
12.4 to< lB 
]2.9 to < 13.5 
13.5 
.2.88 to < 3.10 
S.JO to< J.:JJ 
S.13 to< J.S8 
5..98 
al lu · Oonlztd) ffi Ji. 
> ULN to < 6.0 
6.0 to < 6.4 
6.4 to < 7.2 
~7.l 
(mf'dL; ,mnoV.C.) 
> ULN u, < J.S 
J.S ro < .1.6 
l .610 < 1.8 
:i: 1.8 
al lu · ,Low 
(mf'dL; mmoV.C.) 
'i:.; day: qf a,, 
7.8 to< 8.4 
7.0 to < 7.S 
6.l to < 7.0 
< 6..1 
US to <1.10 
1.75 to< l.95 
1.53 to< 1.75 
< J.J3 
< 7 d((VS of°''' 
6.S t.o < 7.5 
6.0 to < 6.5 
s.so to < 6.0 
< s.so 
l.63 to <l.88 
J.SO to< l.6J 
1.38 to< I.JO 
<U8 
1,1d11111 (Io iMd),,, .i 
01\' 
<LLN to4.0 
J.6 to < 4.0 
J to < 3.6 
<J.2 
(mf'dL; ,mnollL) 
<LlN toJ .O 
0.9 ro < .1.0 
0.810<0.9 
< 0.8 
1111dia1? 
1 ro ollin I 
NA 
NA 
NA 
Ln-1!1 comi1ttnt with 
ma• 
myomial inf.wtion 
or umtabll l:llJina ,u 
d1 m.td by th1, loc.~ 
labor.a.to~• 
r alln, K 111,:Hlcb 
l to<6:,;:UlN 
6to < lOxULN 
]Oto< 2-0 xULN 
~20:,;:Ul.N 
·r 
liDln1,Hi;s 
Uto 1.3 x UL I 
> 1.3 to l.8 x ULN 
> I.I to < 3.5 
~J.Sx ULNQ& 
•R,;on o,i{>, o,i, 
QE. mcr1111 to 1.3 to 
x tll.N Q& mcreaH 
Incru11 of 2.0 · 
< U:,;: puiicipmt' 1 
to 1.5 to < ,2.0 K 
particiPmt' 1 b1111in1 
ban tin1 
pmjcipmt' 1 b1111in1 
·r llnln1 lunoc ,IA 
NA 
< 90 to 60 m~'.miil. or 
< 60 to 30 m min or 
< JO ml/min or 
01' C 
1 ,L 
ml/minll.73 m2 
ml/min/1,73 m2 
ml/min/1. 73 m2 
•R,;ort o,i{>, 0111 
QE. 
QR 
QR 
l O ·to < 30% d1crHH 
30 to < SO¾ 
SO-% d1cr1111 from 
fl-om p1rt1e tpani' s 
d1cu111 from 
paniciPmt' 1 'o111lin1, o.r 
ban tin1 
particiJ>mt' 1 b1111in1 
dial),1is n11d1d 
Gluco.1 
(msfdL; 1111110'1/L) 
F,miJW, Hiah 
I 10 to 125 
> 125 to 250 
> 250 to S00 
500 
~.11 ro < 6.9 5 
6.95 tO' < JJ.8,9 
H.8910' < 17.75 
~.17,7J 
.10,ifrmilt.1, Hi,lt 
I 16 t.o l60 
> 160 to 250 
> 250 to S00 
500 
M4ro<8.89 
8. 8,9 tO' < JJ.8.9 
H.89 to< .27.7J 
~.17,7.S 
U1• the applica.bll formu (i.1., Coclo:roft.Gault in mL/mln o Schwart:, MORD, CKD-Epi m mLlmin/l.73m2). Situ should 
chooH ·th• m ihod d Snad in th.ir 1tudy me! ·hm not SJ)ICifild IHI ·th, m thod mort l'tilvmt to lhe rtudy popub.tion. 
•Remind r: ChooH ih1 ·t1:11tbod tha.t 1,tltcls for ih.1 h11h1T 1r~d1. 
DAIDS AB C!rldi~I Ttbll Contcttd VtrJJ.oll 2.1- Ju.Ir :Wl 7 
~26 


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PARAMETER 
ClucM~,, Low 
(mg/dL; mrnolt!.) 
J month of ~q 
< } m;,ntlt of llglJ' 
L,ctJ(e, ~b 
:Lipu", Hi!':b 
Lipid D•order,1 
(m dL; IIIPJtt.>1/l) 
Ch.c,l,i.,,ter.ol, F'csti11g, 
High 
J 8 ylJQY~ ,o/ fJC·~ 
< 18 J,~'(1.rp ef ag-~ 
L.DL, Fa$ing,,Hi9h 
J 8 y e.tm ,oj af;•B 
.,,. ], to< 18y-"l"Q ,of 
O,g"B 
Trigl,1~erid,1, F1nt.ing, 
Ri,h 
l\1(~n~ium15, L,ow 
(mgq ; mmov.L) 
Pll.o.spbah!, Low 
(mgldL; mrnoVL ) 
14 ywr,. ef q; 
J ro I 4 ,etm ef a.r~ 
< I Jl•"~ ef ~• 
Pot.iudu:m, Hii:;h 
(ml!q ; mm.oL,i.) 
Potasdu~, Low 
(wEq ; mmoL-7,} 
GRADE i 
GRADE 2 
GRADE 3 
Mn,D 
MODERAlE 
SEVERE 
55 to 64 
40, to< 55 
JO to<40 
3.05 to <J.5j 
2.12 t;,<$.05 
1.{J7 tQ < 2.22 
50 to 54 
40to< ,o 
JO to -,; 40 
2. 8 to <J.00 
2.2J tc, < }.78 
J.67tQ < 2.22 
UL. to <2.0 
? 2.0 ll UL.N tvithout 
I1m~ed b.cl.rte with 
x ULN without 
;i.cid!)si: 
pH < 7.3 w:idlov,t life. 
,acido,is 
thre~!li!lfi 
C:OllJe,;JlliW--Ce!I 
LI to<lJ x ULN 
1.5 to < 3.0 x lJI.N 
3.0 to< 5.0 x UlN 
200 t!) < 240 
240 to< 300 
:,. 300 
).}8 to< 6.1!) 
6.19 to< 'i. 7 
:,. 
.7 
1?0 t!) < 200 
200 to <JOO 
300 
4.,t() to< J.15 
j.J j to< '1.17 
:,. 
.77 
130 to < 160 
160 to< ]90 
a? 190 
3.37 to< 4.12 
4.1] to < 4.90 
.:;.-HO 
110 to < l30 
130 t!) < ]90 
2:HIO 
2.85 to< !J.34 
3. H to < HO 
"e-4.90 
150 to 300 
:i-300 to 500 
>500 to< l,000 
1. Jro3.4] 
-;;-J.42to5. 
>5.7 to JJ.4 
1.2 t!) < l.4 
0.9 to< l.2 
0.6 to< 0,9 
0.60 to < 0.70 
0,45 to < 0.60 
0'.30 to< 0.45 
2:0to<ll-N 
1.4 to< 2.0 
1.0 t!)< L4 
0.6Sro <LLN 
().45 to < 0.65 
0'.32 to s: ().4j 
J.O to< 3J 
25 t!) s: J.O 
.5 to s: ., 
().!) i to .;;; J.H 
0.81 to < 0.97 
0'.48 to ,;; 0.8J 
3.5 to< 4.5 
2.5 to < 3.5 
.5 to< J 
l.H to< 1.45 
0.81 to < l.H 
0.48 to < 0.81 
5.6 to --; -6.0 
6.0 t!) <6.5 
65 to< 7.0 
J.6 to < 6.0 
6.0 to< 6.5 
6.S to < .o 
J.O to< 3.4 
2.· t!) s:J.O 
.o to s: J 
3.0 to < :J. 4 
2.i to ,;; :J.O 
2.Q to < 2.$ 
0 J!il0$ AJ3 Cl!'adi~ !ab _ Colr~~d VeRio,I!! U- J!Jl)' l<ll7 
Pa$li 
GRADE 4 
POTENTIALLY 
LIFEr 
THRLUENING 
<JO 
< J.67 
-:JO 
< J.6 
foc:r~~ed b c:b~ with 
pH <7.3 .vilb life• 
thre~lePin~ 
C:O!l~l!el].C 
2: 5.0x ULN 
NA 
NA 
NA 
NA 
::. 1,000 
>11.4 
..;0.6 
< 0.30 
<l.0 
<: ().3) 
<U 
< 0.48 
<U 
< 0.48 
?; 7.0 
?; 7. Q 
<:: .0 
< 2.0 


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Chemistries 
PARAMETER 
Sodium, High 
(mEq/L; mmoM..) 
Sodium, Low 
(mEq/L;. mmoM..) 
Uric .Add, ffig,h 
(m g/dL; mmoW:.) 
GRADE I 
GRADE l 
GR.ADE 3 
MILD 
MODERATE 
SEVERE 
11 
14(; to< l50 
50 to <= 154 
154 to<= 160 
146 to < 15,0 
HO to<= 154 
154 to<:'. 16() 
130 to < l35 
25 to<= 130 
121 to<= 125 
130 to < 135 
125 to<= 13() 
121 to< 115 
7.5 to < 10.0 
0.0 to< 12.0 
12.0 to< 15.0 
().45 to < ()_j!) 
0.59 to< 0. I 
0.71 to< ()}J!) 
R"iIDS .~ Grsdmg.Tab _ Corrected \ e,si,;,,i, 2.1- Jinly 2017 
Page 2:8 
GRADE 4 
POTENTIALLY 
LIFE-
THREA'IENING 
160 
1(5() 
s 12.0 
5 12() 
:':: 15.0 
:".: 0.89 


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Hematology 
PARAMETER 
GRADEi 
GRADI2 
CRADE3 
CRADE4 
m.o 
tlODE.RATE 
SEVER£ 
POTENfIALLY 
LIFE~ 
THREATENING 
Aboolule cD4+ Count, 
Low 
(cel.Vmml; cellsl L) 
> j Jear.t of age 
JOO to <400 
200 to< 300 
100 Io< 200' 
< 100 
(not HJ. JI ief'1Cu:d) 
J{)(} lO < 40() 
00 u, ·< JOO 
J{)() 10 < 10() 
<}()() 
Ab3oluie Lymphocyte 
Cooot,l,ow 
(oellimm1; cells!l.) 
> j Jean ofagB 
600 to< 650 
SOO to< 600 
350 lo< 500 
< 350 
0. 600 ;Jd (JP to 
(}_j{)() X J fP l() 
0',3SO :dOP to 
< 0.JJ0:1'.Jf-P 
(111tlt mt i,vema) 
< 0.'550x J(f 
< O.dOO ;i:J(? 
<:'. O.JO() X l (J' 
Absolute N~otrop~ 
Cooo~ (. 
C) Low 
(~m~; ceUs/L) 
da)IS of ag.e 
800 to J,000 
600 to 799 
400 lo 59§1 
<400 
> 
,0. 800 x 1 OP t,O 1.000 
0.(500 x l fP la ()_ 9P 
,0'.400 x lOP to O.Jf/9 
< 0.4,0Q :d(f 
dOP 
X 10' 
X JOP 
00 
d~-w; qfags 
l,2SOto 1,500 
1,000 to 1,249 
50 Io 999 
-.:750 
1.1SO x lOPio UO() 
J.()00 x lfPla 1..149 
O'. ?SO x lOP M O.flf/9 
< 0.7J0x1Cf 
dOP 
X ]()~ 
;i:JOP 
1 da,_v of age 
4,000to 5,000 
3,000 to J,99P 
I ,SOO to 2,999 
< l,5-00 
4.000x HY to 
5.000 x l rP ta J.9fl9 
1.JOO X lOP to 1.Pf/9 
<UOOxUP 
5.00()x J(f 
X 10~ 
:dOP 
Fibrioo,gie:a., Decreue.d 
)00 to..: 200 
75 to< JOO 
SO to..: 7S 
< so 
(m dL; g/L) 
1.00ro<2.00 
0. J to< 1.00 
,0'.JO to < 0. ;S 
< ().JO 
O.R 
OR. 
O.R 
OA 
0.75to < LOO 
?! 0.50·to<O, s 
02S to,< 0-S-O 
<O.lSx. LLN 
x.l.LN 
,: LL 
x.LLN 
0.E. ru.sociMed with 
g,o59 bl.e~d.ing 
H~moglobm1'. L ii\\' 
(gtdL; m.moVL)li 
;.::J 3.,e,mofage 
10.0 to 10.9 
9.0to< 10.0 
7.0 to<: 9.0 
< 7.0 
(male ono,:) 
'5.19ro d.7f5 
J_j to < '5.19 
4.Uto < S.$ 
< 4.34 
.: l l 1e1m oj age 
9.Sto lo.4 
S.Sto< 9.S 
6.5 to< 8.5 
< 6.S 
,(female on{),) 
5.SfJto d.4' 
5.lJ to < j_fJS 
4.0J to< S.J5 
< 4.0J 
1~ Male and f,m1a e !I-ex ilre de.fined as !eiK at birth, For lra:ns~der participants ::; U yGn ofage who ba\,e been on honnone 
therapy £or mote than 6 c.oos.eccu.tive monthi, grade hemoglobin b.i8ed on the gender \vi.th which they identify (i.e., a ltmg;geoder 
female sliould be graded ll!int the female ~ex at birth h~o.tJ.o.bin h boi:ato,y v.al11ei). 
11 The m.ost comm-only u:sed c:onversio-n fac:tor .o ,oon\"ert 1}1dl to mmolll. is 0.6206. For gnding h.emoglo-bio re:ru.lts obtained by 
m. analytic method with a comretsi.on facliu olher th:m 0.6206, the re!l-ult must be converted to gldL using appropriate, contcer.sioo 
£i.dot i'orthe piart~ul» bbotatoty. 
D.AIDS AE GiallingtaMe Carree e.d 'ii'-e~si0.n2.Muly 20-17 
P'age:29 


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p .n:,.;.~ - -=-= 
J7 dOJ',l Q,fa,, 10 < H 
y,an ef'ai• 
(mak and/1t1ta/1) 
36 to 56 da,;is o/a,• 
(mak and/1.rna/1) 
22 to 35 da,;is q/a,, 
(mal, and/Im.al,) 
8 ro s.11 d~ r,/.q• 
(mak and/e._rn.a/1) 
s 7 da:;µ0/41•· 
(mak andfi ma/1) 
INR, Hl1b 
(not on anlico11ulitio:n 
lherapy) 
M•th mo,1lobin 
(% h•mopobin) 
p ,,HJa;b 
(not on 
liQ01,1ulitio:n 
ditrlp)') 
P '1MI 11 D 
I 
(c1ll1/mm1; ~•/ls.IL) 
p Hla1L 
(not on aniico1111litio:n 
lherapy 
WB , De~rt 1 
(ull1/mm3; ~•lls/L) 
> 7d.~o/a,• 
s 7 dtiJ,•: Q,f ap 
RAD l 
GRAD 2 
RAD 
MILD 
10D RA . 
9.S to 10. 
S.S to< 9.S 
6.S to< S.S 
J.8810 U8 
5.2S to< J,88 
4.03 ro < 5 . .1J 
B.StoU 
7.0 to< a.s 
6.0•tt>< 7.0 
J.26 ro $.99 
4.S2to<J,1d 
3. 72 to < 4.3.2 
9.S to 11.0 
S.O 10 < 9.S 
6.7 to< S.O 
J.8810 U6 
4.94 to< J,88 
4.Hro < 4.94 
ll.O to 13.0 
9.0to < 11.0 
8.0 to< 9.0 
6.81 ro 8.J() 
5.J7to < 6.81 
4.96ro < 5.57 
lS.O to 14.0 
lO.O to< 110 
9.0 to< lO.O 
8.05ro8.71 
6.J 9 to< 8,()$ 
J,S9ro < 6.l9 
l.l ·to< U x ULN 
LS to < 2 ,0 x UL • 
2.0 ·to< 3.0x ULN 
S.O ·to< 10.0% 
lO.O to< 15.0 • 
lS.O to <20.0% 
l.l ·to< U6 
l.66 to < 2.3 3 
2JJ to< 3.00 
xULN 
:cULN 
xULN 
l00,000 to 
50,000 to 
25,000 to 
<llS,000 
< 100,000 
< S0,000 
,]()().()()() w~ 
5().()()() 
J()~ ro 
2J,()()0 ;,cJ()P iO 
< /)$.()0()'/d(/P 
< J ()().()()() :d OP 
< 5().0()()xJO' 
l.1 ·to < 1.25 
l.2S to < 1.5 0 
l.SO to <100 
x.ULN 
xULN 
x.ULN 
2,000 to 2,4Sl'9 
l,S 00 to 1,999 
l ,000 1.o l ,4Sl'9 
,1,()()() ;,d()P 1(1 2,499 
J.J()() JI)' to 1.999 
.J' ()()() X l (JP 1(1 J ,499 
d()P 
x .10~ 
-:,:J()P 
S,SOO to 6,9Sl'9 
4,000 to S,499 
2,SOO lo 3,9Sl'9 
J.S()() X J (JP 1(1 6,999 
4.00() JI)' 10 J,499 
2.500 x l()P t(I J.999 
J()P 
X ]()~ 
J()P 
D.A:iDiS AB Orldta1 Ttbll Corrtcttd Vtncla-212. l- JWr 2017 
Pap30 
RAD 
POT NTI.ULY 
LIFE-
:r 
< 6.5 
< ,t.()J 
< 6.0 
< 3.72 
< 6.7 
<4.H 
< s.o 
-< 4.96 
< 9.0 
<5.$9 
! J,O,: ULN 
! 20.0% 
! lOOx. ULN 
< 25,000 
<15.0()() JO' 
! lOOx.ULN 
< 1,000 
< J.()0() JO' 
< 2,.500 
< 1.$0() JO' 


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128 
 
Urinalysi 
PARAMETER 
Gly,;o~uda (ra,ndQm 
eo!lectian teded by 
dipstidE) 
H10ma1uria (not to \le 
reporled ha.~ed on 
dipslidE findings or on 
blood be!i<1ved to b,i of 
me11,tn.ial Qr~ili) 
!Prot~inuda (r~idom 
eolle<:tion tested by 
dipstick) 
GRADE I 
GR.WE:? 
GRADE .3 
fil,I) 
IODERATE 
SEV[.RE 
Tr;,ee 
1+ or 
l+ or > l~Q to 
> +or> SOO mg 
_50 mg 
::,500 m!:: 
6 to °" 10 FtBC,. per 
?: 10 RBC• per high 
vrQ~!, \llith OY 
hi~ power field 
power field 
without dot! OR 
Wilh RBC mu OB, 
i.!><licated 
I+ 
l+ 
J+ orhi~er 
DA!DS All Gtamn::: Table Carremd V:eniG~. 2. J .Ju!y WI 7 
Page 31 
GR.ADE4 
POTENTIALLY 
LIFE-
THREATENING 
NA 
Li.~-Utre~nir\i:: 
•0011!:equene~ 
NA 


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Appendix A. 
Total Bilirubin Table for Term and Preterm eonates 
PARiUofETER 
GRADEl 
GR.ADE2 
GRADE3 
GRADE4 
:MILD 
~[ODER.ATE 
SEVERE 
POTENTIALLY 
LIFE-
THREATENING 
Tot.1Bilirubio 15, High 
(mg/dL; µmoVL) 19 
Ten11. Neo...,,_r,?l 
4tose 7 
7 to se 10 
]Oto< 17 
?: 17 
"'24 horrnofage 
68.4 to"' JJP. 
119. to< 1 l 
171 to se 29,J. 
?: 29{).7 
24 to "' 48 hour., of 
5 to se 8 
8to se 12 
12 to< 19 
?: 19 
age 
85.5 to"' 136.8 
J3.'5.8 to< 205.2 
205.2 to < 324.9 
?: 324.9 
48to <:'. 2 hour., of 
B-5 tose 13 
13to se 15 
15to<22 
?: 22 
a_ge 
145.35to < 222.3 
222.3 to< 25tU 
25(5.5 to < 376.2 
?: 376.2 
2 houn to"' 
da,_1~ 
11 to< 16 
16 to se 18 
Hlto< 24 
?: 24 
of age 
188.1 to"' 2 3.15 
273.6 to< 30 .8 
30' .8to<410.4 
?: 41().4 
to 28 daJ-'• of age 
5 tose 10 
!Otose 20 
20 to<25 
?: 25 
(area.st feeding) 
85.5to"' 1 1 
171 to"' 342 
341 lo<:'. 427.5 
?: 42 .5 
to 28 da,.vs of age 
I.I tose L6x ULN 
1.6 to se 2.6 x ULN 
2.6 to< 5.0 x UL .. 
?: 5.0 x ULN 
{not breast feeding) 
Pretum. N eona.r.?O 
Same il.S for Tora.I 
Same as for Totd 
Same il.S for Tora.l 
Same as for TotQl 
35 to"' 3 
l'BBks 
Bilinibin, 1£,gh, 
Biluubin, High, 
Bil.in,bin, 1£,glt, 
Bilirubin, High, 
gestational age 
TermNeoJtJJ.ts (ba,sed 
Tenn Neo11a.re (bi!.Sed 
Term NeoAQU (based 
Tenn Neona.tB (based 
o:r, days ohge). 
011 day• of age). 
on day$ of age). 
o:n days of age). 
32 to s: 35 ,,eeks 
NA 
NA 
IO to< 14 
?: 14 
gestatio>1aJ age am1 
171 lo s: 23!).4 
;,: 239.4 
< 7 dll!Y ofa,ge 
28 to <:'. 32 weeks 
NA 
NA 
,6to< IO 
?: 10 
gestati<maJ age am1 
101.6 to<:'. 171 
;,: 171 
< 7 da,_1~ of age 
< 18»eeh 
NA 
NA 
5 to s: 8 
?;:8 
gestational age am1 
85.5 to"' 136.8 
;,:136.8 
• 
< 7 dll!.'~ of a,ge 
to 28 dll!.1~ ,of a,ge 
5tosel0 
!Oto< 20 
20 to< 25 
?: 25 
,(area.st fe.eding) 
85.5to"' 1 1 
171 to< 342 
341 lo <:'. 427.5 
?:42 .5 
to 28 da,_vs of age 
I.I tose L6x ULN 
1.6 to s: 2.6 x ULN 
2.6 to < 5.0 x UL ... 
?: 5.0 x UL. r 
,(not breast feeding) 
II Severity grading for total bilirubin in neonates is comprex because of rapidly changing total bilirubin normal ranges. in the first 
week of life followed by the be:r,ign phenomenon of brnast milk j anndice ~fler the first week of life. Se,;;erity grad:ing m this 
appendix conespo11ds approxim;Jf:ely to cut--0ffi for ind:ic;;lio11s forphototherapy at grade 3 and for ""change transfusion at grade 
4. 
19 A laboratory value of 1 mg/dL is equi,,,--,,lent to 1 .1 µmoll:L. 
lO Definitions: Tenn is defined ~s:::: 37 weeks gest;,tional ;age; near-term, as?: 35 weeks geetatio,n.al age; pre!,;nn, as< 35 weeks 
gestational age; ;a:r,d neonate, as O to 28 days of age. 
DAIDS AE Gtading Tallle Correcwi Vuaimo.2.]-fuly 2.0l 
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10.5. 
Appendix 5. Eye Symptom Assessment Forms 
10.5.1. 
Study TBA7371-002, Eye Symptom Assessment Form, Screening Phase 
THE ASSESSOR WILL ASK THE PARTICIPANT QUESTIONS (ITALICS) AND REPORT 
ANSWERS AS INDICATED 
Special attention should be paid to the following symptoms offered by the participant: blurred vision with 
glasses/contact lenses on, photophobia (sensitivity to light), increased lacrimation (tearing, not to be 
confused with crying), decreased color vision. 
Date (MM/DD/YYYY)  ___________Time (h.min) __________Study Day (-1, -2, -3)_______ 
Assessor ‘s name ______________________________________________________________ 
1) History  
• 
Have you had any eye problems in one or both eyes in the last month? (yes/no) 
If no, go to point 2) 
If “yes”: 
• 
What were you experiencing? 
• 
Did you see an eye doctor? 
• 
Has it resolved? 
(Assessor to report patient’s feedback; record relevant patient quotes) 
_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________ 
2) Current  
• 
Are you having any problems in one or both eyes now or in the last 24 hours? 
• 
Now? (yes/no) ______ 
• 
In the last 24 hours? (yes/no) _____ 
If no: 
• 
The assessment is complete. We are done for today! 
 If yes: 
• 
In your own words, please describe each eye symptom and answer the questions I will ask as 
precisely as you can.  
 


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FIRST SYMPTOM 
• 
Describe this eye symptom  (Assessor to report relevant participant quotes): 
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________
________________________________________________ 
Medical term (Assessor to provide preferred medical term for the symptom): 
_________________________________________________________________________ 
• 
One or both eyes? If one, which one? _______________________________________ 
 
• 
When did it start? (dd/mm/yyyy) _________   time (h.min)___________ 
 
• 
Is it still ongoing? (yes no) _______ 
 
• 
If no, how long did it last?   _____hours, _____minutes  
 
• 
What made it better? ______________________________________________________ 
________________________________________________________________________ 
• 
What made it worse? ______________________________________________________ 
________________________________________________________________________ 
• 
Are you currently receiving any treatment for this? (yes/no) 
 
• 
If yes, what treatment(s)? (Assessor to report brand and/or generic name[s]) 
______________________________________________________________________________
______________________________________________________________________________
____________________________________________________________ 
 
• 
Assessor to define seriousness of symptom (non-serious/serious) based on definitions provided in 
Section 10.2.2. __________________________________________________________________               
 
• 
Assessor to define intensity (severity) of symptoms based on grading provided in Section 10.2.5.3 
and definitions provided in Section 10.4 (Appendix 4, page 20).  
 
________________________________________________________________________ 
 
 
 
 
 
 


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SECOND SYMPTOM 
• 
Describe this eye symptom  (Assessor to report relevant participant quotes): 
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________
________________________________________________ 
Medical term (Assessor to provide preferred medical term for the symptom): 
_________________________________________________________________________ 
• 
One or both eyes? If one, which one? _______________________________________ 
 
• 
When did it start? (dd/mm/yyyy) _________   time (h.min)___________ 
 
• 
Is it still ongoing? (yes no) _______ 
 
• 
If no, how long did it last?   _____hours, _____minutes  
 
• 
What made it better? ______________________________________________________ 
________________________________________________________________________ 
• 
What made it worse? ______________________________________________________ 
________________________________________________________________________ 
• 
Are you currently receiving any treatment for this? (yes/no) 
 
• 
If yes, what treatment(s)? (Assessor to report brand and/or generic name[s]) 
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________ 
 
• 
Assessor to define seriousness of symptom (non-serious/serious) based on definitions provided in 
Section 10.2.2. __________________________________________________________________               
 
• 
Assessor to define intensity (severity) of symptoms based on grading provided in Section 10.2.5.3 
and definitions provided in Section 10.4 (Appendix 4, page 20).  
______________________________________________________________________________ 
 
 
 
 
 
 
  


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[Add # ] SYMPTOM  
(Assessor to add more pages like this one if the participant reports more than 3 symptoms). 
• 
Describe this eye symptom  (Assessor to report relevant participant quotes): 
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________
________________________________________________ 
Medical term (Assessor to provide preferred medical term for the symptom): 
_________________________________________________________________________ 
• 
One or both eyes? If one, which one? _______________________________________ 
 
• 
When did it start? (dd/mm/yyyy) _________   time (h.min)___________ 
 
• 
Is it still ongoing? (yes no) _______ 
 
• 
If no, how long did it last?   _____hours, _____minutes  
 
• 
What made it better? ______________________________________________________ 
________________________________________________________________________ 
• 
What made it worse? ______________________________________________________ 
________________________________________________________________________ 
• 
Are you currently receiving any treatment for this? (yes/no) 
 
• 
If yes, what treatment(s)? (Assessor to report brand and/or generic name[s]) 
______________________________________________________________________________
______________________________________________________________________________
___________________________________________________________ 
 
• 
Assessor to define seriousness of symptom (non-serious/serious) based on definitions provided in 
Section 10.2.2. __________________________________________________________________               
 
• 
Assessor to define intensity (severity) of symptoms based on grades provided in Section 10.2.5.3 
and definitions provided in Section 10.4 (Appendix 4, page 20).  
________________________________________________________________________ 
 
 
 
 
 


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10.5.2. Study TBA7371-002, Eye Symptoms Assessment                                                        
Study Treatment Phase (Days 1, 4, 7, 10, 14) and Follow-up Phase (Days 15, 28, 42) 
THE ASSESSOR WILL ASK THE PARTICIPANT QUESTIONS (ITALICS) AND REPORT 
ANSWERS AS INDICATED 
Special attention should be paid to the following symptoms offered by the participant: blurred vision with 
glasses/contact lenses on, photophobia (sensitivity to light), increased lacrimation (tearing, not to be 
confused with crying), reduced color vision. 
 
Date (MM/DD/YYYY) ________Time (h.min) __________                                                                         
Study Day (1, 4, 7, 10, 14, 15, 28, 42, Early Withdrawal Visit) ______ 
Assessor ‘s name ______________________________________________________________________ 
 
• 
Are you having any problems in one or both eyes now? (yes/no) 
• 
Have you had any problem since the last eye check? (yes/no) 
If no to both questions: 
• 
The assessment is complete. We are done for today! 
 If yes to one or both questions: 
• 
In your own words, please describe each eye symptom and answer the questions I will ask as precisely 
as you can.  
 
 
 
 
 
 
 
 
 
 
 
 
FIRST SYMPTOM 


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• 
Describe this eye symptom  (Assessor to report relevant participant quotes): 
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________ 
Medical term (Assessor to provide preferred medical term for the symptom): 
_________________________________________________________________________ 
• 
One or both eyes? If one, which one? _______________________________________ 
 
• 
When did it start? (dd/mm/yyyy) _________   time (h.min) ___________ 
 
• 
Is it still ongoing? (yes no) _______ 
 
• 
If no, how long did it last?   _____hours _____minutes  
 
• 
Is it the same, better or worse compared to last time? ___________________________________ 
 
• 
What made it better? _____________________________________________________________ 
______________________________________________________________________________ 
 
• 
What made it worse? _____________________________________________________________ 
______________________________________________________________________________ 
 
• 
Assessor to define seriousness of symptom (non-serious/serious) based on definitions provided in 
Section 10.2.2. _________________________________________________________________ 
 
• 
Assessor to define intensity (severity) of symptoms based on grades provided in Section 10.2.5.3 
and definitions provided in Section 10.4 (Appendix 4, page 20).  
______________________________________________________________________________ 
 
 
 
 
 
 
 
SECOND SYMPTOM 


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• 
Describe this eye symptom  (Assessor to report relevant participant quotes): 
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________ 
Medical term (Assessor to provide preferred medical term for the symptom): 
_________________________________________________________________________ 
• 
One or both eyes? If one, which one? _______________________________________ 
 
• 
When did it start? (dd/mm/yyyy) _________   time (h.min) ___________ 
 
• 
Is it still ongoing? (yes no) _______ 
 
• 
If no, how long did it last?   _____hours _____minutes  
 
• 
Is it the same, better or worse compared to last time? ____________________________ 
 
• 
What made it better? __________________________________________________________ 
___________________________________________________________________________ 
 
• 
What made it worse? ______________________________________________________ 
________________________________________________________________________ 
 
• 
Assessor to define seriousness of symptom (non-serious/serious) based on definitions provided in 
Section 10.2.2. __________________________________________________________________ 
 
• 
Assessor to define intensity (severity) of symptoms based on grades provided in Section 10.2.5.3 
and definitions provided in Section 10.4 (Appendix 4, page 20).  
______________________________________________________________________________ 
 
 
 
 
 
 
 
 
 
 
 
 
 [Add # ] SYMPTOM  


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(Assessor to add more pages like this one if the participant reports more than 3 symptoms). 
• 
Describe this eye symptom  (Assessor to report relevant participant quotes): 
_______________________________________________________________________________
_______________________________________________________________________________
__________________________________________________________ 
• 
Medical term (Assessor to provide preferred medical term for the symptom): 
_________________________________________________________________________ 
• 
One or both eyes? If one, which one? _______________________________________ 
 
• 
When did it start? (dd/mm/yyyy) _________   time (h.min) ___________ 
 
• 
Is it still ongoing? (yes no) _______ 
 
• 
If no, how long did it last?   _____hours_____minutes  
 
• 
Is it the same, better or worse compared to last time? ____________________________ 
 
• 
What made it better? ______________________________________________________ 
________________________________________________________________________ 
• 
What made it worse? ______________________________________________________ 
________________________________________________________________________ 
 
• 
Assessor to define seriousness of symptom (non-serious/serious) based on definitions provided in 
Section 10.2.2. __________________________________________________________________               
 
• 
Assessor to define intensity (severity) of symptoms based on grades provided in Section 10.2.5.3 
and definitions provided in Section 10.4 (Appendix 4, page 20)  
______________________________________________________________________________ 
 
 
 
 






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10.7. 
Appendix 7. Document History  
 
DOCUMENT HISTORY 
Document 
Date 
Original Protocol (Version 1): 
03 Apr 2019  
Amendment 1 (Version 2): 
17 Apr 2019 
Amendment 2 (Version 3): 
25 Sep 2019 
Amendment 3 (Version 4): 
07 Jul 2020 
Changes in Version 2: 
• Updated protocol number (Title Page) 
• Extended screening period to 7 Days (Table 4, Section 1.1.8, Section 8) 
• Changed PK sampling schema (Tables 4 and 5 and Section 8.7) 
• Eliminated late PK sampling timepoints for patients receiving BID and TID dosing (Tables 4 
and 5 and Section 8.7) 
• Changed laboratory I/E criteria to specify lab values that are exclusionary for DAIDS Grade 
2 or greater abnormalities (Section 5.2, Section 8.3.3) 
• Updated masking rules (Section 6.3.2) 
• Eliminated time of Day window for first dose administration (Table 4, Section 6.1.3) 
• Safety labs added on Day 3 and updates to exploratory biomarker collection (Table 4) 
• 
 
Changes in Version 3:  
• Protocol title updated in bold print (Title Page)  
• Table of Abbreviations:  
o Acronym of “GMRI” changed to “Gates MRI” and definition changed from “Gates 
Foundation Medical Research Institute” to “Bill & Melinda Gates Medical Research 
Institute” (Page 6)  
o Definition of mg as “milligrams” added to Table (Page 7) 
o Definition of PA as “Posterior-Anterior” regarding chest X-rays added (Page 7) 
• Changed text for weight-based dosage for HRZE (Rifafour® e-275) from "> 70 kg: 5 tablets" 
to "71 kg and over: 5 tablets" specifically as stated in the Commercial Package Insert. (Page 
13) 
• In Table 4: 
o For “Overnight sputum collection for eligibility assessment”, adjusted formatting so all 
elements are legible. (Page 17) 
o For “Blood/serum sample collection for PK measurements”, removed PK draw scheduled 
during screening period as it is deemed not necessary for PK analysis. (Page 18) 
o For footnote #2 regarding “Hospital admission and discharge” text clarified from - Study 
participants will be hospitalized “before start of Screening Phase” to “by Day -3 of the 
Screening Phase” (Page 18) 


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o For footnote #4 regarding “Chest X-rays”, text corrected from “Good quality Antero-
Posterior (AP) chest X-rays” to read “Good quality Posterior-Anterior chest X-rays”, as 
Posterior-Anterior is the correct orientation for a standard chest X-ray. (Page 18) 
o In footnote #7, spelling of “Cephaid” corrected to “Cepheid”. (Page 19) 
o In footnote #12, regarding “Overnight sputum collection for EBA assessment and 
exploratory measurements”, text corrected to refer reader to footnote #7 (overnight 
sputum collection) instead of footnote #6 (urine collection) for details on how the first 
overnight sputum will be used. (Page 20) 
o In footnote #14, regarding “Blood/serum sample collection for PK measurements”, as 
performed in the table, the text outlining the blood sampling for PK scheduled for the 
screening period has been deleted as the sample is not needed for the PK analysis, so the 
text “. (Page 20) 
• In Section 2.1, text refined here to clarify issues with current TB treatment – changed from 
“Two are the main consequences of this profile. First, TB treatments require large 
commitments of resources and infrastructure, typically lacking in the countries where TB is 
most prevalent. Second,…” to “Two of the main consequences of this profile are - first, TB 
treatments require large commitments of resources and infrastructure, typically lacking in the 
countries where TB is most prevalent, and second,…” (Page 23) 
• In Section 4.1: 
o “Overall Study Design”, changed text from - An IDMC will make “dose escalation 
recommendations” to “dose escalation recommendations”; the sponsor ultimately makes 
the decision to escalate using the IDMC recommendation as an important part of the 
decision making process. (Page 30) 
o To clarify text, “during” was added to “Within each cohort, there will be no replacement 
for the first 2 early withdrawals (drop-outs) occurring during the during the Treatment 
Phase.” (Page 31) 
• In Section 5.2, “Exclusion Criteria”, Criteria #18 - #21, correctly re-numbered as Criteria #17 
- #20. (Page 37) 
• In Section 6.1.3 “Administration”: 
o Changed text for weight-based dosage for HRZE (Rifafour® e-275) from "> 70 kg: 5 
tablets" to "71 kg and over: 5 tablets" specifically as stated in the Commercial Package 
Insert. (Page 40) 
o Text added to clarify how to handle if a patient’s weight changes between specified 
weight bands during the course of the Study Treatment period; the investigator will 
determine which of the measured weights to use for dosing. (Page 41) 
• In Section 6.2 “Preparation/Handling/Storage/Accountability” for consistent instructions 
across trial related trial documents, changes made: 
o Section 6.2.1 “Preparation”, text clarified as “TBA-7371 will be prepared 
extemporaneously for 250 mL or 500 mL of a 25 mg/mL suspension” (Page 41) 
o In Section 6.2.3 “Storage”, The “do-not-use-beyond-date of 14 Days after compounding 
has been assigned” corrected to be “7 Days after compounding has been assigned.” (Page 
41) 


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• Section 8.1.2 “Chest X-Rays” – text corrected from “Anterior-Posterior” to “Posterior-
Anterior” which is the correct orientation for standard chest X-rays. (Page 48) 
• Section 8.1.5 “Urine Drug Screening” – text corrected to refer reader to renumbered 
exclusion criterion #19 (from previously #20). (Page 48) 
• Section 8.1.6.2 “Acid Fast Bacilli Detection” – text clarified to reflect proper laboratory 
evaluation planned for trial with “direct microscopy” changed to “concentrated smear 
microscopy” and also with “on direct microscopy” deleted from paragraph 3. (Page 49) 
• Section 8.2.1 “Overnight Sputum for EBA assessment and Exploratory Measurements”, 
changed “The first (Day -7 to -3) and second (Day-2) overnight sputum samples” to “The 
first (Day -7 to -3) or second (Day-2) overnight sputum samples” to indicate either can be 
used to assess eligibility. (Page 49). 
• Section 8.3.1 “Physical Examination”, measuring height was deleted from “A focused 
physical examination will be performed as directed by medical history on Days 7, 15, 28 and 
42”; height only needs to be assessed during the screening period, not in subsequent focused 
physical examinations. (Page 50) 
• In Section 8.5 “Concomitant Treatments”, text added to specify that if a concomitant 
treatment that would have precluded enrollment is deemed necessary “during the Study 
Treatment Phase”, the participant will be discontinued from the study. (Page 59) 
• In Section 8.7 “Pharmacokinetics”, blood sampling original planned during the screening 
period for the morning at approximately the same time the 1st daily dose study drug will be 
administered was deleted as the sample is not necessary for the PK analysis; a pre 1st dose 
blood sample is already planned. (Page 60) 
• In Section 9.7.1 “Independent Data Monitoring Committee (IDMC)”, redundant text, “The 
IDMC may request additional information, or a pause in recruitment and vaccination, while 
safety data are being evaluated”, deleted from 5th paragraph; text already stated earlier in 3rd 
paragraph. (Page 72)  
• Section 10.2.4 “Definition of AESI”, text correction made – from “≥Grade 2 intensity 
(severity) and/or serious AR related to decrease of diastolic blood pressure (DBP)” to 
“≥Grade 2 intensity (severity) and/or serious AE related to decrease of diastolic blood 
pressure (DBP)”. (Page 81) 
• In Appendix 3. Contraceptive Guidance and Collection of Pregnancy, text added to cover 
both contraception requirements for male participants and the course of action for 
pregnancies of partners of male participants has been added: (Page 88) 
• Male contraception: 
o Male participants of childbearing potential must agree to use an acceptable method of 
contraception for 3 months after the last dose of the study medication and must also 
refrain from sperm donation through 3 months after receiving the last dose of study 
medication.  
o Male and female participants will be provided with information on acceptable methods of 
contraception as part of the informed consent process and will be asked to sign the ICF 
stating that they understand the requirements for avoidance of pregnancy.  


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o Pregnancies of partners of male participants: In the event of a pregnancy by a female 
participant or pregnancy by a sexual partner of a male participant, the processes outlined 
below must be followed.  
• Section 10.6 “Appendix 6 – List of Prohibited Medications” (Page 132) 
o Redundant confusing text “..and other the list is not comprehensive” deleted 
o Text was added to indicate that Rifafour® as anti-TB medication is allowed for patients 
randomized to receive HRZE during the 14-Day Study Treatment Phase. 
o Delamanid which is now approved and used in South Africa was added to the list. 
Changes in Version 4: 
Content-related changes are outlined in the below table. In addition, updates and revisions 
related to grammar, punctuation, and consistency were also incorporated into this protocol 
amendment version. 
Overall Rationale: 
• Primarily as a result of the global COVID-19 pandemic, this amendment was 
implemented to enhance safety measures to include screening and monitoring for SARS-
CoV-2 infection to mitigate risks of transmission among participants in this trial and site 
staff supporting it.  Additionally, telephonic follow-up has been included for follow-up 
period visits for exceptional circumstances due to the local status of the COVID-19 
pandemic to monitor patient safety while reducing risk for SARS-CoV-2 transmission.  
• Additional aspects of the changes incorporated to enhance evaluation of patient safety 
and improve trial processes and interpretation of results include: 
o Color vision testing was changed from use of the older/former paper-based Color 
DX test to the computerized Color DX (Waggoner) test to allow for more 
standardized training of sites for administering the test and for more precise 
assessment of any potential color vision changes.  The analysis plan has been 
updated accordingly. 
o Serum sodium and potassium levels were added to the regular scheduled clinical 
safety lab assessments to enhance interpretation of patient hemodynamic status 
and renal function.  Assessment of these levels was inadvertently omitted from 
the schedule of assessments in previous versions.  No additional blood sampling 
is required with adding these assessments to those already scheduled. 
o An additional PK sample was added for patients who withdraw from the trial 
during the study treatment period to enhance interpretation of any important 
safety findings leading to withdrawal. 
o Allowance for unscheduled visits during the follow-up period (when patients will 
be on regular TB treatment) was added in the event an interim safety assessment 
is deemed necessary by the investigator.  
o The 2 overnight sputum collection attempts used for confirming participant 
eligibility based on sputum volume production were shifted to the Day -7 to Day -
3 period to improve screening logistics. 
o Confirmation of susceptibility to isoniazid and rifampicin for patient TB isolates 
from baseline and Day 15.   
 


CONFIDENTIAL 
Section Number 
Section 1.1.4.2 
Secondary Objectives and 
Endpoints 
Safety 
Section 3.2 
Secondary Objectives and 
Endpoints 
Safety 
Section 1.1.8 
Timing 
Table 3 Scheduled Visits 
and Activities and 
Table 3 Scheduled Visits 
and Activities Footnotes 
Protocol Gates MRI-TBD03-201 
Text in Amendment 2 (Version 3) 
Mean/median changes in color vision scores from 
screening to lowest scores during days 1-15. 
Change in frequency of pa11icipants with eye symptoms 
(all, severe, serious) and change in mean visual acuity 
score and color vision scores from day 1 to days 4, 7, 10, 
14 and 15. 
Change in frequency of pa11icipants with eye symptoms 
(all, severe, serious) and change in mean visual acuity 
score and color vision scores from screening to days 28 
and 42 and from days 1-15 ( combined) to days 28-42 
(combined). 
The estimated duration of the study (first subject first visit 
[FSFV] to last subject last visit [LSL V]) will be 
approximately 1 year. 
c. 
Early Withdrawal Visit (EWV). Participants who 
withdraw before Day 14 v.iill be asked to complete 
the EWV assessments within 2 Days of withdrawal. 
Paiticipants who complete the Study Treatment 
Phase, but do not retum for the Day 28 visit will be 
asked to retum for the Day 42 visit. 
Gates Medical Reseai·ch Institute 
144 
Version 4, 07 Jul 2020 
Text in Amendment 3 (Version 4) 
Frequency of pa1t icipants with any new color vision 
abnonnalities (tritan, protan, deutan) in one or both eyes and 
de ·e.e of severi 
mild, moderate, and severe 
Change in frequency ofpa1t icipants with eye symptoms (all, 
severe, serious) and change in mean visual acuity score and 
frequency of color vision abnormalities (tritan, protan, 
deutan) in one or both eyes and degree of severity (mild, 
moderate, and severe from Da 1 to Da s 4, 7, 10, 14 and 15. 
Change in frequency ofpa1t icipants with eye symptoms (all, 
severe, serious) and change in mean visual acuity score and 
frequency of color vision abnormalities (tritan, protan, 
deutan) in one or both eyes and degree of severity (mild, 
moderate, and severe) from screening to Days 28 and 42 and 
from Da s 1-15 combined to Da s 28-42 combined . 
The estimated duration of the study (first subject first visit 
[FSFV] to last subject last visit [LSL V]) was originally 
expected to be approximately 1 year. The duration of the 
study will however be extended as necessary due to COVID-
19 andemic-related restrictions. 
Added: COVID-19/SARS-CoV-2 Testing at Day -7 to -3, Day7, 
and Day 15 
Consolidated Screening Visit days. 
c. 
Early Withdrawal Visit (EWV) or Unscheduled Visit. 
Participants who withdraw before Day 14 will be asked to 
complete the EWV assessments within 2 Days of 
withdrawal. Pa1ticipants who complete the Study 
Treatment Phase, but do not retum for the Day 28 visit 
will be asked to retum for the Day 42 visit. If access to 
sites is limited due to the local status of COVID-19 
pandemic, the Day 28 and Day 42 visits could potentially 
be conducted by telephone. Procedures and assessments 
conducted dw-in an unscheduled visit will be at the 


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Footnote #7 
Overnight sputum collection for eligibility assessment. 
The 1st of the 3 overnight sputum collections conducted 
during the Screening Period (day -7 to -3) will be used to 
assess eligibility as follows: sputum volume (must be at 
least 10 mL), acid-fast bacilli detection, Mtb positivity 
and rifampicin sensitivity via the GeneXpert® diagnostic 
system (Cepheid). In case of suboptimal 1st overnight 
sputum collection, the above procedures will be 
conducted on samples from the 2nd overnight sputum 
collection (day -2). Also see# 12 below. 
Footnote #10 
Eye assessment. A trained staff member will assess: i) 
eye symptoms using a standardized script (Appendix 5), 
ii) visual acuity by means of the Rosenbaum Pocket Eye 
Screener, ii) color vision by means of the ColorDX Color 
test and as follows: 
Footnote #11 
Study drug will be administered at least 1 hour before 
and at least 2 hours after a meal, followed by 200 mL of 
water. 
Footnote #12 
Overnight sputum collection fo1· EBA assessment and 
exploratory measurements. Overnight sputum will be 
collected from 3 PM to 7 AM of the following day (16 
hours) on 3 screening days during Screening Phase (days 
-7 to -3, -2, -1) and on 14 consecutive days dw-ing the 
Studv Treatment Phase (davs 1 to 14). The last collection 
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discretion of the investigator in consultation with the 
medical monitor. 
Footnote #3: Added: 
Focused PE may be conducted during an unscheduled visit at 
the discretion of the investi~ator. 
Footnote #7 
Overnight sputum collection for eligibility assessment. 
Sputum assessment, including volume, will be performed by a 
Sponsor-approved central laboratory (see laborato1y study 
instmction document). The 1st of the 3 overnight sputum 
collections (Day -7 to Day -3) conducted during the 
Screening Period will be used to assess eligibility as follows: 
sputum volume (must be at least 10 mL), acid-fast bacilli 
detection, Mycobacterium tuberculosis (Mtb) positivity and 
rifampicin sensitivity via the GeneXpe1t® diagnostic system 
(Cepheid). In case inclusion criteria cannot be met from the 
1st overnight sputum collection, one or more of the above 
procedures can be conducted on a 2nd overnight sputum 
collected during the Day -7 to -3 screening period if the 
patient is domiciled at the site for both. 
Footnote #10 
Eye assessment. A trained staff member will assess: i) eye 
symptoms using a standardized script (Section 10.5, 
Appendix 5), ii) visual acuity by means of the Rosenbaum 
Pocket Eye Screener, iii) color vision by means of the 
Waiz1zoner Computerized Color Vision Test and as follows: 
Footnote #11 
Fasting must occur at least 2 hours before dosing and at least 
1 how· after dosing. Study drng administration will be 
followed by 200 mL water. 
Footnote #12 
Overnight sputum collection for EBA assessment and 
exploratory measurements. Overnight sputum will be 
collected from 3 PM to 7 AM of the following Day (16 
hours) on Days -2 and -1 during Screening Phase and on 
14 consecutive Days during the Study Treatment Phase 


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Section Number 
Table4 
Timing of Measurements on 
Days 1, 4, 7, 10, and 14 of 
Study Treatment Phase 
STP 
Table4 
Timing of Measurements on 
Da s 1, 4, 7, 10, and 14 of 
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will finish at 7 AM of day 15. All samples, except the 
first (day -3, see# 7 above) will be used for EBA 
assessment. 
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(Days 1 to 14) for EBA assessment. The last collection 
will finish at 7 AM of Day 15. Dmg susceptibility testing 
for isoniazid and rifampicin, and minimum inhibitory 
concentrations (MIC) of TBA-73 71 will be performed on 
either ofDay -2 or Day -1, and again on Day 14. 
New Footnote #15: Clarified window for blood draws 
New Footnote #17: Added 
Coronavirus Disease (COVID-19) / Severe Acute 
Respiratory Syndrome Coronavirus 2 (SARS-CoV-2 
Testing). COVID-19 testing will be conducted via PCR 
using a test product authorized by SAHPRA at an 
accredited public or private sector laboratory. A specimen 
will be collected during the screening period between Day-
7 to Day-3, and a negative result must be confumed prior 
to randomization. For safety monitoring purposes, testing 
will also be perfo1med at Day 7 (±2 Days), on Day 14 OR 
Day 15 before discharge, and/or at any other time that 
infection is suspected. 
Clarified window for blood draws 
Added: EWV column 
Added: Blood/serum draws at EWV 
Added: 
a. Early Withdrawal Visit (EWV) or Unscheduled Visit. 
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Study Treatment Phase 
complete the EWV assessments within 2 Days of withdrawal. 
(STP) 
Participants who complete the Study Treatment Phase, but do 
Footnotes 
not retmn for the Day 28 visit will be asked to retmn for the 
Day 42 visit. If access to sites is limited due to the local status 
of the COVID-19 pandemic, the Day 28 and Day 42 visits 
could potentially be conducted by telephone. Procedures and 
assessments conducted during an unscheduled visit will be at 
the discretion of the investigator in consultation with the 
medical monitor. 
Section 5.1 Inclusion 
C1ite1ia #1 - Deleted the following text: 
Criteria 
Weight Consider whether any restriction on weight or BMI 
is needed for this study intervention/stage of development 
and delete if not required. 
C1ite1ia #2 - Deleted the following text: 
Disease Characteristics For studies in healthy vohmteers, 
begin with this criterion. State whether rescreening will be 
allowed and the circmnstances lmder which rescreening can 
occur ( eg, laborato1y value range) and cross reference 
Section 5 .4 if aoorooriate: 
Crite1i a #3 - Deleted the following text: 
• 
For studies in patients, provide disease-related 
considerations: standard, accepted diagnostic c1iteria 
(consider supplying laboratory reference ranges or 
clinical diagnostic criteria in an appendix). Include 
duration/severity of disease or disorder if appropriate. 
• 
When appropriate, specify a realistic and pragmatic 
inclusion range for each test or marker of interest. Take 
into consideration any known assay variance or error 
rate as well as biological variation to avoid creating 
protocol violation issues. 
• 
State whether rescreening will be allowed and the 
circmnstances lmder which rescreening can occm· ( eg, 
laboratory value range) and cross reference Section 6.4, 
if appropriate. 
• 
Check whether additional infonnation associated with 
the disease area can be fmmd in the therapeutic area 
librruies. 
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C1ite1ia 3b 
Criteria 3b 
sputum smear positivity on direct microscopy for acid-
sputum smear positivity for acid-fast bacilli using fluorescent 
fast bacilli, defined as at least 1 + on the IUATLD/WHO 
microscopy, defined as at least 1 + on the International Union 
scale 
Against Tuberculosis and Lung Disease (IUATLD)/WHO 
scale 
C1ite1ia 4 
Criteria 4 
Pa1ticipants must be able to produce at least 10 mL of 
Pa1ticipants must be able to produce at least 10 mL of sputum 
sputum during the overnight sputum collection ( day -7 to 
during the screening overnight sputum collection (two 
-3 or day -2 of the Screening Phase). 
attempts can be made during Day -7 to -3 to meet the volume 
requirement if the patient is domiciled at the site for both), as 
assessed by a Sponsor-aooroved central laboratory. 
Section 5.2 Exclusion 
Added Criteria #2 -
Criteria 
Tested positive for COronaVIms Disease (COVID-
19)/SARS-COV-2 during the Screening Period with a PCR-
based assay. 
Section 5.4 Screening 
Rescreening is not permitted. 
Rescre.ening is not pennitted, except in special circumstances. 
Failw·es 
The investigator may review rescreening eligibility, on a 
case-by-case basis, with the Sponsor. 
Section 6.1.3 
Study drugs will be administered at least 1 hour before 
Fasting must occw· at least 2 hours before dosing and at least 
Administration 
and at least 2 hours after a meal, followed by 200 mL of 
1 how· after dosing. 
water. 
Section 7.2. 
Added: 
Pa1ticipant 
A paiticipant will discontinue study treatment and end in 
Discontinuation/Withdrawal 
clinic hospitalization, if the participant tests positive for 
from the Study 
COVID-19/SARS-CoV-2 anytime during the study treatment 
period, and will be referred for on-going TB treatment per 
national guidelines and for fwther evaluation for COVID-19. 
If the participant allows and the PI agrees, telephone follow-
up may be completed in place of onsite visits on Day 28 and 
Day 42. 
Section 8.1 
Screening assessments can be done at any time during 
Screening assessments can be done at any time during this 
Screening Assessments and 
this period, except for the written informed consent, 
period, except for the v.•ritten informed consent, which must 
Procedures 
which much be given before any scre.ening is sta1ted, the 
be given before any screening is sta1ted, the overnight sputum 
overnight sputum collection for eligibility assessment, 
collection for eligibility assessment and the screening sample 
which must be completed on or before Day -3, and the 
for COVID-19/SARS-Co V-2, which must be completed on or 
overnight sputum collection for EBA, which much be 
before Day -3, and the overnight sputum collection for EBA 
done consecutively on Day -2 and Day -1. 
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New Section 8.1.3 
COVID-19/SARS-Co V-2 
New Section 8.1.7 
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Ovemight sputum ( collected from 3 PM to 7 AM of the 
following moming) will be collected 3 times during the 
Screening Phase and 14 times during the Study 
Treattnent Phase, as described in Section 8.2.1 below. 
The first (between day - 7 and -3) and if necessary the 
second (day-2) ovemight sputum sainples will be used to 
assess eligibility through the sputum volume 
measw·ement, acid-fast bacilli detection and molecular 
tests for Mtb positivity ad rifampicin sensitivity. 
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assessment, which much be done consecutively on Day -2 and 
Day-1. 
Added the following to eligibility list 
• 
COVID-19/SARS-CoV-2 test 
• 
Sputum assessment, including volume, will be performed 
by a Sponsor-approved central laborato1y (see laborat01y 
study insttuction document). 
COVID-19/SARS-Co V-2 
In accordance with the SAHPRA Policy on Conduct of 
Clinical Trials of Health Products during the Current COVID-
19 Pandemic, issued 25 March 2020, this protocol 
amendment reflects the new and modified processes that were 
implemented in response to COVID-19. This amendment 
accommodates for changes related to the pandemic that are 
needed to minimize risk of transmission of SARS-CoV-2 
among paiticipants and staff and builds on strong infection 
control site practices, which are already in place, to reduce 
risk of TB tt·ansmission as an airbome infectious disease. 
PCR-based COVID-19/SARS-CoV-2 testing will be 
conducted by the site and a negative result must be confinned 
prior to randomization. In case of a positive COVID-
19/SARS-Co V-2 test during the screening period, the 
pa1ticipant will be excluded per the Exclusion Criterion in 
Section 5.2. 
Ovemight sputum ( collected from 3 PM to 7 AM of the 
following moming) will be collected bet\¥een Day - 7 and 
Day-3 and analyzed to assess eligibility through the sputum 
volume measw-ement, acid-fast bacilli detection and 
molecular tests for Mtb positivity and rifampicin sensitivity. 
If inclusion criteria cannot be met from the 1st overnight 
sputum collection, a second ovemight sputum sample may be 
collected dw-ing Day -7 to Day -3 and one or more of the 
above procedw-es can be repeated. The patient must be 
domiciled at the site for the overnight sputum collection and 
sputum samples will be analyzed by a Sponsor-approved 
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New Section 8.1. 7. 1 
Pa1ticipants must be able to produce at least 10 mL of 
Paiticipants must be able to produce at least 10 mL of sputum 
Ovemight Sputum Volume 
sputum during the ovemight collection (inclusion 
during the overnight collection (Inclusion Criterion, Section 
criterion# 4). If this volume is not reached on the sample 
5.1). If this volume is not reached on the sample(s) taken 
taken between day -7 and day -3, the sputum volume 
between Day -7 and Day -3, the paiticipant will be excluded. 
produced on day -2 will be used for eligibility. If a 
All volume assessments will be performed by a Sponsor-
volume of least 10 mL is not reached a.gain, the 
approved central laboratory (see laborato1y study instmction 
paiticioant will be excluded. 
document). 
New Section 8.1.7.2 
Acid-fast bacilli will be sought by concentrated smear 
Acid-fast bacilli will be sought by concentrated smear 
Acid-fast bacilli detection 
microscopy on a sputum sample obtained from the 
microscopy on a sputum sample obtained from the overnight 
ovemight collection performed between day -7 and day -
collection perfonned between Day -7 and Day -3. In case of 
3. If for whatever reason the sample obtained is 
suboptimal 1st ovemight sputum collection, the microscopy 
suboptimal as specified in the laboratory manual, a 
can be conducted on a 2nd overnight sputum collected 
sample from the day -2 ovemi!mt collection can be used. 
between Day -7 and Day -3. 
New Section 8.1.7.3 
A commercial moleculai· test to assess Mtb positivity and 
A commercial molecular test to assess Mtb positivity and 
Molecular tests for Mtb 
rifampicin sensitivity, GeneXpe1t® diagnostic system 
rifampicin sensitivity, GeneXpe1t® diagnostic system 
positivity and rifampicin 
(Cepheid), will be can-ied out on a sputum sample 
(Cepheid), will be ca1ried out on a sputum sample obtained 
sensitivity 
obtained from the ovemight collection taken between day 
from the ovemight collection taken between Day -7 and Day -
-7 and day -3. If for whatever reason the sample obtained 
3. In case of inconclusive results from the 1st ovemight 
is suboptimal, a sample from the day -2 overnight 
sputum sample, the GeneXpert® can be conducted on a 2nd 
collection can be used. 
ovemight sputum collected betv.•een Day -7 and Day -3. 
Section 8.2.1 
Ovemight sputum will be collected from 3 PM to 7 AM 
Ovemight sputum will be collected from 3 PM to 7 AM of the 
Ovemight Sputum for EBA 
of the following moming. Ovemight sputum collection 
following moming. 
assessment and Exploratory 
will occur on 3 days/nights during the Screening Phase 
Measurements 
( days -7 to -3, -2 and -1) and every day/night ( day 1 to 
The ovemight sputum samples collected on Day -2 and Day -
day 14) during the Study Treatment Phase. 
lofthe Screening Phase will be used to detennine baseline 
EBA Subsequent ovemight sputum samples will be collected 
The first ( day -7 to -3) or second ( day-2) overnight 
eve1y day/night (Day 1 to Day 14) to assess changes in 
sputum samples of the Screening Phase will be used to 
bacterial burden during the Study Treatment Phase. 
assess eligibility as described in section 8.1.6. above. 
Eady bactericidal activity will be assessed on ea.ch sputum 
The second (day -2) and third (day -1) ovemight sputum 
sample by 3 different methods: 1) CFU on solid media culture 
samples of the screening Phase will be used to detennine 
(prima1y), 2) time to sputum culture positivity (TTP) in 
baseline EBA 
MGIT culture, 3) LAM assay. Confirmation ofMtb will be 
performed on solid media and MGIT cultures as necessa1y 
Eady bactericidal activity (EBA) will be assessed on 
using available commercial methods. 
ea.ch sputum sample by 3 different methods: 1) colony 
foffning units (CFU) on solid media culture (primary), 2) 
A commercial molecular test to assess isoniazid and 
time to sputum culture positivity (TTP) in Mycobacteria 
rifampicin sensitivity, GenoTvoe MTBDRplus (HAIN 
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Growth Indicator Tube (MGIT) culture, 3) sputum 
Lifesciences), will be utilized on positive MTB cultures from 
lipoarabinomannan (LAM) assay. 
Day-2 (or, if Day -2 unavailable, Day -1) and Day 14 to 
assess the dmg susceptibilities at each visit. In addition, MICs 
ofTBA-7371 will be batch tested on positive MTB cultures 
from Day -2 (or, if Day -2 unavailable, Day -1) and Day 14. 
Details on sputum collection, handling and testing 
procedures, and on the laboratory are provided in the 
study specific manual(s). 
Details on sputum collection, handling and testing 
procedures, and on the laboratory are provided in the 
laboratory study instruction document. 
Section 8.2.2 
Added: 
Samples for exploratory 
The participant should spontaneously produce (i.e., not 
endpoints 
induced) a spot sputum specimen for collection into RNA 
preservation media at each specified visit. If the specimen 
cannot be collected due to participant inability to produce 
sputum, or due to operational limitations with RNA media 
collection kits, it is not considered a protocol deviation and 
participants remain eligible for trial participation. 
Section 8. 3 .1. 
Added: 
Physical Examination 
A focused PE may be conducted during an unscheduled visit 
at the discretion of the investigator. 
New Section 8.3.2. 
Added: 
COVID-19/SARS-Co V-2 
COVID-19/SARS-Co V-2 
PCR-based COVID-19/SARS-Co V-2 testing will be 
conducted at Day 7 (±2 Days), on Day 14 OR Day 15 before 
discharge, and/or at any other time that infection is suspected. 
In case of positive COVID-19/SARS-CoV-2 test during the 
study treatment period, the participant will discontinue study 
treatment, will end in clinic hospitalization, and will be 
refen-ed for on-going TB tr·eatrnent per national guidelines 
and for further evaluation for COVID-19. In case of a 
positive COVID-19/SARS-CoV-2 test on Day 14 or Day 15 
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at the end of the study treatment period, participants v.iill be 
refen-ed for on-going TB treatment per national guidelines 
and for further evaluation for COVID-19. 
New Section 8.3.7. 
The 3 eye assessment procedures will be conducted by 
The visual acuity test and Waggoner Computerized Color 
Eye Assessment 
staff members trained by an ophthalmologist. 
Vision Test (updated computerized version of the paper-based 
ColorDX test) will be conducted by staff members trained by 
an ophthalmologist. 
Details on use of the Rosenbaum Pocket Eye Screener and 
Details on use of the Rosenbaum Pocket Eye Screener 
Waggoner Computerized Color Vision Test are provided in 
and Color DX Color Vision Test are provided in the 
the study specific manual(s). 
Studv Manual. 
Section 8.3.8. 
Added: 
Eady Withdrawal Visit 
If a patient is withdrawn from the study due to a positive 
COVID-19/SARS-CoV-2 test and maintains consent, a 
telephone follow-up may be documented on Day 28 and Day 
42. 
New Section 8.3.9 
Added: 
Unscheduled Visit 
Procedures and assessments conducted during an unscheduled 
visit will be at the discretion of the investigator in 
consultation with the medical monitor. 
New Section 8.3.10 
Added: 
Pa1ticipant Follow-Up 
On Day 15, participants will be transfen-ed to the local TB 
clinic, following completion of all study assessments. 
Unscheduled assessments may be performed, following 
transfer, for purposes of safety follow-up. In exceptional 
circumstances as assessed by the investigator in consultation 
with the medical monitor (e.g. issues related to COVID-
19/SARS-CoV-2, etc.), participants may have telephone 
follow up for Day 28 and Day 42. 
New Section 8.4.2.3 
Each AE/SAE will be evaluated by the principal 
Each SAE will be evaluated by the sponsor. based on 
Assessment of AE/SAE 
investigator or medically qualified designee to assess 
applicable product information (e.g. Investigator Brochure or 
Expectedness 
whether it is expected based on applicable product 
Package Inse1t). 
information (e.g. Investigator Brochw·e or Package 
Inse1t). 
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Section Number 
Section 8.4.3. 
Repo1ting Requirements for 
SAE, Serious ADR, AESI 
and Other Events 
NewTable9 
Summaiy of Prima1y and 
Secondaiy Endpoints and 
Analyses 
Secondaiy Safety 
Protocol Gates MRI-TBD03-201 
Text in Amendment 2 (Version 3) 
The sponsor or designee will have the opportunity to 
confinn the expectedness based on the clinical judgement 
of the medical monitor and sponsor designee. If an AE is 
considered expected by the investigator but the sponsor 
believes that the event is unexpected, the sponsor will 
upgrade the case to 'unexpected' status. The sponsor or 
designee will never downgrade a case from unexpected 
to ex ected. 
All fatal and life-threatening serious adverse drug 
reactions (ADR) are to be repo1t ed to South African 
Health Products Regulato1y Authority (SAHPRA) within 
7 calendar days after first knowledge with a complete 
repo1t to be subinitted within an additional 8 calendar 
days. Serious, ADRs that are not fatal or life threatening 
are to be reported to SAHPRA no later than 15 calendar 
days after first knowledge. An investigator who receives 
a Serious ADR report or other specific safety information 
(e.g., summary or listing ofSAEs) from the sponsor will 
review and file it. 
Endpoint 
Mean/median changes in color vision scores from 
screening ( s) to lowest scores during days 1-15 
Statistical Analysis 
Mean and median changes in color vision scores from 
screening to lowest score will be SUlllffiarized by 
treatment group. 
Endpoint 
Change in frequency of pa1ticipants with eye symptoms 
(all, severe, serious) and change in mean visual acuity 
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All fatal and life-threatening serious unexpected ADR are to 
be reported to South African Health Products Regulat01y 
Authority (SAHPRA) within 7 calendar days after first 
knowledge with a complete repo1t to be subinitted within an 
additional 8 calendar days. Serious, unexpected ADRs that 
are not fatal or life threatening are to be repo1ted to SAHPRA 
no later than 15 calendar days after first knowledge. An 
investigator who receives a Serious, unexpected ADR report 
or other specific safety info1mation (e.g., sUlllffiaiy or listing 
ofSAEs/SADRs) from the sponsor will review and file it. 
Endpoint 
Frequency of participants with any new color vision 
abnonnalities (tritan, protan, deutan) in one or both eyes and 
degre.e of severity (mild, moderate, severe) 
Statistical Analysis 
Frequency of participants with any new color vision 
abnonnalities, as well as the specific type of abnonnality 
(tritan, protan, deutan) will be SUlllffiarized by the number of 
eyes the abnonnality occw·s in (one or both), severity (inild, 
moderate, severe and treatment rou . 
Endpoint 
Change in frequency ofpa1t icipants with eye symptoms (all, 
severe, serious) and change in mean visual acuity score and 
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and color vision scores from day 1 to days 4, 7, 10, 14 
deutan) in one or both eyes and degree of severity (mild, 
and 15. 
moderate, and severe) from Day 1 to Days 4, 7, 10, 14 and 15. 
Statistical Analysis 
Statistical Analysis 
The change in frequency of participants with eye 
symptoms (all, severe, serious) and change in mean 
Frequency of pa1t icipants with any new color vision 
visual acuity and color vision scores from day 1 to days 
abnonnalities, as well as the specific type of abnormality 
4, 7, 10, 14 and 15 will be provided by treatment group. 
(tritan, protan, deutan) will be summarized by the number of 
eyes the abnonnality occurs in (one or both), severity (mild, 
moderate, severe) and treatment group. 
Endpoint 
Endpoint 
Change in frequency of pa1ticipants with eye symptoms 
Change in frequency of participants with eye symptoms (all, 
( all, severe, serious) change in mean visual acuity and 
severe, serious) and change in frequency of participants with 
color vision scores from baseline (day 0) to days 28 and 
any new color vision abnonnalities (tritan, protan, deutan) in 
42 and from days 1-15 (combined) to days 28-42 
one or both eyes and degree of severity (mild, moderate, 
(combined). 
severe) from baseline (Day 0) to Days 28 and 42 and from 
Statistical Analysis 
Days 1-15 (combined) to Days 28-42 (combined). 
The change in frequency of participants with eye 
Statistical Analysis 
symptoms (all, severe, serious) and change in mean 
visual acuity and color vision scores from screening to 
Frequency of participants with any new color vision 
days 28 and 42, and from days 1-15 ( combined) to days 
abnonnalities, as well as the specific type of abnormality 
28-42 (combined) will be provided by treatment group. 
(tritan, protan, deutan) will be summarized by the number of 
eyes the abnonnality occw·s in (one or both), severity (mild, 
moderate, severe) and treatment group. 
Section 9.4.1.2. 
All efficacy analyses will be performed in the ntlTT 
All efficacy analyses will be perfo1med in the ntlTT 
Secondary Bactericidal 
population, with per-protocol and completer populations 
population, with sensitivity analyses perfo1med in the per-
Activity Analyses 
perfonned to assess the robustness of results. 
protocol population to assess the robustness of results. 
New Section 10.2.2 
Added: 
Definition of ADR 
Definition of ADR 
"Adverse drug reaction" or "adverse reaction" means a 
response to a medicine in hwnans which is noxious and 
wtintended and which occurs at any dose and which can also 
result from overdose, misuse or abuse of a medicine. The 
phrase "responses to a medicinal product" means that a causal 
relationship betv.•een a medicinal product and an adverse 
event is at least a reasonable possibility, i.e., the relationship 
cannot be rnled out. 
New Section 10.2.3 
Other situations: 
Is a medically significant / important event or reaction: 
Definition of SAE 
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New Section 10.2.5 
Adverse events of special interest (AESis) are adverse 
Adverse events of special interest (AESis) are adverse events 
Definition of AESI 
events that the sponsor wants to monitor carefully. 
that the sponsor wants to monitor carefully and which are 
subject to expedited reporting (within 24 how·s) from the 
investigator to the Sponsor or representative following the 
same process and timelines than the SAEs. 
New Section 10.2.6.1 
SAE will be assessed for severity, causal relationship to 
SAE will be assessed for severity and causal relationship to 
AE and SAE Recording 
the study vaccine, and expectedness by the investigator. 
the study investigational medicinal product. 
New Section 10.2.7.1 
All fatal and life-threatening adverse dmg reactions 
All fatal and life-threatening Suspected Unexpected Serious 
Repo1ting to Sponsor 
(ADRs) are to be reported to SAHPRA with 7 calendar 
Adverse Reactions (SUSARs) are to be reported to SAHPRA 
Delegate's (CRO Safety 
days after first knowledge with a complete repo1t to be 
within 7 calendar days after first knowledge with a complete 
Team) Via the Electronic 
submitted within an additional 8 calendar days. Serious 
repo1t to be subinitted within an additional 8 calendar days. 
Data Collection Tool 
ADRs that are not fatal or life threatening need to be 
Non-fatal and life-threatening SUSARs need to be repo1t ed to 
repo1ted to SAHPRA no later than 15 calendar days after 
SAHPRA no later than 15 calendar days after first 
first knowledge. 
knowledge. The same timelines apply to follow-up 
information received for the SUSARs. 
Section 11.0 
Deleted: 
References 
13. Burger DA and Schall R. A Bayesian Nonlinear 
Mixed-Effects Regression Model for the Characterization 
of Early Bactericidal Activity of Tuberculosis Dmgs. 
Jownal ofBiophannaceutical Statistics 2015; 25: 1247-
1271 
Gates Medical Research Institute 
155 


CONFIDENTIAL 
Protocol Gates MRI-TBD03-201  
Version 4, 07 Jul 2020 
 
Gates Medical Research Institute 
156 
11. 
References  
1. Rifafour® e-275 Package Insert dated 13 Apr 2103, Sanofi-Aventis South Africa (pty) ltd. 
This document is included in the study specific manual(s).  
2. Rifafour® e-275 Safety Update, CCDS v2-3 dated 19 Apr 2018 (based on Package Insert 
dated 13 Apr 2013), Sanofi-Aventis South Africa (pty) ltd. This document is included in 
the study specific manual(s). 
3. Diacon AH, et al. Randomized Dose-Ranging Study of the 14-Day Early Bactericidal 
Activity of Bedaquiline (TMC207) in Patients with Sputum Microscopy Smear-Positive 
Pulmonary Tuberculosis. Antimicrobial Agents and Chemotherapy 2013: 57(5): 2199-2203 
4. Zumla A et al. Tuberculosis treatment and management—an update on treatment regimens, 
trials, new drugs, and adjunct therapies. Lancet Respir Med 2015; 3: 220–34 
5. Horsburgh CR et al. Treatment of Tuberculosis. N Engl J Med 2015; 373:2149-60. 
6. https://www.tballiance.org/why-new-tb-drugs/inadequate-treatment 
7. Comstock, G. W. Epidemiology of tuberculosis. Am Rev Respir Dis 1982; 125 (3 Pt 2), 8-
15. 
8. Allen S et al. Two-year incidence of tuberculosis in cohorts of HIV-infected and uninfected 
urban Rwandan women. Am Rev Respir Dis 1992; 146:1439-1444. 
9. Selwyn PA et al. High risk of active tuberculosis in HIV-infected drug users with cutaneous 
anergy. JAMA 1992; 268; 504-509. 
10. WHO. Global Tuberculosis Report 2016. Geneva: World Health Organization. 
http://www.searo.who.int/tb/documents/global-tuberculosis-report-2016/en/ 
11. Jindani, A., et al. The early bactericidal activity of drugs in patients with pulmonary 
tuberculosis. Am Rev Respir Dis, 1980;. 121: 939-49. 
12. Donald PR et al. Early bactericidal activity of antituberculosis agents. Expert Rev Anti Infect 
Ther 2001; 1: 141–155. 
 
 
 


Signature Page for Gates MRI-TBD03-201 Protocol Version 4 - 7 Jul 2020 v4.0
Document Number: TBD03-CLIN-000010 v4.0
Approval
Clinical Development
15-Jul-2020 17:46:53 GMT+0000

SAP_001.pdf: 
Statistical Analysis Plan: Gates MRI-TBD03-201
Study Title:
A phase 2a, dose escalation, controlled, randomized study to 
evaluate safety, early bactericidal activity (EBA) and 
pharmacokinetics of TBA-7371 in adult participants with
rifampicin-sensitive pulmonary tuberculosis
Study Number:
Gates MRI-TBD03-201
Study Phase: 
2a
Sponsor:
Bill & Melinda Gates Medical Research Institute (Gates MRI)
245 Main Street
Cambridge, MA 02142
Version 
Amendment 1
NCT#:
NCT04176250
Date:
4 October 2022 
Confidentiality Statement
This document contains confidential and proprietary information, and is not to 
be distributed to any third party.
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TBA-7371
Bill & Melinda Gates Medical Research Institute
Statistical Analysis Plan: Gates MRI-TBD03-201
04-October-2022
Confidential
Page 2 of 53
1
TABLE OF CONTENTS
1
TABLE OF CONTENTS .........................................................................................................2
LIST OF TABLES...........................................................................................................................4
LIST OF FIGURES .........................................................................................................................4
LIST OF APPENDICES..................................................................................................................4
2
SIGNATURE PAGE ................................................................................................................5
3
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS...........................................6
4
INTRODUCTION ....................................................................................................................9
5
OBJECTIVES AND ENDPOINTS..........................................................................................9
5.1
Primary Objectives and Endpoints.......................................................................................9
5.2
Secondary Objectives and Endpoint......................
.......................................................10
5.3
Exploratory Objectives ......................................................................................................12
6
STUDY DESIGN CONSIDERATIONS............
................................................13
6.1
Study Design......................................................................................................................13
6.1.1
Study Schema...............................................................................................................14
6.2
Sample Size Determination................................................................................................14
6.3
Efficacy Measures.........................
........................................................................15
6.4
Safety Measures.................................................................................................................15
6.5
Pharmacokinetic Measures ...
....................................................................17
7
STUDY POPULATIONS.......................................................................................................17
7.1
Populations for Analyses ...................................................................................................17
8
CHANGES IN CONDUCT OR PLANNED ANALYSES FROM THE PROTOCOL.........18
9
OVERALL STATISTICAL CON IDERATIONS................................................................18
9.1
General Conventions..........................................................................................................18
9.2
Definitions..........................................................................................................................19
9.3
Interim Analysis.................................................................................................................19
9.4
Handling of Missing Data..................................................................................................20
9.4.1
Missing or Partial Dates for Adverse Events...............................................................20
9.4.2
Missing Incomplete Dates for Prior or Concomitant Medications ..............................20
9.4.3
Missing Efficacy Data..................................................................................................20
9.5
Independent Data Monitoring Committee (IDMC)...........................................................20
9.6
Masking (Blinding)............................................................................................................20
9.7
Pooling Strategy for Study Sites........................................................................................21
9.8
Visit Windows/Unscheduled Visits...................................................................................21
10 STATISTICAL ANALYSIS METHODS..............................................................................21
10.1
Participant Disposition.......................................................................................................21
10.2
Demographics and Baseline Characteristics......................................................................21
10.3
Treatment Exposure...........................................................................................................22
10.4
Protocol Deviations............................................................................................................22
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CT OR PLANNED
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ata


TBA-7371
Bill & Melinda Gates Medical Research Institute
Statistical Analysis Plan: Gates MRI-TBD03-201
04-October-2022
Confidential
Page 3 of 53
11 EFFICACY PARAMETERS..................................................................................................22
11.1
Log CFU/mL Counts .........................................................................................................22
11.1.1
Primary Analysis..........................................................................................................22
11.1.2
Secondary Analysis......................................................................................................25
11.1.3
Sensitivity Analysis .....................................................................................................25
11.1.3.1
ANCOVA model using average change from baseline.........................................25
11.1.3.2
Random intercepts and slopes model across all data points ..................................25
11.2
Secondary Efficacy Endpoints...........................................................................................26
11.2.1
Time to Sputum Culture Positivity ..............................................................................26
11.2.2
Sputum Lipoarabinomannan........................................................................................26
11.3
Subgroup Analyses ............................................................................................................27
11.4
Interim Analysis.....................................................
.....................................................27
11.5
Sensitivity Analysis ...........................................................................................................27
12 SAFETY ANALYSES ...........................................................................................................27
12.1
Adverse Events ..................................................................................................................27
12.1.1
Primary Safety Analysis ..............................................................................................28
12.1.2
Secondary Safety Analyses........
......................................................28
12.1.2.1
Adverse Events ......................................................................................................28
12.2
Eye Symptoms ...................................................................................................................29
12.3
Visual Acuity .....................................................................................................................31
12.4
Color Vision.......................................................................................................................32
12.5
Vital Signs..........................................................................................................................33
12.5.1
Intraday Vital Signs Results.........................................................................................33
12.5.2
Daily Vital Signs Results.............................................................................................33
12.5.3
Orthostatic Vital Signs Results....................................................................................34
12.6
Electrocardiogr
...........................................................................................35
12.6.1
Intraday ECG Res lts ..................................................................................................35
12.6.2
Daily ECG Results.......................................................................................................36
12.7
Clinical Safety Laboratory Measurement ..........................................................................36
12.8
COVID-19/SARS-CoV-2 Test ..........................................................................................37
12.9
Drug Susceptibilities and MIC of TBA-7371....................................................................37
13 PHARMACOKINETIC ANALYSES....................................................................................37
13.1
TBA-7371 Pharmacokinetics.............................................................................................38
13.2
TBA-7371 Concentration-Effect Relationship ..................................................................39
13.3
Exposure-Response Analysis.............................................................................................39
14 PHYSICAL EXAMINATION ...............................................................................................40
15 CONCOMITANT MEDICATIONS ......................................................................................40
16 REFERENCES .......................................................................................................................41
17 APPENDICES ........................................................................................................................42
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TBA-7371
Bill & Melinda Gates Medical Research Institute
Statistical Analysis Plan: Gates MRI-TBD03-201
04-October-2022
Confidential
Page 4 of 53
LIST OF TABLES
Table 1. 
Primary Objectives and Endpoint ............................................................................9
Table 2. 
Secondary Objectives and Endpoint ......................................................................10
Table 3. 
Efficacy Endpoint ..................................................................................................15
Table 4. 
Safety Endpoint......................................................................................................15
Table 5. 
PK and PK/PD Endpoint........................................................................................17
Table 6. 
Populations for Analyses .......................................................................................18
LIST OF FIGURES
Figure 1. 
Study Schema.........................................................................................................14
LIST OF APPENDICES
Appendix 1
Schedule of Activities............................................................................................42
Appendix 2
Imputation Rules for Missing or Partial Dates for AEs.........................................47
Appendix 3
Imputation Rules for Missing or Partial Dates for Concomitant Medications ......48
Appendix 4
SAS Code...............................................................................................................49
Appendix 5
Document History..................................................................................................52
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Gates_MRI-TBD03-20 l_Statistical Analysis Plan_ 04Oct2022 
Vault eTMF Document Number: VV-TMF-29915 I 1.0 
TBA-7371 
Statistical Analysis Plan: Gates MRI-TBD03-201 
2 
SIGNATURE PAGE 
Bill & Melinda Gates Medical Research Institute 
04-October-2022 
Study Title: 
A phase 2a, dose escalation, controlled, randomized study to 
evaluate safety, early bactericidal activity (EBA) and 
phannacokinetics of TBA-73 71 in adult pa1ticipants with 
rifampicin-sensitive pulmonaiy tuberculosis 
Study Nu 
:ocuSigned by: 
Gates MRI-TBD03-201 
l(J 
Signer Name 
Signing Time: 10-0ct-2022 111 :24:48 EDT 
l 
Signing Reas . 
1 
ument 
Prepared by:---F60BA739EB864856A2326BBOC7_AB_C_4_08 __ _ 
Biostatistician II 
~~I1eMings, lnc. 
l(J 
Signer Name:----
Signing Reaso~
ment 
Signing Time: 10-0ct-2022 111 :26:33 EDT 
Reviewed b · 
asoccsoEAE5 
Approved by: 
Approved by: 
Approved by: 
Confidential 
Senior Manager, Biostatistics 
MMS Holdings, fuc. 
Ph.D. 
Po1tfolio Statistics Leader 
Gates MRI 
MD, MSc 
Clinical Development Leader 
Gates MRI 
Clinical Operations Leader 
Gates MRI 
10-0ct-2022 I 11:24:59 EDT 
Date: ________ _ 
10-0ct-2022 I 11:26:36 EDT 
Date: ----------
Date: ________ _ 
Date: ----------
Date: ----------
Page 5 of 53 


TBA-7371
Bill & Melinda Gates Medical Research Institute
Statistical Analysis Plan: Gates MRI-TBD03-201
04-October-2022
Confidential
Page 6 of 53
3
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
ADR
Adverse Drug Reaction(s)
AE
adverse event(s)
AESI
adverse event of special interest
AIC
Akaike Information Criteria
ATC
Anatomical Therapeutic Chemical
AUCinf
Area Under the Plasma Concentration-Time Curve Extrapolated to 
Infinity
AUClast
Area Under the Plasma Concentration-Time Curve up to the Last 
Measurable Drug Concentration
AUCtau
Area Under the Plasma Concentration-Time Curve to the End of the 
Dosing Period
BACFU
Bactericidal Activity as Assessed by CFU
BALAM
Bactericidal Activity as Assessed by Sputum LAM Assay
BATTP
Bactericidal Activity as Assessed by TTP
BCI
Bayesian Credi lity Interval
BID
Bis in Die ( atin for twice  day)
BP
Blood Pressure
bpm
Beats Per Minute
BT
Body Temper ture
BW
Body Weight
CFU
Colony Forming Units
CI
Confidence Interval
Cmax
Maximum Plasma Drug Concentration
Cmin
Minimum Plasma Drug Concentration
CRO
Contract Research Organization
CV
Coefficient of Variation
DBP
Diastolic Blood Pressure
EBA
Early Bactericidal Activity
EWV
Early Withdrawal Visit
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TBA-7371
Bill & Melinda Gates Medical Research Institute
Statistical Analysis Plan: Gates MRI-TBD03-201
04-October-2022
Confidential
Page 7 of 53
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
HRZE
Isoniazid (H), Rifampicin (R), Pyrazinamide (Z), Ethambutol (E)
Gates MRI
Gates Medical Research Institute
HR
Heart Rate
IDMC
Independent Data Monitoring Committee
LAM
Lipoarabinomannan
LLOQ
Lower Limit of Quantification
MAR
Minimum angle of resolution
MIC
Minimum Inhibitory Concentrat on
min
Minute
mL
Milliliter
MGIT
Mycobacteria Grow  
ator Tube
mITT
Modified Intent-to-T at
PD
Pharmacodynamics
PE
Physical Examination
PK
Pharmacokinetics
PP
Per Protocol
PT
Prothrombin Time
QD
Quaque Di  Latin for once a day)
QTcF
QT Corrected for HR Using Fridericia’s Method
RR
Respiratory Rate
SAE
Serious Adverse Event(s)
SAP
Statistical Analysis Plan
SBP
Systolic Blood Pressure
SoA
Schedule of Activities
SoC
Standard of Care
SOC
System Organ Class
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TBA-7371
Bill & Melinda Gates Medical Research Institute
Statistical Analysis Plan: Gates MRI-TBD03-201
04-October-2022
Confidential
Page 8 of 53
TB
Tuberculosis
TID
Ter in Die (Latin for three times a day)
Tmax
Time to Maximum Plasma Drug Concentration
TNTC
Too numerous to count
TTP
Time to sputum culture Positivity
λz
Elimination Rate Constant
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Gates_MRI-TBD03-20 l_Statistical Analysis Plan_ 040ct2022 
Vault eTMF Document Number: VV-TMF-29915 I 1.0 
TBA-7371 
Statistical Analysis Plan: Gates MRI-TBD03-201 
Bill & Melinda Gates Medical Research Institute 
04-October-2022 
5.2 
Secondary Objectives and Endpoint 
Seconda1y EBA, safety and phaim acokinetics/phaim acodynamics (PK/PD) objectives and 
associated endpoints are summai·ized in Table 2. 
Table 2. 
Secondary Objectives and Endpoint 
ob·ectives 
End oint 
Earl bactericidal Activi 
Demonstrate the EBA of the first • 
2 days (screening ["O"] to day 2) 
Slope, i.e. average change per day, from Screening 
(Day 0) to Day 2 [BAcru(0-2)] of the log10CFU/mL 
and of the remaining 12 days 
(day 2 to day 14) of 5 dose 
regimens ofTBA-7371 
monotherapy and HRZE, as 
assessed by CFU counts on solid 
media culture 
counts; 
• 
Slope from Day 2 to Day 14 [BAcru(2-14)] of the 
log10CFU/mL counts. 
Demonstrate the EBA of 5 dose 
TTP: 
regimens ofTBA-7371 
monotherapy and of HRZE, as 
assessed by alternative methods: 
• 
Time to sputum culture 
positivity (TTP) in 
Mycobacteria Growth 
fudicator Tube (MGIT) 
culture 
• 
Sputum lipoarabinomannan 
(LAM) assay 
Safe 
Assess the adverse event (AE) 
profile of each dose regimen of 
TBA-7371 and HRZE over the 
14-da treatment eriod. 
Assess the impact on eye 
symptoms, visual acuity and 
color vision of each dose 
regimen ofTBA-737 and HRZE 
over the 14-day treatment 
period. 
Confidential 
• 
Slope of the time to TTP in the MGIT system from 
Screening (Day 0) to Day 14 [BArrp(0-14)], 
• 
Slope of the TTP in the MGIT system from Screening 
(Day 0) to Day 2 [BATTP(0-2)]; 
• 
Slope of the TTP in the MGIT system from Day 2 to 
Day 14 [BATTP(2-14)]; 
LAM: 
• 
Slope of the log concentration of sputum LAM from 
Screening (Day 0) to Day 14 [BALAM(0-14)]; 
• 
Slope of the log concentration of sputum LAM from 
Screening (Day 0) to Day 2 [BALAM(0-2)]; 
• 
Slope of the log concentration of sputum LAM from 
Da 2 to Da 14 BALAM 2-14 . 
Frequency from Day 1 through Day 15 of pa1ticipants with 
AE and frequency of AEs: overall, by system organ class 
(SOC) and preferred te1m; by seriousness, intensity 
severi 
, ex ectedness and relatedness to stud dm . 
From Day 1 through Day 15: 
• 
Frequency of paiticipants with any new (vs. Screening) 
eye symptom in one or both eyes. 
• 
Mean and frequency distribution of duration of each 
eye symptom. 
• 
Mean and frequency distribution of percentage of days 
with an e e s 
tom and each of the e e s 
toms. 
Page 10 of 53 


TBA-7371
Bill & Melinda Gates Medical Research Institute
Statistical Analysis Plan: Gates MRI-TBD03-201
04-October-2022
Confidential
Page 11 of 53
Table 2. 
Secondary Objectives and Endpoint
x
Mean/median changes in visual acuity score from 
Screening to lowest score during Days 1-15.
x
Frequency of participants with any new color vision 
abnormalities (tritan, protan, deutan) in one or both 
eyes and degree of severity (mild, moderate, severe).
Assess the impact on heart rate
(HR), blood pressure (BP) and 
electrocardiogram (ECG) profile 
of each dose regimen of 
TBA-7371 and of HRZE over 
the 14-day treatment period.
From Day 1 through Day 15:
x
Mean and frequency distribution of changes in heart 
rate (HR), systolic blood pressure (SBP) and diastolic 
blood pressure (DBP) as measured by the following 2 
(BP) or 3 (HR) methods:

Manual HR, SBP and DBP from vital signs,
after at le
 
 minutes in supine position 
(“manual, supine”);

Manu
, SB  and DBP from vital signs,
after  
 
nutes in standing position 
(“manual, 2-minute standing”);

HR from ECG, supine position (“ECG, supine”)
x
Frequency of participants with ≥25% increase in HR, 
decrea
 n SBP, decrease in DBP vs. baseline as 
measured with any of the methods described above.
x
Mea  and frequency distribution of percentage of days 
with ≥ 25% increase in HR, decrease in SBP, decrease 
in DBP vs. baseline.
Mean/median change from Screening through Day 15 
in PR, RR, QRS, QT, and QTcF interval values from 
baseline ECG.
Assess whether there is 
tachyphylaxis over the 
-day 
treatment period for HR, SBP, 
DBP and eye symptoms
x
Mean change in HR, SBP, and DBP from Day 1 to 
Days 4, 7, 10, 14, and 15 for each of 2 BP and 3 HR 
measurement methods described above.
x
Change in frequency of participants with eye 
symptoms (all, severe, serious) and change in worst 
visual acuity score and frequency of color vision 
abnormalities (tritan, protan, deutan) in one or both 
eyes and degree of severity (mild, moderate, and 
severe) from Day 1 to Days 4, 7, 10, 14, and 15.
Assess whether cardiovascular 
and/or ophthalmic adverse 
events persist or recur up to 4 
weeks after discontinuation of 
treatment with TBA-7371.
x
Mean change in HR, SBP, and DBP from Baseline to 
Days 28 and 42 and from Day 14 to Days 28 and 42
as measured by the following 2 (BP) or 3 (HR) 
methods:

Manual HR, SBP and DBP from vital signs,
after at least 10 minutes in supine position
(“manual, supine”);
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Gates_MRI-TBD03-20 l_Statistical Analysis Plan_ 040ct2022 
Vault eTMF Document Number: VV-TMF-29915 I 1.0 
TBA-7371 
Statistical Analysis Plan: Gates MRI-TBD03-201 
Bill & Melinda Gates Medical Research Institute 
04-October-2022 
Table 2. 
Secondary Objectives and Endpoint 
• Manual HR, SBP and DBP from vital signs, 
after 2 (±0.5) minutes in standing position 
("manual, 2-minute standing"); 
• HR from ECG, supine position ("ECG, supine") 
• Change in frequency of pa1ticipants with eye 
symptoms ( all, severe, serious) and change in mean 
visual acuity score and frequency of color vision 
abnonnalities (tritan, protan, deutan) in one or both 
eyes and degree of severity (mild, moderate, and 
severe) from Screening to Days 28 and 42 and from 
Days 1-15 (combined) to Days 28-42 (combined). 
Assess whether there are 
For each blood/semm and mine parameter: 
meaningful changes in safety 
• Mean, median, highest and lowest value . 
laborato1y measmement 
• Shift tables from Screening to Day 3, Day 7, Day 14, 
and Dav 42. 
Secondary, PK and PK/PD 
-
Evaluate the phannacokinetics 
TBA-73 71 concentration profiles and PK parameters over 
ofTBA-7371 monotherapy over 
the 14-day treatment interval: Cma.x, Tmax, C1ast, T1ast, 
the 14-day treatment period. 
AUCinf, AUC1 st, AUCtau, Cnun, half-life, accumulation 
ratios. 
Identify the lowest exposme to 
Expected concentration associated with 90% of the 
ofTBA-7371 associated with 
maximal TBA-7371 EBA effect (EC90). 
maximal EBA effect. 
5.3 
Ex lorator 
p 
y ob·ectives 
J 
Details of explorato1y objectives will be,included in separate operational and/or analysis plans. 
Results of explorato1y objectives may be repo1ted separately from the main clinical study repo1t. 
Explorato1y objectives may include but are not limited to: 
• 
Exploration of the correlation between EBA and biomarkers such as mycobacterial 
cell-free DNA, ribosomal RNA ratio assay, sputum and/or peripheral blood gene 
expression profiles and serum cytokines or other proteins, mine LAM, and bacterial 
genotypic evaluations for emergence of resistance; 
• 
Testing of susceptibility to TBA-7371 [minimum inhibito1y concentration (MIC)]; 
• 
Population PK modeling. 
Confidential 
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6
STUDY DESIGN CONSIDERATIONS
6.1
Study Design
This is an interventional, 5-cohort, 3-step dose escalation clinical trial in adult participants
between 18 to 60 years of age with rifampicin-sensitive pulmonary tuberculosis (TB). The 
escalation will occur sequentially in 3 steps: from Cohort I to Cohorts II and III, from Cohorts II 
and III to Cohort IV and from Cohort IV to Cohort V (see Figure 1). Within the 1st escalation 
step, participants will be randomized equally (1:1) to Cohort II or Cohort III, which have the
same total daily dose (200 mg, see below). Within each cohort, participants will be randomized 
unequally (5:1) to TBA-7371 or HRZE (isoniazid [H] / rifampicin [R] / pyrazinamide [Z] / 
ethambutol [E]) fixed dose combination tablets. Rifafour® e-275 (Sanofi) tablets, a commercial 
presentation of HRZE approved and available in South Africa, will be used in the study. The 
study is open-label with masked laboratory assessments (except PK).
Each participant will undergo 3 study phases: Screening 
 
g up to 7 days, with no TB 
treatment; a 14-day Study Treatment Phase on TBA-7371 or HRZE; and a 28-day Follow-up 
Phase on standard of care TB treatment.
An IDMC will make dose escalation recommendations to the Sponsor. After the last Cohort I 
participant completing the Study Treatment Phase (day 14), the IDMC will recommend whether 
Cohort II and Cohort III can start enrollment (1st escalation step). The same approach will be 
taken for the 2nd escalation step fro  
rts II & III to Cohort IV and for the 3rd escalation step 
from Cohort IV to Cohort V. For each escalation step, the “go  / no-go” recommendation will be 
based on accumulating safety data provided in an un-masked fashion to the IDMC. Additional 
data (e.g. PK) may be provided if available as supporting evidence.
Authorized study site personnel will dispense each dose of study drug.
This study will be open label for study participants, study site personnel, IDMC members, 
laboratory personnel involv
 
 measurements and all sponsor and contract research 
organization (CRO) personnel. The study will be masked (blinded) for personnel involved in the 
conduct of all other laboratory procedures (including those for the primary end-point).
Study participants will be hospitalized for up to 7 days for the Screening Phase and will remain 
in hospital until the day after the last dose of study drug is dispensed (day 15). Written informed 
consent must be given before any screening procedure is started. Participants will leave the 
hospital on day 15 after all procedures scheduled for that day have been completed.  Thereafter, 
participants will undergo scheduled visits on days 28 and 42 (±3 days) as outpatients during the 
Follow-up Phase.
Candidates will be screened to achieve 90 randomized study participants. Within each dose 
escalation cohort, 18 participants will be randomly assigned in a 5:1 ratio to TBA-7371 (N=15) 
or HRZE (N=3). The total sample size of the HRZE group (all cohorts combined) will be 15, 
assuming all cohorts will be allowed to undergo treatment.
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Th


Gates_MRI-TBD03-20 l_Statistical Analysis Plan_ 04Oct2022 
Vault eTMF Document Number: VV-TMF-29915 I 1.0 
TBA-7371 
Statistical Analysis Plan: Gates MRI-TBD03-201 
Bill & Melinda Gates Medical Research Institute 
04-October-2022 
Within each cohort, there will be no replacement for the first 2 early withdrawals (drop-outs) 
occuning in the Treatment Phase. Drop-outs from the 3rd onwards will be replaced to ensure that 
the total number of paiiicipants completing study treatment in each coho1i is at least 16. 
Paiiicipants who withdraw prematurely during the Follow-up Phase will not be replaced. 
6.1.1 
Study Schema 
Figure 1. 
Study Schema 
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6.2 
Sample Size Determination 
1 
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Anticipating all coho1is are to be assessed in the study, approximately 90 paiiicipants will be 
randomized in a 5:1 ratio to either TBA-7371 or control group, totaling N = 15 pa1i icipants for 
each TBA-7371 treatment and control groups (receiving treatment with HRZE). 
Bactericidal effect 
Based on Diacon et al (Diacon, 2013) standard deviations associated with BAcFU(0-14) were 
relatively consistent across 5 treatment groups, ranging from 0.05 to 0.08. If we assume 
conservatively that the tiu e standai·d deviation of the BAcru(0-14) measures for the TBA-7371 
ti·eatment groups is equal to 0.1, then with N = 15 per group we have 80% (90%) power to detect 
a tme group mean BAcFU(0-14) reduction of 0.067 (0.079), using a I-sided alpha = 5%. For 
reference, the observed BACFU(0-14) reduction in Diacon et al, 2013 were 0.040, 0.056, 0.077, 
0.104, and 0.122 for Bedaquiline 100 mg, 200 mg, 300 mg, 400 mg and standard HRZE, 
respectively. 
Safety 
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With N = 15 per group, we have approximately 80% (90%) probability to observe at least one 
AE if the true AE rate is 10% (15%). We have only 54% probability to observe at least one AE if 
the true AE rate is 5%. Across the five TBA-7371 treatment groups (N=75), we have 90% 
probability to observe at least one AE if the true AE rate is 3.0%.
6.3
Efficacy Measures
Table 3. 
Efficacy Endpoint
Endpoint
Primary EBA
Slope, i.e. average change per day, from Screening (Day 0) to Day 14 
[BACFU(0-14)] of the log CFU counts.
Secondary EBA
x
Slope, i.e. average change per day from Screening (Day 0) to Day 2 
[BACFU(0-2)] of the log CFU counts.
x
Slope, i.e. average change per 
 
 Day 2 to Day 14 
[BACFU(2-14)] of the l g CFU counts.
x
Slope of the time to sputum culture positivity (TPP) in the MGIT 
system from Screening (“0”) to Day 14 [BATTP(0-14)].
x
Slope of the TPP in the MGIT system from Screening (Day 0) to 
Day 2 [BATTP(0-2)].
x
Slope of the TPP in the MGIT system from Day 2 to Day 14 
[BATTP(2-14)].
x
Slope of the log con
tration of sputum LAM from Screening (Day 
0) to Day 14 [BALAM(0-14)]
x
Slope of the log concentration of sputum LAM from Screening (Day
0) to Day 2 [BALAM(0-2)]
x
Slop  of the log concentration of sputum LAM from Day 2 to Day 
14 [BALAM(2-14)].
6.4
Safety Measures
Table 4. 
Safety Endpoint
Endpoint
Primary safety
Frequency of study participants who experienced one or more severe
(≥ grade 3) and/or serious AEs from Day 1 through Day 15.
Secondary safety
Adverse events from Day 1 through Day 15:
x
Frequency from Day 1 through Day 15 of participants with AEs and 
frequency of AEs: overall, by system organ class and preferred 
term; by seriousness, severity, expectedness and relatedness to study 
drug.
Eye symptoms from Day 1 through Day 15:
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the MGI
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)].
he TPP in the MGI
PP in the M
2-14)].
4)].
e of the log concen
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ay 14 [BALAM(
Slope of the log con
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0) to D
) to Day 2 [BA
ay 2 [B
x
Slop  of the lo
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14 [BA
4 [BALAM(2
$


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Table 4. 
Safety Endpoint
x
Frequency of participants with any new (vs. Screening) eye 
symptom in one or both eyes.
x
Mean and frequency distribution of duration (hours) of each eye 
symptom.
x
Mean and frequency distribution of percentage of days with any eye 
symptom and each of the eye symptoms.
x
Mean/median change in visual acuity score from Screening to 
lowest score during Days 1-15.
x
Frequency of participants with any new color vision abnormalities 
(tritan, protan, deutan) in one or both eyes and degree of severity 
(mild, moderate, severe).
Heart rate (HR) and blood pressure (BP) from Day 1 through Day 15:
x
Mean and frequency d
bution of changes in HR, SBP and DBP 
as measured by the follo
  
P) or 3 (HR) methods:
o
Manual H
 BP and DBP from vital signs, after at least 10
minutes in supine position (“manual, supine”);
o
Manua HR, SBP and DBP from vital signs, after 2 (±0.5) 
minutes in standing position (“manual, 2-min standing”);
o
HR from ECG, supine position (“ECG, supine”)
x
Frequency of participants with ≥25% increase in HR, decrease in 
SBP, 
crease in DB  s. baseline as measured with any of the 
methods described above.
x
Mean an  r
y distribution of percentage of days with ≥25% 
increase in HR, decrease in SBP, decrease in DBP vs. baseline.
x
Mean/median change from screening through day 15 in RR, PR, 
QRS, QT, QTcF values from baseline ECG.
Tachyphylaxis over the 14-day treatment period for HR, SBP, DBP and 
eye symptoms:
x
Mean change in HR, SBP and DBP from Baseline (Day 1, pre-dose)
to Days 4, 7, 10, 14, and 15 for each of the 2 BP and 3 HR 
measurement methods described above.
x
Change in frequency of participants with eye symptoms (all, severe, 
serious) and change in worst visual acuity score and frequency of 
color vision changes from Day 1 to Days 4, 7, 10, 14 and 15.
Cardiovascular and/or ophthalmic AEs persistence or recurrence up to 4 
weeks after discontinuation of treatment with TBA-7371:
x
Mean change in HR, SBP and DBP from Baseline (Day 1, pre-dose) 
to Days 28 and 42 and from Day 14 to Days 28 and 42 for each of 
the following measurement methods:
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thods described ab
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n and frequenc
increase in HR,
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x
Mean/median
Mean/median
QRS, QT, Q
QRS, Q
hyla


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Table 4. 
Safety Endpoint
o
Manual HR, SBP and DBP from vital signs, after at least 10
minutes in supine position (“manual, supine”);
o
Manual HR, SBP and DBP from vital signs, after 2 (±0.5)
minutes in standing position (“manual, 2-min standing”);
o
HR from ECG, supine position (“ECG, supine”)
x
Change in frequency of participants with eye symptoms (all, severe, 
serious) and change in worst visual acuity score and frequency of 
color vision changes from Screening (Day 0) to Days 28 and 42 and 
from Days 1-15 (combined) to Days 28-42 (combined).
Safety laboratory measurements:
x
Mean, median and range of ea
 
/serum and urine safety 
parameter at screening, Days 3, 7, 14, 
 42.
x
Shift tables of blood/serum and urine safety parameter from 
screening to Days 3, 7, 14 and 42.
6.5
Pharmacokinetic Measures
Table 5. 
PK and PK/PD Endpoint
Endpoint
Secondary PK 
and PK/PD
x
TBA-7371 concentration profiles and PK parameters over the 14-day 
treatment interval: Cmax, Tmax, Clast, Tlast, AUCinf, AUClast, AUCtau, 
Cmin, half-li , a
umulation ratios.
x
Correlation between TBA-7371 AUC, Cmax, T>MIC and CFU counts 
on solid media culture.
x
Expected concentration associated with 90% of the maximal 
TBA-7371 EBA effect (EC90).
7
STUDY POPULATIONS
7.1
Populations for Analyses
Analysis populations are show in Table 6.
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Correlation betw
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xpected co
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s:
of each blood/s
ch blood
Days 3, 7, 14, and
ys 3, 7, 14, 
/serum and urine sa
m and ur
3, 7, 14 and 
, 14 and 42.
42
YH
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nt
SU
737
S


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Table 6. 
Populations for Analyses
Population
Description
Randomized population
All participants randomly assigned to study intervention, who either 
have randomized date or randomization number.
Modified intention to 
treat (mITT) efficacy 
population
All participants randomly assigned to study intervention, who 
received at least one dose of the study intervention.  Participants will 
be analyzed according to the intervention they actually received.
Per Protocol (PP) 
efficacy population
All participants randomly assigned to study intervention, who 
received the study intervention, and did not substantially deviate 
from the protocol procedures.
Participants who substantially deviated will be identified prior to 
database lock.
Participants will be analyzed according to the intervention they 
actually received.
Safety population
All participants randomly assigned to study intervention and who 
received at least one dose of the study intervention.  Participants will 
be analyzed accor
  he 
e
tion they actually received.
PK population
All participants who received at least one dose of TBA-7371 and 
have at least one pair of pre
d post-dose blood samples with 
measurable concentrations.
8
CHANGES IN CONDUCT R 
ANNED ANALYSES FROM THE 
PROTOCOL
No changes have been m
  he planned analyses.
9
OVERALL STATI T
L CONSIDERATIONS
9.1
General Conventions
Treatment groups consist of the following study interventions:
1. TBA-7371 100 mg QD
2. TBA-7371 100 mg BID
3. TBA-7371 200 mg QD
4. TBA-7371 100 mg TID
5. TBA-7371 400 mg QD
6. HRZE QD
The nomenclatures of study interventions will be used to display in tables, figures, and listings.
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ATISTI
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ns


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All measured variables and derived parameters will be listed individually and, if appropriate, 
tabulated using descriptive statistics. For categorical variables, summary tables will be provided 
giving sample size, absolute and relative frequency. For continuous variables, summary tables 
will be provided giving sample size, arithmetic mean, geometric mean (if appropriate), standard 
deviation, coefficient of variation (if appropriate), median, minimum and maximum. For 
variables with non-normal distribution, medians and interquartile range will be calculated, and 
the appropriate non-parametric tests will be applied. Unless specified otherwise, all confidence 
intervals will be two-sided 95% confidence intervals. Given the primary endpoint is tested using 
a one-sided test at 0.05, the corresponding 90% confidence interval will be provided.  One-sided 
p-value will be displayed with 4 decimal places; if the p-value is less than 0.0001, display as
“<0.0001”.
Change from baseline or screening for a measured variable at a particular post-baseline time 
point will be computed as the value at the post-baseline time point minus the baseline or 
screening value, as appropriate.
Percentages will be displayed with one decimal place and pe cent ges for zero counts will be 
omitted from the presented results. If the percentage is greater than 0 but rounds to 0.0% (e.g. 
0.04%), display as “(<0.1)”.
SAS code of SAS procedures that will be used to perform efficacy and safety analyses is 
provided in Appendix 4. 
9.2
Definitions
Screening EBA Measure: Average of the EBA measurements (i.e., log CFU, TTP in MGIT, 
and log concentration of sputum LAM) from the day -2 and day -1 overnight sputum samples of 
the screening phase will be used to determine the screening EBA measurement. If one of the 
overnight sputum samples is missing, the single non-missing sample will be directly used as the
screening EBA measurement.
Baseline definition for other efficacy and safety variables: The last assessment made prior to 
the first administered dose of study intervention will be considered baseline for analysis 
purposes. Baseline values of ECG and vital signs are measured on Day 1 before the first dose of 
study medication is administered. 
Day 1: Study day 1 is the day of first administration of TBA-7371 or HRZE.  Positive study days
will be counted forward from Day 1. Day -1 will be the date immediately preceding Day 1, and 
negative study days will be counted backward from Day 1.
9.3
Interim Analysis
No formal interim analysis is planned in this trial.
Unmasked safety and (if available) PK data on each cohort will be provide to the Independent 
Data Monitoring Committee (IDMC) to aid in recommendations related to dose escalation.
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s missing the
he
ent.
fi


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9.4
Handling of Missing Data
9.4.1
Missing or Partial Dates for Adverse Events
Missing or partial AE start dates will be imputed for the purpose of determining whether the AEs 
are treatment emergent.  Data handling rules for missing or partial start/stop date for AEs are 
detailed in Appendix 2. The missing or partial dates will be displayed in the data listings as 
reported on the electronic case report form (eCRF) rather than the imputed dates.
9.4.2
Missing Incomplete Dates for Prior or Concomitant Medications
Missing or partial medication start or stop dates will be imputed for the purpose of determining 
whether the medication are taken concomitantly. Data handling rules for missing or partial
start/stop date medications are detailed in Appendix 3. The missing or partial dates will be 
displayed in the data listings as reported on the eCRF ather than the imputed dates.
9.4.3
Missing Efficacy Data
Unless specified otherwise, no imputation for missing efficacy data will be performed for the
planned efficacy analyses.
9.5
Independent Data Monitoring C
tee (IDMC)
The IDMC is established to oversee the 
y of this study and to make a go/no-go 
recommendation at each dose es alat
 
.
The IDMC will operate according to the most current version of the IDMC charter, outlined in 
the introduction section of this document. The IDMC structure, participants and other details 
are provided in the charter and are not repeated in this document. The charter describes the 
scope of responsibilities of the IDMC and identifies its members. Additionally, it outlines the 
meeting schedule and format, provides procedures for ensuring confidentiality, and explains the 
administrative procedures that will be followed. The IDMC charter provides meeting 
information and other details.
The IDMC will review patient profiles containing unmasked safety and, if available, PK data 
during regularly scheduled safety review meetings. The IDMC may request additional 
information, or a pause in recruitment and study treatment, while safety data are being 
evaluated.
9.6
Masking (Blinding)
This study will be open label for study participants, study site personnel, IDMC members,
laboratory personnel involved in PK measurements and all sponsor and CRO personnel. The 
study will be masked (blinded) for personnel involved in the conduct of all other laboratory 
procedures (including those for the primary end-point).
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9.7
Pooling Strategy for Study Sites
Data will be pooled across all study sites.
9.8
Visit Windows/Unscheduled Visits
Efficacy and safety analyses will use the nominal visits as collected in the study database, 
thereby, visit windows will not be applied.
Unscheduled visits will not be included in by-visit summaries or analysis, but may contribute 
to the baseline value and worst post-baseline assessments.
10 STATISTICAL ANALYSIS METHODS
10.1
Participant Disposition
The number and percentages of participants for each population (m
T, PP, Safety, and PK) will 
be summarized. For computing percentages, the denominator will be the number of participants
in the mITT population.
Participants’ disposition will be summarized for the following study phases:
Screening Phase:
The numbers and percentages of participants who were screened, screen failures, and reasons for 
screen failure. For computing percentages, the denominator will be the number of participants
screened.
Study Treatment Phase:
The number and percentages of participants who were randomized, completed treatment, 
discontinued treatment and reasons for discontinuation of treatment, completed study, 
discontinued study and reasons for discontinuation of study will be tabulated by treatment group
and will be summarized for mIT
 PP, Safety and PK populations. For computing percentages, 
the denominator will be the number of participants for the given population and treatment group.
10.2
Demographics and Baseline Characteristics
Demographic parameters (age, sex, race, and ethnicity) and other baseline characteristics (body 
weight, body mass index (BMI), HIV status, CD4+ T-cell count (if HIV-positive), HR, DBP, 
SBP, current eye symptom, visual acuity impairment in one or both eyes, color vision deficiency 
in one or both eyes, log CFU on solid culture, TTP in liquid MGIT culture, and log concentration 
of sputum LAM, drug susceptibility testing for isoniazid and rifampicin, and minimum inhibitory 
concentrations (MIC) of TBA-7371) will be summarized by treatment group for all participants 
in the mITT and safety populations.
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TBA-7371
Bill & Melinda Gates Medical Research Institute
Statistical Analysis Plan: Gates MRI-TBD03-201
04-October-2022
Confidential
Page 22 of 53
Continuous variables will be summarized using descriptive statistics (n, mean, standard deviation,
and median, minimum, maximum). Categorical variables will be summarized using counts and 
percentages.
A data listing of demographics and baseline characteristics will be provided.
10.3
Treatment Exposure
For each participant in the safety population, duration of exposure to study drug will be calculated 
as (last dose  date – first dose date + 1). Duration of exposure will be summarized as both 
continuous and categorical variables by treatment group. For categorical presentation, the 
frequency and percentage of participants in each of the following categories will be presented: ≤3
days, 4 to 6 days, 7 to 9 days, 10 to 13 and 14 days by tre t
nt group.
A data listing of treatment exposure will be provided.
10.4
Protocol Deviations
A summary of the frequency and percentage of participants in the safety population with major 
protocol deviations for each deviation category will be provided by treatment group. A
participant with multiple occurrences of a major protocol deviation in the same deviation 
category will only be counted once. A listing of pro o
l deviations by treatment group and 
participant will be provided.
11 EFFICACY PARAMETERS
11.1
Log CFU/mL Counts
11.1.1
Primary Analysis
CFU/mL counts are derived from CFU count per mL collected from the Middlebrook 7H11S 
plates of overnight sputum samples, where sputum is collected twice during the screening phase
(Days -2 and -1) and daily on 14 consecutive days during the study treatment phase (Days 1 to
14). CFU/mL will be calculated as follows:
ܥܨܷȀ݉ܮൌ݉݁ܽ݊݋݂ݐݓ݋ܥܨܷ݌݈ܽݐ݁ܿ݋ݑ݊ݐݏ
݈݀݅ݑݐ݅݋݂݊ܽܿݐ݋ݎൈͲǤͻͲͻ ൈͲǤʹ
where 0.909 is a 10:1 dilution of sputum in sputasol and 0.2 mL is the volume on the plate.
The following rules and convention will apply for handling of the following categories:
x
Contaminated or no result: The CFU/mL counts associated with contaminated or no 
result samples will be set to missing. 
x
Too numerous to count (TNTC ≥401 colonies): The CFU/mL counts associated with 
TNTC samples will be set to 401.
x
CFU/mL counts <5: The CFU/mL counts will be set to 5.
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om


TBA-7371
Bill & Melinda Gates Medical Research Institute
Statistical Analysis Plan: Gates MRI-TBD03-201
04-October-2022
Confidential
Page 23 of 53
The primary end-point will be the slope of the log10CFU/mL counts from Screening to Day 14 
[BACFU(0-14)], i.e., average change in log10CFU/mL count per day over 14 days. The 
log10CFU/mL counts vs. time profiles over 14 days of treatment may be biphasic, i.e. the rate of 
change in log CFU changes over time. A simple solution (Diacon et al., 2013) is to characterize 
the participant-specific log CFU count vs. time profiles using a bilinear regression model, which 
has been proved to fit the data of many TB bactericidal agents quite well, especially over the 
time interval of 14 days.  
The form of the bilinear regression model is given by:
ଵ଴ܥܨܷȀ݉ܮൌߙെߚଵή ݐ൅ߝǢ
ݐ൑ߢǢ
ଵ଴ܥܨܷȀ݉ܮൌߙ൅ሺߚଶെߚଵሻή ߢെߚଶή ݐ൅ߝǢ
ݐ൐ߢ
where the parameters ߙand ߢare the intercept and node parameter of the regression curve, 
respectively, the slopes ߚଵand ߚଶcharacterize the line  
line on or before the node (ݐ൑ߢ) 
and after the node (ݐ൐ߢ), respectively, and ߝis the error term as umed to be independently
distributed normally with mean zero and variance ߪଶ. The parameters are constrained to aid in 
convergence as such: ߙ൐Ͳǡ ͳ ൏ߢ൏ͳͶǡ ߪଶ
, all 
. The SAS PROC NLMIXED
procedure will be used to fit the bilinear regression model for individual participants in each 
treatment group. Suggested starting values for the parameters are ሺߙǡ ߚଵǡ ߚଶǡ ߢሻൌሺ͸ǡͲǡͲǡʹሻ
however a grid search approach can be followed to obtain sensible starting values. See SAS code 
in the Appendix which uses a grid search and picks the best fitting model.
If the bilinear regression model is selected, the average change in log10 CFU/mL per day over 14 
days will be estimated for each 
cipant ݅by:
ܤܣ஼ி௎ሺͲ െͳͶሻ௜
ߢƸ௜ߚመଵ௜൅൫ͳͶ െߢƸ௜ሻߚመଶ௜൯ሿȀͳͶ
where ߚመଵ௜is the estimated slope prior to the estimated inflection point ߢƸ௜, and ߚመଶ௜is the estimated 
slope after the estimate  nflection point ߢƸ௜. The parameters of main interest include the slopes 
ߚመଵ௜and ߚመଶ௜, and the inflection points, ߢƸ௜, and can be readily estimated using least squares.
BACFU(0-14) can be estimated i  ROC NLMIXED directly.
In the case where a subject does not have a non-missing measurement at Day 14, we have that
ܤܣ஼ி௎ሺͲ െݐ௟௔௦௧ሻ௜ൌሾߚመଵ௜൅൫ݐ௟௔௦௧െߢƸ௜ሻߚመଶ௜൯ሿȀݐ௟௔௦௧
where ݐ௟௔௦௧is the last time point at which CFU was observed.
However, it is also likely that some of the participant specific log10CFU/mL count vs. time 
profiles will be better characterized using a simple linear regression model.
The form of the simple regression linear model is given by:
݈݋݃ଵ଴ܥܨܷȀ݉ܮൌߙെߚଵή ݐ൅ߝ
where the parameters ߙand slope ߚଵare the intercept and the slope that characterize the linear 
decline, and ߝis the error term assumed to be independently distributed normally with mean zero 
and variance ߪଶ. The SAS PROC NLMIXED procedure will also be used to fit a simple linear 
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ed slope prior to th
slope prior to th
d inflection point
lection p
on points,
po
n P


TBA-7371
Bill & Melinda Gates Medical Research Institute
Statistical Analysis Plan: Gates MRI-TBD03-201
04-October-2022
Confidential
Page 24 of 53
regression model for individual participants in each treatment group in order to ensure the 
Akaike information criteria (AIC) values for the linear and bilinear models are based on the same 
form of the likelihood function. Suggested starting values for the parameters are ሺߙǡ ߚଵሻൌሺ͸ǡͲሻ
however a grid search approach can be followed to obtain sensible starting values.
If the linear regression model is selected, the average change in log10CFU/mL count per day over 
14 days will be estimated by the constant linear regression slope estimate, ߚመଵ௜, i.e.
ܤܣ஼ி௎ሺͲ െͳͶሻ௜ൌߚመଵ௜Ǥ
Therefore, for each participant, slopes will be estimated using both bilinear and simple linear 
regression models, and the better fit model based on lower AIC will be selected for that 
participant and used to estimate BACFU(0-14). The log10CFU/mL screening measurement used in 
the model will be the average of the two individual screeni
 measurements. BACFU(0-14) will 
be calculated for each participant within a treatment group individually, and then used as the 
response variable in an ANCOVA model, with a fixed effect for treatment group and screening 
log10CFU/mL count as a covariate. Treatment group means from the ANCOVA model will be 
used to quantify the evidence that each of the tre m
t group mean BACFU(0-14) is less than 0 
(i.e., that the treatment group mean has a negative slope on average). The mITT population will 
be used for the primary efficacy analysis with ana
 sin  the per-protocol population 
performed to assess the robustness of results. The SAS P
C MIXED procedure will be used to 
fit an ANCOVA model.
Multiplicity will be handled by me
 
  
d
 sequential approach. The five TBA-7371
treatment regimens will be divided into 3 testing groups: Group 1 = Cohort V (400 mg QD) and
Cohort IV (100 TID); Group 2 = Cohort III (
0 mg QD) and Cohort II (100 BID); and Group 3
= Cohort 1 (100 QD). Group 1, or the group with the highest cohort allowed by the IDMC will 
be tested first using a Ho
 
 adjustment: if the maximum and minimum 
one-sided p-values are ≥0.05 and ≥0.025, respectively, formal testing will be stopped and all 
cohorts below will be declare   i ure; if the maximum and minimum one-sided p-values are   
≥0.05 and <0.025, formal tes ng will be stopped but the regimen with p-value <0.025 will be 
declared a success; if the maximum and minimum one-sided p-values are <0.05 and <0.025, both 
cohorts will be declared a success and testing will proceed to Group 2 regimens with the same 
step-down approach to continue until a failed cohort is observed.
The study will be declared a success if at least one of the TBA-7371 treatment groups achieves a
statistically significant 1-sided p-value and demonstrates an acceptable safety profile.
Geometric mean and geometric mean ratio of post-baseline to baseline of CFU/mL counts with 
95% confidence interval (CI) at each time point will be presented in line plots by treatment 
group.  In addition, observed and fitted lines of bilinear and linear regression models of
log10CFU/mL counts over time will be presented for each participant. 
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ng


TBA-7371
Bill & Melinda Gates Medical Research Institute
Statistical Analysis Plan: Gates MRI-TBD03-201
04-October-2022
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11.1.2
Secondary Analysis
EBA measures BACFU(0-2) and BACFU(2-14) will be calculated from the bilinear regression 
model and assessed similarly as described for BACFU(0-14) in Section 11.1.1. There will be no 
adjustment for multiple comparisons and no formal success criteria for all secondary EBA 
measurements.
In order to estimate BACFU(0-2) and BACFU(2-14), the parameter ߢis fixed at 2 so that the 
bilinear model used becomes
ଵ଴ܥܨܷȀ݉ܮൌߙെߚଵ௜ή ݐ൅ߝǢ
ݐ൑ʹǢ
ଵ଴ܥܨܷȀ݉ܮൌߙ൅ሺߚଶ௜െߚଵ௜ሻή ʹ െ
ଶ௜ή ݐ൅ߝǢ
ݐ൐ʹ
and therefore we have for participant ݅that
ܤܣ஼ி௎ሺͲ െʹሻ௜
መଵ௜
and
ܤܣ஼ி௎ሺʹ െ
ሻ௜
መଶ௜Ǥ
11.1.3
Sensitivity Analysis
Two approaches will be conduct
 s 
tivit  a alysis of CFU efficacy analysis.
11.1.3.1
ANCOVA model using average change from baseline
Given that treatment ends on D
 
 ACFU(0-14) of log10CFU/mL counts over 14 days of 
treatment will be estimated by calculating an average of the change from baseline to day 14 in 
log of CFU as follows:
ܤܣ஼ி௎ሺͲ െͳͶሻ௜ൌଵ଴ሺܥܨܷȀ݉ܮሻଵସെଵ଴ሺܥܨܷȀ݉ܮሻ௕௔௦௘
ͳͶ
Ǥ
An ANCOVA model will be fitted as done in Section 11.1.1. If the CFU is missing at Day 14, 
then the latest time point with a measurement with the corresponding denominator will be used, 
e.g. if the latest day with a CFU measurement is Day 10, then the divisor in the formula above
will be 10.
11.1.3.2
Random intercepts and slopes model across all data points
A mixed model with random intercepts and slopes will be fitted in order to estimate the average 
change from baseline to Day 14. It will use all log CFU data points for all participants and time 
points. The model is given by
ଵ଴ܥܨܷȀ݉ܮൌߙ൅ݑ௜൅ሺߚଵ൅ܾ௜ሻݐ൅ߚଶ௝ܺଵ௝൅ߚଷ௝ܺଵ௝ݐ൅ߚସܺଶ௜൅ߝ௜௝
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ߚ
ʹሻ௜ൌߚመଵ௜
ி௎ሺʹ െͳͶ
ͳͶሻ௜ൌߚመଶ
ed as sensitivi y an
s sensitivit
odel using average
using averag
s on
on Day 14,
ay 14, BA
BACF
C
ated by calc lating
by calculating


TBA-7371
Bill & Melinda Gates Medical Research Institute
Statistical Analysis Plan: Gates MRI-TBD03-201
04-October-2022
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where ݐൌͲǡͳǡ ǥ ǡͳͶ, ܺଵ௝is the dummy indicator for treatments ݆ൌͳǡ ǥ ǡͷ with HRZE as the 
reference group, ܺଶ௜the covariate for baseline log10CFU/mL, ݑ௜the random intercepts with 
distribution ݑ௜׽ ܰሺͲǡ ߪ௨
ଶሻ, ܾ௜the random slopes with distribution ܾ௜׽ ܰሺͲǡ ߪ௕
ଶሻand  ߝ௜௝׽
ܰሺͲǡ ߪଶሻ. An unstructured covariance structured will be used for the variance-covariances of the 
random effects. It may be simplified to variance components (option “vc”) if the former doesn’t 
yield convergence or there is no gain in model fit as decided through the AIC. The fixed effects 
of the model are given by day ݐ, treatment group ܺ௝, baseline log10CFU/mL and the interaction 
between time and treatment group.
The average slope over time for each treatment group will be estimated and reported with 90% 
confidence intervals using the time and interaction effects, i.e. 
ሺߚመଵ൅ߚመଷ௝ሻǤ
11.2
Secondary Efficacy Endpoints
11.2.1
Time to Sputum Culture Positivity
When time to sputum culture positivity for  pa ticipant  
 concluded by Day 42 (i.e., > 42 
days), the value will be defined to be 43 days. F r eac  participant, linear and bilinear regression 
models will be fit, and the better fit model based on lower AIC similarly as described for 
BACFU(0-14) in Section 11.1.1 will be used to estimate BATTP(0-14), BATTP(0-2) and 
BATTP(2-14) of TTP from Screening to Day 14, Screening to Day 2 and Day 2 to Day 14, 
respectively. BATTP(0-14), BATTP(0-2) and BATTP(2-14) will be analyzed using an ANCOVA 
model, with a fixed effect for treatment group and baseline TTP as a covariate. An ANCOVA 
model will be used to quanti
 
 
de
 t at the each of the treatment group mean 
BATTP(0-14), BATTP(0-2) and BATTP(2-14) is less than 0.
Mean and mean change 
 
 f TTP with 95% CI at each time point will be presented 
in line plots by treatment group.  
 ddition, observed and fitted lines of bilinear and linear 
regression models of TTP over time will be presented for each participant.
11.2.2
Sputum Lipoarabinomannan
When a value of concentration of sputum LAM is < lower limit of quantification (LLOQ), the 
value will be defined to be half of LLOQ. For each participant, linear and bilinear regression 
models will be fit, and the better fit model based on lower AIC similarly as described for 
BACFU(0-14) in Section 11.1.1 will be used to estimate BALAM(0-14), BALAM(0-2) and 
BALAM(2-14) of log concentration of sputum LAM from Screening to Day 14, Screening to Day 
2 and Day 2 to Day 14, respectively. BALAM0-14), BALAM(0-2) and BALAM(2-14) will be 
analyzed using an ANCOVA model, with a fixed effect for treatment group and baseline log
value of concentration of sputum LAM as a covariate. An ANCOVA model will be used to 
quantify the evidence that each of treatment group mean BALAM(0-14), BALAM(0-2) and 
BALAM(2-14) is less than 0.  
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oup.  In a
im


TBA-7371
Bill & Melinda Gates Medical Research Institute
Statistical Analysis Plan: Gates MRI-TBD03-201
04-October-2022
Confidential
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Geometric mean and geometric mean ratio of post-baseline to baseline of concentration of 
sputum LAM with 95% CI at each time point will be presented in line plots by treatment group.
In addition, observed and fitted lines of bilinear and linear regression models of log 
concentration of sputum LAM over time will be presented for each participant. 
11.3
Subgroup Analyses
Subgroup analyses will be performed with respect to the primary efficacy variable. The 
subgroups will include the following: 
x
Sex: female and male
x
Age group: <45 and ≥45 years old
x
HIV: positive and negative (using the Baseline assessment)
11.4
Interim Analysis
No formal interim analysis is planned in this trial.
Unmasked safety and (if available) PK data on each cohort will be provided to the IDMC for 
dose escalation recommendations.
11.5
Sensitivity Analysis
All sensitivity efficacy analyses will be performed in the per-protocol population to assess the 
robustness of results.
If the study identifies participants who are randomized to the HRZE treatment group with 
confirmed isoniazid-resistant and rifampicin susceptible tuberculosis based on the Hain test, a 
sensitivity analyses of efficacy endpoints will be performed in the HRZE treatment group after
excluding these participants from the mITT population.
12 SAFETY ANALYS
All safety analyses will be performed in the Safety population.
12.1
Adverse Events
Adverse events (AEs) will be recorded from the time a participant has signed the informed
consent until end of study. Each verbatim AE term will be coded to a SOC and preferred term 
using the most recent version of the Medical Dictionary for Regulatory Activities dictionary 
version 22.0 or higher.  Intensity for each AE will be graded as Grade 1 (Mild), Grade 2 
(Moderate), Grade 3 (Severe), Grade 4 (Potentially Life-threatening), or Grade 5 (Death) 
according to the Division of Acquired Immunodeficiency Syndrome (DAIDS) Table for 
Grading the Severity of Adult and Pediatric Adverse Events [DAIDS 2017].
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pants from the mI
from the mI
ES


TBA-7371
Bill & Melinda Gates Medical Research Institute
Statistical Analysis Plan: Gates MRI-TBD03-201
04-October-2022
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If the start date of an AE is incomplete or missing, the event will be assumed to be started after day 
1, unless the incomplete start date (month and/or year) or the stop date (complete or incomplete)
clearly indicates that the event started before study day 1. 
Summaries of system organ class (SOC) and preferred term will be sorted alphabetically by SOC 
and by decreasing frequency of preferred term in the all TBA-7371 group (then alphabetically 
for ties).  If a participant has more than one AE at a given level (e.g. SOC and preferred term), 
the participant will only be counted once within that level. 
An AE listing by participant will display all reported AEs up to end of Follow-up visit (Day 42) 
or the Early Withdrawal visit, and will include the verbatim term in addition to the SOC and 
preferred term. This listing will also include all relevant data associated with the event: e.g. date 
of onset, date resolved, date of first dose, date of last dose, severity, frequency, outcome, 
relationship to study drug, action taken with study drug, a d required therapy. When a date is 
presented, the study day associated with the date will also be displayed. Separate listings will be 
presented for participants with serious adverse events (S
s , participants with AEs leading to 
discontinuation and participants who died, if any. 
12.1.1
Primary Safety Analysis
AEs with grade 3 intensity or greater are classified as severe AEs. The frequency distribution of 
participants who experienced 1, 2, or ≥3 severe AEs occurring from Day 1 through Day 15 will 
be summarized by treatment group. The frequenc  nd proportion (expressed in percent) of 
participants and 95% CI for prop
i ns i  eac  category will be provided. For computing 
proportions, the denominator is the number of participants in the Safety population for the given 
treatment group.
Serious AEs will be summarized similarly as described for severe AEs.
12.1.2
Secondary Safety Analyses
12.1.2.1
Adverse Events
An AE overview table containing frequency and proportion (expressed in percent) of participants 
with AEs from Day 1 through Day 15 will be summarized by treatment group for the following:
x
Any AE
x
AEs with highest intensity [Grade 1, 2, and ≥3 (severe)]
x
AEs related to study drug
x
AEs leading to study drug discontinuation
x
Serious AEs
x
Serious adverse drug reactions
x
AEs of special interest (AESI)
In this trial the following AEs will be reported as AESI:

Anaphylactic reaction
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and 
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be displ
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Es), partici
par
classified as sever
sified a
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re AE
vere AEs occu
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y and
frequenc
ortions in each cate
ns in each 
s the number of par
number o
marized similarly a
marized similarly
Safety Analyses
ty Analy
ts


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Bill & Melinda Gates Medical Research Institute
Statistical Analysis Plan: Gates MRI-TBD03-201
04-October-2022
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
≥Grade 2 intensity and/or serious AE related to increase of HR;

≥Grade 2 intensity and/or serious AE related to decrease of SBP;

≥ Grade 2 intensity and/or serious AE related to decrease of DBP;

≥ Grade 2 intensity and/or serious eye symptom-related AE;

Per clinical discretion, the Investigator has clinical discretion to call an AE as an
AESI even if these specific grading criteria are not specifically met.
Additionally, the frequency of AEs and frequency and proportion (expressed in percent) of 
participants with AE will be provided by SOC and PT and by treatment group for the following:
x
Any AE 
x
AEs with highest intensity [Grade 1, 2, and ≥3 (severe)]
x
AEs related to study drug
x
AEs leading to study drug discontinuation
x
Serious AEs 
The frequency of AEs and frequency and prop
on (e
e  n percent) of participants with 
AE will be provided by PT and by treatmen  
 or the following:
x
Serious adverse drug reactions
x
AEs of special interest
12.2
Eye Symptoms
Analysis of eye symptom-related AEs for all eye symptoms, severe eye symptoms, and serious 
eye symptoms will be based on new events that occurred after Screening. Severe eye symptoms 
are events that are assigned with grade 3 intensity or greater.
The frequency distribution of participants who experienced 1, 2, or ≥3 eye symptom-related AEs
in one or both eyes during Day 1 to Day 15 will be summarized by treatment group for all eye 
symptoms, severe eye symptoms, and serious eye symptoms. The frequency and proportion 
(expressed in percent) of participants and 95% CI for proportions will be provided for the 
summary. For computing proportions, the denominator is the number of participants in the 
Safety population for the given treatment group.  
Additionally, the frequency of symptom-related AEs and frequency and proportion (expressed in 
percent) of participants with eye symptom-related AEs in one or both eyes will be provided by 
PT and by treatment group for the following:
x
All eye symptoms
x
Severe eye symptoms
x
Serious eye symptoms
x
The frequency and proportion of participants with eye symptom-related AEs in one or 
both eyes that observed at Days 1, 4, 7, 10, 14, 15, Days 1-15 combined (i.e. any eye 
symptom-related AE observed on any Days 1-15), 28, 42, and Days 28-42 combined (i.e. 
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04-October-2022
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Page 30 of 53
any eye symptom-related AE observed on any Days 28-42) will be provided by treatment 
group for the following: All eye symptoms
x
Severe eye symptoms
x
Serious eye symptoms
For the by-time point summary, the denominator for the proportion is the number of participants
with eye symptom assessment at the given time point. 
Any day that a participant reported an eye symptom-related AE in one or both eyes after 
screening will be counted toward the number of days of having eye symptoms in the study for 
that individual. Number of days of having eye symptoms will be summarized by treatment group 
using descriptive statistics for the following:
x
All eye symptoms
x
Severe eye symptoms
x
Serious eye symptoms
Additionally, categorical number of days of havi
eye s
ptoms for participants with these 
events will be summarized by treatment group as 
ws:
x
1-3 days
x
4-6 days
x
7-9 days
x
10-12 days
x
13-15 days
x
≥16 days
The summary will includ  he frequency an  proportion (expressed in percent) of participants for 
each category. For co
ng p
port
, the denominator will be the number of participants 
with eye symptom-related AEs in t e treatment group.
Average duration, expressed i  ours, of eye symptom-related AEs in one or both eyes that were 
observed after screening for an individual participant will be computed as the average of duration
of these events. Average duration, will be summarized by treatment group using descriptive 
statistics for the following:
x
All eye symptoms
x
Severe eye symptoms
x
Serious eye symptoms
Additionally, categorical average duration of eye symptoms for participants with these events 
will be summarized by treatment group as follows:
x
≤1 hour
x
>1-3 hours
x
>3-5 hours
x
>5-24 hours
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n h


Gates_MRI-TBD03-20 l_Statistical Analysis Plan_ 04Oct2022 
Vault eTMF Document Number: VV-TMF-29915 I 1.0 
TBA-7371 
Statistical Analysis Plan: Gates MRI-TBD03-201 
• 
>24 hours 
Bill & Melinda Gates Medical Research Institute 
04-October-2022 
The summaiy will include the frequency and propo1iion ( expressed in percent) of paiiicipants for 
each catego1y. For computing propo1iions, the denominator will be the number of paiiicipants 
with eye symptoms in the treatment group. 
Explorato1y safety analysis may be perfo1med to fmiher assess eye symptoms ( all, severe, 
serious) repo1ied from Day 1 through Day 15 if deemed to add value. The data may be fit in the 
same spirit as the efficacy model using hierarchical Bayesian nonlineai· mixed-effects logistics 
regression model, or other simpler model-based assessments. 
12.3 
Visual Acuity 
The visual acuity scores will be conve1ied to logMAR scale for analyzing change from baseline. 
LogMar scale is computed as logMAR = -log(visual acuity score in decimal scale). 
Visual Acuity Score 
Decimal Scale 
Loe:MAR Scale 
20/20 
1.00 
0.00 
20/25 
0.80 
...... 
0.10 
20/30 
. -,., 
0.18 
20/40 
0.50 
0.30 
20/50 
-
0.40 
0.40 
20/70 
0.29 
0.54 
20/100 
0.20 
0.70 
20/200 
JI 
0.10 
1.00 
20/400 
~f 
0.05 
1.30 
20/800 
, 
0.03 
1.60 
fu logMAR scale, lower scores coITespond to better vision, and as acuity becomes worse, the 
value of the logMAR increases. 
Worst logMAR score is define · t, be the highest value oflogMAR scores measured on left and 
right eyes at a given time point. The changes in worst logMAR score from baseline to Days 1, 4, 
7 10, 14, 15, Days 1-15 combined (i.e. most worst logMAR score on any Days 1-15), 28, 42, and 
Days 28-42 combined (i.e. most worst logMAR score on any Days 28-42) will be summai·ized 
by treatment group using descriptive statistics. 
Additionally, the changes in worst logMAR score from Days 1-15 combined to Days 28-42 
combined will be summai·ized similarly as described above. 
The futemational Classification of Diseases 11 [ICD-11, 2018] classifies for distance vision 
impai1ment is as follows: 
Classification of Vision Impairment 
Distance Visual Acuity 
N01mal 
Equal to or better than 20/40 
Mild 
Worse than 20/40 and equal to or better than 20/70 
Confidential 
Page 31 of 53 


Gates_MRI-TBD03-20 l_Statistical Analysis Plan_ 04Oct2022 
Vault eTMF Document Number: VV-TMF-29915 I 1.0 
TBA-7371 
Statistical Analysis Plan: Gates MRI-TBD03-201 
Moderate 
Severe 
Blindness 
Bill & Melinda Gates Medical Research Institute 
04-October-2022 
Worse than 20/70 and equal to or better than 
20/200 
Worse than 20/200 and equal to or better than 
20/400 
Worse than 20/400 
The highest classification of vision impai1ment of left and right eyes at the given time point will 
be selected for the analysis. The frequency and propo1tion of paiticipants for each level of the 
classification of vision impaiiment at baseline, Days 1, 4, 7, 10, 14, 15, Days 1-15 combined (i.e. 
worst vision impai1ment at any Days 1-15), 28, 42, and Days 28-42 combined (i.e. worst vision 
impai1ment at any Days 28-42) will be summarized by treatment group. For the by-time point 
summa1y, the denominator for the propo1tion is the number of paiticipants with visual acuity 
assessment at the given time point. 
The frequency and propo1tion of paiticipants for each level of the ci- ssification of vision 
impai1ment at baseline that transitioned to a level of the classification of vision impaiiment at 
Days 1, 4, 7, 10, 14, 15, Days 1-15 combined (i.e. worst vision impaiiment at any Days 1-15), 
28, 42, and Days 28-42 combined (i.e. worst vision impairment at any Days 28-42) will be 
provided by treatment group. For the by-time point summary, the denominator for the propo1tion 
is the number of pa1ticipants with non-missing values at baseline and the given post-baseline 
time point. 
Additionally, the transition of levels of classification of vision impaiiment from Days 1-15 
combined to Days 28-42 combined will be summarized similai·ly as described above. 
12.4 
Color Vision 
The three color vision defic;ts ar ... deutan, protan, and tritan. The degree of severity of color 
vision deficit is graded as l'lormal, mild, moderate, or severe. The severity of color vision 
abno1mality will be assigned to the highest degree of severity of the 3 color vision deficits. For 
example, the severities of deutan, protan, and tritan are mild, moderate, n01mal, respectively, for 
one of the eyes. For this case, moderate will be assigned as the highest level of severity for color 
vision abno1mality. 
The highest level of severity of color vision abno1mality of left and right eyes at the given time 
point will be selected for the analysis. The frequency and propo1tion of paiticipants for each 
level of the severity of color vision abno1mality at baseline, Days 1, 4, 7, 10, 14, 15, Days 1-15 
combined (i.e. worst color vision abno1mality at any Days 1-15), 28, 42, and Days 28-42 
combined (i.e. worst color vision abno1mality at any Days 28-42) will be summai·ized by 
treatment group. For the by-time point summaiy , the denominator for the propo1tion is the 
number of paiticipants with visual acuity assessment at the given time point. 
The frequency and propo1tion of paiticipants for each level of the severity of color vision 
abno1mality at baseline that transitioned to a level of the severity of color vision abno1mality at 
Days 1, 4, 7, 10, 14, 15, Days 1-15 combined (i.e. worst color vision abno1mality at any Days 
Confidential 
Page 32 of53 


TBA-7371
Bill & Melinda Gates Medical Research Institute
Statistical Analysis Plan: Gates MRI-TBD03-201
04-October-2022
Confidential
Page 33 of 53
1-15), 28, 42, and Days 28-42 combined (i.e. worst color vision abnormality at any Days 28-42)
will be provided by treatment group. For the by-time point summary, the denominator for the
proportion is the number of participants with non-missing values at baseline and the given
post-baseline time point.
Additionally, the transition of levels of severity of color vision abnormality from Days 1-15 
combined to Days 28-42 combined will be summarized similarly as described above.
12.5
Vital Signs
12.5.1
Intraday Vital Signs Results
Intraday values of vital signs (HR, SBP, and DBP) measured while in supine and while in 
standing at predose, and 2.5h, 10.5h, and 16.5h after the time of 1st daily dose of study drug on 
Days 1, 4, 7, 10, and 14 and changes from predose taken on the same day will be summarized 
using descriptive statistics by treatment group. Line plots of mea  
 intraday HR, SBP, and 
DBP measured while in supine and while in standing by treatment group will be provided.
Potentially clinically important criteria of intraday chang s rom presdose in HR, SBP, and DBP 
while measured in supine and while in standing are defined as follows:
x
≥25% increase in supine HR 
x
≥25% increase in standing HR
x
≥25% decrease in supine SBP
x
≥25% decrease in standing SBP
x
≥25% decrease in supine DBP
x
≥25% decrease in standing DBP
For each of the criteria, the 
 
 proportion (expressed in percent) of participants who 
met the criterion at each time oint will be provided by treatment group. For the by-time point
summary, the denominator for the proportion is the number of participants in the treatment group 
with non-missing values at predose and the given post-predose time point taken on the same day.
12.5.2
Daily Vital Signs Results
Daily values of vital signs (HR, SBP, and DBP) measured while in supine and while in standing 
at baseline (Day 1 predose), Days 2 (predose), 3, 4 (predose), 5, 6, 7 (predose), 8, 9, 10 
(predose), 11, 12, 13, 14 (predose), 15, 28, and 42 and changes from baseline will be 
summarized by treatment group using descriptive statistics. Line plots of mean of daily HR, 
SBP, and DBP measured while in supine and while in standing by treatment group will be 
provided.
Potentially clinically important criteria for changes from baseline in HR, SBP, and DBP while 
measured in supine and while in standing are defined as follows:
x
≥25% increase in supine HR 
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time point
e p
wil
or the p
th


TBA-7371
Bill & Melinda Gates Medical Research Institute
Statistical Analysis Plan: Gates MRI-TBD03-201
04-October-2022
Confidential
Page 34 of 53
x
≥25% increase in standing HR
x
≥25% decrease in supine SBP
x
≥25% decrease in standing SBP
x
≥25% decrease in supine DBP
x
≥25% decrease in standing DBP
For each of the criteria, the frequency and proportion (expressed in percent) of participants who 
met the criterion at each time point will be provided by treatment group. For the by-time point 
summary, the denominator for the proportion is the number of participants in the treatment group 
with non-missing values at baseline and the given post-baseline time point.
For each of the criteria, any day that a participant whose vital signs results met the criterion will 
be counted toward the number of days with the criterion e  in the study for that individual. 
Number of days with the criterion met will be summarized by treatment group using descriptive 
statistics.
Additionally, categorical number of days with the criterion met will be summarized by treatment 
group as follows:
x
1-3 days
x
4-6 days
x
7-9 days
x
10-12 days
x
13-15 days
x
≥16 days
The summary will include the frequency and proportion (expressed in percent) of participants for 
each category. For com
g proportions, the denominator will be the number of participants in 
the treatment group who met the respective criterion.
12.5.3
Orthostatic Vital Signs Results
Orthostatic change in HR, SBP, and DBP is calculated as vital signs measurement recorded in 
standing position minus vital signs measurement recorded in supine position at same time point.
Percentage orthostatic change in HR, SBP, and DBP is calculated as vital signs measurement 
recorded in standing position minus vital signs measurement recorded in supine position at same 
time point divided by vital signs measurement recorded in supine position at same time point.
Orthostatic changes in HR, SBP, and DBP at predose, and 2.5h, 10.5h, and 16.5h after the time 
of 1st daily dose of study drug on Days 1, 4, 7, 10, and 14 and daily measurements at Baseline, 
Days 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 28, and 42 will be summarized by treatment 
group using descriptive statistics. Line plots of mean of orthostatic change in HR, SBP, and DBP 
measured while in supine and while in standing by treatment group will be provided.
Potentially clinically important criteria for orthostatic hypotension are defined as follows:
x
≥25% increase in orthostatic HR 
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al Signs R
Sig


TBA-7371
Bill & Melinda Gates Medical Research Institute
Statistical Analysis Plan: Gates MRI-TBD03-201
04-October-2022
Confidential
Page 35 of 53
x
≥25% decrease in orthostatic SBP
x
≥25% decrease in orthostatic DBP
x
≥20 mmHg decrease in orthostatic SBP
x
≥10 mmHg decrease in orthostatic DBP
For each of the criteria, the frequency and proportion (expressed in percent) of participants who 
met the criterion at each time point will be provided by treatment group. For the by-time point 
summary, the denominator for the proportion is the number of participants in the treatment group 
with non-missing values at the given time point.
Any day that a participant met a potentially clinically important criterion of orthostatic 
hypotension will be counted toward the number of days with orthostatic hypotension in the study 
for that individual. Number of days with orthostatic hypotension will be summarized by 
treatment group using descriptive statistics for each of the criteria.
Additionally, categorical number of days with ortho
 
will be summarized by 
treatment group as follows:
x
1-3 days
x
4-6 days
x
7-9 days
x
10-12 days
x
13-15 days
x
≥16 days
The summary will include the frequency and p
portion (expressed in percent) of participants for 
each category. For comput ng p
rtions, the denominator will be the number of participants in 
the treatment group who met the respective criterion.
12.6
Electrocardiogram
12.6.1
Intraday ECG Results
Intraday values of ECG variables (HR, QRS duration, RR, PR, QT, and QTcF intervals)
measured at predose, and 2.5h, 10.5h, and 16.5h after the time of 1st daily dose of study drug on 
Days 1, 4, 7, 10, and 14 and changes from predose taken on the same day will be summarized 
using descriptive statistics by treatment group.
Potentially clinically important criteria for QTcF are defined as follows:
x
Observed: 451 to 480, 481 to 500, and >500 msec
x
Change from predose taken on the same day: 31 to 60, and >60 msec
For each of the criteria, the frequency and proportion (expressed in percent) of participants who 
met the criterion at each time point will be provided by treatment group. For the by-time point
summary, the denominator for the proportion is the number of participants in the treatment group 
with non-missing values at predose and the given post-predose time point taken on the same day.
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ten
te
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lt


TBA-7371
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04-October-2022
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Page 36 of 53
Additionally, intraday value of ECG variables for sex subgroup (female and male) will be 
summarized similarly as described above. Boxplots of intraday values of QTcF by treatment 
group and sex will be provided.
12.6.2
Daily ECG Results
Values of ECG variables (HR, QRS duration, RR, PR, QT, and QTcF intervals) measured at 
baseline (Day 1 predose), Days 4 (predose), 7 (predose), 10 (predose), 14 (predose), 15, 28, and 
42 and changes from baseline will be summarized using descriptive statistics by treatment group.
Potentially clinically important criteria for QTcF are defined as follows:
x
Observed: 451 to 480, 481 to 500, and >500 msec
x
Change from baseline: 31 to 60, and >60 msec
For each of the criteria, the frequency and proportion (expressed in percent) of participants who 
met the criterion at each time point will be provided by treatment group. For the by-time point
summary, the denominator for the proportion is the n mber of 
icipants in the treatment group 
with non-missing values at baseline and the given post-bas ine time point.
Additionally, values of ECG variables for sex subgroup (female and male) will be summarized 
similarly as described above. Boxplots of daily values of QTcF by treatment group and sex will 
be provided.
12.7
Clinical Safety Laboratory Measurement
Clinical safety laboratory parameters include: 
Haematology
complete blood count [red blood cells (erythrocytes), haemoglobin, 
platelets nd white blood cells (leukocytes)] and differential (absolute 
counts) including neutrophils, lymphocytes, monocytes, eosinophils 
and basophils.
Serum chemistry
alanine aminotransferase, aspartate aminotransferase, alkaline 
phosphatase, total bilirubin, blood urea nitrogen, creatinine, sodium, 
potassium.
Serum coagulation
prothrombin time, partial prothrombin time, international normalized 
ratio.
Urinalysis
specific gravity, pH, glucose, protein, blood, ketones, bilirubin, 
urobilinogen, nitrite, leukocyte esterase.
Clinical laboratory values for haematology, serum chemistry, coagulation, and urinalysis safety 
at baseline (screening), Days 3, 7, 14 and 42 changes from baseline will be summarized by 
treatment group using descriptive statistics. Changes may be assessed on the raw (difference) or 
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(expressed in p
ressed in
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the number of 
umber o part
iven post
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basel
sex subgroup (fem
subgroup 
of daily values of Q
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atory Measurem
Measur
rameters include:
eters include:
platelets nd wh
latelets nd wh
counts) includ
nt
d basoph
bas
$S
$


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Bill & Melinda Gates Medical Research Institute
Statistical Analysis Plan: Gates MRI-TBD03-201
04-October-2022
Confidential
Page 37 of 53
log (fold change) scale, depending on the whether the distribution of the measure is more 
appropriately described by a normal or lognormal distribution, respectively.
For urinalysis with categorical results, the frequency and proportion (expressed in percent) of 
participants will be tabulated for each category at baseline, Days 3, 7, 14, and 42 by treatment 
group. For the categorical urinalysis by-visit summary, the denominator for the proportion is the 
number of participants with non-missing values in the treatment group for the given parameter
and time point.
Shift tables will used to summarize haematology, serum chemistry, and coagulation laboratory 
values by treatment group. Shift tables will display transition of participants having lab values
categorized as low, normal, or high with respect to their lab parameters reference ranges at 
baseline to normal, low or high at Days 3, 7, 14, and 42. For the by time point summary, the 
denominator for the proportion is the number of participants with non-missing values at baseline 
and the given time point in the treatment group for the given lab parameter.
All laboratory test results will be listed. The listings will in
de date and study day of collection. 
All units will be displayed in Système International units. Out of reference ranges values will be 
flagged in the data listings (e.g., ‘L’ or ‘H’).
12.8
COVID-19/SARS-CoV-2 Test
The frequency and proportion of participants having negative or positive COVID-19/SARS-
CoV-2 test will be summarized by treatment group at Days 7 and 15. For computing proportions, 
the denominator is the number of participants in the Safety population for the given treatment 
group and visit.
12.9
Drug Susceptibilities and MIC of TBA-7371
Drug susceptibility testing for isoniazid and rifampicin and MICs of TBA-7371 will be 
performed at Screening and Day 14. The frequency and proportion of participants having 
isoniazid resistance and/or rifampicin resistance detected by line probe assay will be provided by 
treatment group at Screening and Day 14. Any participant found to have isoniazid or rifampicin
resistance by line probe assay will have further resistance testing performed and descriptive 
summaries of those results will be compiled. For computing proportions, the denominator is the
number of participants in the Safety population for the given treatment group and visit. 
MIC of TBA-7371 will be summarized by treatment group using descriptive statistics at 
Screening and Day 14.
13 PHARMACOKINETIC ANALYSES
All PK and PK/PD analyses will be performed for the PK population.
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ay 14


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13.1
TBA-7371 Pharmacokinetics
Timing of TBA-7371 sampling for participants randomized to TBA-7371 will be as follows:
QD Dosing
BID Dosing
TID Dosing
Screening Phase
Predose
Predose
Predose
Study Treatment 
Phase
1.
Predose on Days 1, 2,
4, 7, and 14.
2.
30 min, 1h, 2.5h, 3h,
4h, 6h, 7h, 10.5h, 12h,
and 16.5h on days 1,
7, and 14.
1.
Predose on Days 1,
2, 4, 7, and 14.
2.
30 min, 1h, 2.5h, 3h,
4h, 6h, 7h, 10.5h,
and 12h on days 1,
7, and 14.
1.
Predose on Days 1,
2, 4, 7, and 14.
2.
30 min, 1h, 2.5h, 3h,
4h, 6h, and 7h on
days 1, 7, and 14.
TBA-7371 concentrations below the limit of quantitation will be set to 0.  TBA-7371 
concentrations will be summarized by treatment group 
i
 
inal time points for all 
participants in the PK population. The following desc iptive statistics will be provided: N, 
arithmetic mean, standard deviation, arithmetic percent coefficient of variation (CV), median, 
minimum, maximum, geometric mean, and geometric e
nt CV. Linear and semi-log plots of 
individual and mean concentrations versus n
al time will be presented by treatment group. 
Plasma concentration of TBA-7371 having 
ue 0 will be excluded from semi-log plots.
The following PK parameters of Days 1, 7, and 14 will be derived using non-compartmental 
model.
Day 1
Day 7
Day 14
Cmax, Tmax, Clast, Tlast, AUCinf, 
AUClast, AUCtau, Cmin, 
half-life,
C ax, Tmax, Clast, Tlast, AUCinf, 
AUClast, AUCtau, Cmin, 
half-life, accumulation ratio 
(Cmax of day 1/Cmax of day 7)
Cmax, Tmax, Clast, Tlast, 
AUCinf, AUClast, AUCtau, 
Cmin, half-life, accumulation 
ratio (Cmax of day 1/Cmax of 
day 14)
x
Cmax – maximum plasma concentration 
x
Cmin – minimum plasma concentration
x
Tmax – time to maximum plasma concentration 
x
λz – elimination rate constant. The elimination rate constant will be calculated as the negative 
of the slope of the terminal log-linear segment of the plasma concentration-time curve. The 
slope will be determined from a plot of the natural log of the terminal plasma concentrations 
against time; at least 3 terminal plasma concentration time points, beginning with the final 
concentration ≥ LLOQ and not including Cmax, will be selected for the determination of λz; 
the regression will have a coefficient of determination R² ≥ 0.9000.
x
Half-life – terminal half-life = ln(2) / λz.
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$


Gates_MRI-TBD03-20 l_Statistical Analysis Plan_ 040ct2022 
Vault eTMF Document Number: VV-TMF-29915 I 1.0 
TBA-7371 
Statistical Analysis Plan: Gates MRI-TBD03-201 
Bill & Melinda Gates Medical Research Institute 
04-October-2022 
• 
AUC1ast - area under the plasma concentration-time curve from O up to the last measurable 
concentration ~ LLOQ. AUC is calculated using the linear trapezoidal method. 
• 
AUCinf- AUC extrapolated to infinity. AUCinf = AUC1ast + C1ast / Az, where C1ast is the last 
measurable concentration 
LLOQ and Az is the tenninal phase rate constant. 
• 
AUCtau - AUC to the end of the dosing period. 
PK parameters of days 1, 4, 7, and 14 will be summarized using descriptive statistics number of 
paiiicipants, arithmetic mean, standai·d deviation, arithmetic percent CV, median, minimum, 
maximum, geometric mean, and geometric percent CV and will be provided by treatment group. 
13.2 
TBA-7371 Concentration-Effect Relationship 
Speannan coITelations, simple lineai· regressions and graphical visualizations will be used to 
summarize coITelation between TBA-7371 AUCinf, Cmax, T>MIC and CFU counts on solid 
media culture. The SAS PROC CORR and PROC REG will be used to compute Speaiman 
coITelations and fit simple lineai· regression models. The slope with 95% confidence interval, as 
well as the R-squared will be repo1ied for the simple lineai· regression. This will be reported by 
treatment group as well as overall. 
13.3 
Exposure-Response Analysis 
The exposure-response Emax model will be used to estimate EC90 as follows: 
where: 
BAepu(O _14) = Emax·Cmax(ss) + £ 
ECso+ Cmax(ss) 
• 
BAcFu(0-14) is the average change in log(CFU) counts over each day from screening to day 
14. 
• 
Emax is the maximal TBA-73 71 EBA effect. 
• 
EC 50 is the expected concentration of TBA-73 71 associated with 50% of Emax · 
• 
Cmax(ss) is the steady state Cmax ofTBA-7371 measured at day 14. 
• 
£ is a random eITor assumed to be n01m ally distributed with mean zero and constant vai·iance 
cr2. 
Exposure-response analysis will be perfo1med in the PK population with paiiicipants having PK 
data measured on day 14. The SAS PROC NLMIXED procedure will be used to fit an Emax 
model. Maximum likelihood estimates and corresponding 95% Cls for Emax and ECso will be 
provided. The prediction of EC90 to reach 90% of Emax is computed as 
EC90 = 9 · EC50 
Confidential 
Page 39 of53 


TBA-7371
Bill & Melinda Gates Medical Research Institute
Statistical Analysis Plan: Gates MRI-TBD03-201
04-October-2022
Confidential
Page 40 of 53
95% CI for the estimate of EC90 will be provided.  An exposure-response curve of Emax model 
will be produced and vertical reference lines for EC50 and EC90 will be provided for each 
treatment group as well as overall.
Alternative sigmoid exposure-response model may be explored if deemed appropriate.
14 PHYSICAL EXAMINATION
Clinically significant physical examination findings will be provided in a listing.
15 CONCOMITANT MEDICATIONS
All concomitant medications will be coded using the Wo d Health Organization Drug 
Dictionary, March 1, 2018 version or later. The Anatomical Therapeutic Chemical (ATC) Level 
3 and preferred name will be used to list and summarize the data.  
The frequency and percentage of participants taking concomitant medication will be summarized 
by drug class (ATC Level 3) and medication preferred term and b  treatment group. Multiple 
concomitant medications usage by a participant in the same ATC category will be counted only 
once.
All concomitant medications will be provided i   sting.
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ded in a li


TBA-7371
Bill & Melinda Gates Medical Research Institute
Statistical Analysis Plan: Gates MRI-TBD03-201
04-October-2022
Confidential
Page 41 of 53
16 REFERENCES
1. Diacon AH, et al. Randomized Dose-Ranging Study of the 14-Day Early Bactericidal
Activity of Bedaquiline (TMC207) in Patients with Sputum Microscopy Smear-Positive
Pulmonary Tuberculosis. Antimicrobial Agents and Chemotherapy 2013: 57(5): 2199-2203.
2. Burger DA and Schall R. A Bayesian Nonlinear Mixed-Effects Regression Model for the
Characterization of Early Bactericidal Activity of Tuberculosis Drugs. Journal of
Biopharmaceutical Statistics 2015; 25: 1247-1271.
3. Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes
of Health US Department of Health and Human Services (DAIDS) Regulatory Support
Center. 2017. Table for grading the severity of adult and pediatric adverse events. Corrected
version 2.1. https://rsc.niaid.nih.gov/sites/default/files/daidsgradingcorrectedv21.pdf.
4. World Health Organization. ICD-11 for mortality and morbidity statistics (ICD-11 MMS)
2018 version. https://icd.who.int/browse11/l-m/en.
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ity and morbidity s
and morbid
m/en.


17 APPENDICES 
Gates_MRI-TBD03-20 l_Statistical Analysis Plan_ 040ct2022 
Vault eTMF Document Number: VV-TMF-29915 I 1.0 
Appendix 1 Schedule of Activities 
Assessments 
Screening Daya 
Study Treatment Day 
A± 15-minute time window is allowed 
for all measurements 
-7 to -3 
·2 
·1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
Written informed consent 1 
X 
,. 
I\'\ 
Hospital admission or discharge 2 
X 
Demography and medical and 
r 
X 
t reatment history 
. J 
Physical examination 3 
X 
X 
Chest x-ravs 4 
X 
Blood/serum sample collection for HIV 
X 
test and CD4 count 
Serum sample collection for pregnancy 
X 
status assessment 
Blood/serum sample collection for din. 
X 
X 
X 
safety lab assessment5 
' 
Urine sample collection for clinical 
X 
X 
X 
safety lab assessment 
Urine sample collection for isoniazid 
X 
and drug screening 6 
Overnight sputum collection for 
eligibility asses. (volume, acid-fast 
X 
bacilli Mtb pos. and rifampicin 
sensitivity) 7 
Vital signs and body weight recording 8 
X 
X 
X 
X 
X X X 
X 
X 
X 
X 
X 
ECG recording 9 
X 
X 
X 
X 
X 
Eye assessment (visual acuity, color 
X 
X 
X 
X 
X 
vision, symptoms) 10 
Follow-up 
EWVc 
Dav b 
12 
13 
14 
15 
28 
42 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


Gates_M RI-TBD03-20 l_Statistical Analysis Plan_ 04Oct2022 
Vault eTMF Document Number: VV-TMF-29915 I 1.0 
TBA-7371 
Bill & Melinda Gates Medical Research Institute 
Statistical Analysis Plan: Gates MRI-TBD03-201 
04-October-2022 
Assessments 
Screening Daya 
Study Treatment Day 
Follow-up 
EWVc 
Da
b 
A ± 15-minute time window is allowed 
for all measurements 
-7 to -3 
·2 
·1 
1 
2 
3 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
28 
42 
Study drug (IMP) administration 11 
X 
X 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
Overnight sputum collection for EBA & 
X 
X 
X 
X 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
exploratory measures. 12 
Spot sputum collection for exploratory 
X 
X 
X 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
measurements 13 
Recording of AE, SAE (incl. serious 
X 
X 
X 
X 
X 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ADR) and AESI 14 
Recording of concomitant treatments 
X 
X 
X 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood/serum sample collection for PK 
X 
X 
X 
X 
measurements 15 
a. Screening (Days -7 to -1). Screening procedures will be cor ucted during the up to 7-Day screening period. Screening assessments can be done at 
any t ime during this period, except for the written infr med consent, which must be given before any screening is started, the overnight sputum 
collection for eligibility assessment, which must be completed on or before Day -3, and the overnight sputum collection for EBA, which must be 
done consecutively on Day-2 and Day-1. Subjects may be hospitalized for the entire screening period at the investigator's discretion, but must be 
hospitalized starting on Day-3. 
b. Follow-up (Days 15 to 42). Allowed window for Day 28 and Day 42 visits: +/- 3 Days. 
c. Early Withdrawal Visit (EWV) or Unscheduled Visit. Participants who withdraw before Day 14 will be asked to complete the EWV assessments 
within 2 Days of withdrawal. Participants who complete the Study Treatment Phase, but do not return for the Day 28 visit will be asked to return for 
the Day 42 visit. If access to sites is limited due to the local status of COVID-19 pandemic, the Day 28 and Day 42 visits could potentially be 
conducted by telephone. Procedures and assessments conducted during an unscheduled visit will be at the discretion of the investigator in 
consultation with the medical monitor. 
1. Written informed consent will be given before any screening procedure is started. 
Confidential 
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TBA-7371
Bill & Melinda Gates Medical Research Institute
Statistical Analysis Plan: Gates MRI-TBD03-201
04-October-2022
Confidential
Page 44 of 53
2. Hospital admission and discharge. Study participants will be hospitalized by Day -3 of the Screening Phase and will remain in hospital until the Day
after the last dose of study drug is dispensed (Day 15). Discharge from hospital will occur on Day 15 after all procedures planned for that Day are
completed. Upon discharge, participants will be referred to the national TB treatment program for standard of care (SoC) treatment.
3. Physical examination (PE). Full PE will be conducted during the Screening Phase; focused PE (guided by medical history) will be conducted on Days
7, 15, 28, 42. Focused PE will be conducted at EWV if the participant discontinues between Day 1 and Day 14. Focused PE may be conducted
during an unscheduled visit at the discretion of the investigator.
4. Chest X-rays. Good quality Posterior-Anterior chest X-rays will be accepted if conducted within 1 week prior to Day -7. If not available, chest X-rays
will be conducted during the Screening Phase.
5. Blood/serum sample collection for clinical safety laboratory assessment. The Day 3 and 7 sampling will occur before the 1st dose of study drug.
6. Urine sample collection drug screening: cannabinoids, cocaine, amphetamines, opi
s, 
hamphetamines.
7. Overnight sputum collection for eligibility assessment. Sputum assessment, including volume, will be performed by a Sponsor-approved central 
laboratory (see laboratory study instruction document). The 1st of the 3 overnight sputum collections (Day -7 to Day -3) conducted during the 
Screening Period will be used to assess eligibility as follows: sputum volume (must be at least 10 mL), acid-fast bacilli detection, Mycobacterium 
tuberculosis (Mtb) positivity and rifampicin sensitivity via the GeneXpert® diagnostic sys
m (Cepheid). In case inclusion criteria cannot be met from 
the 1st overnight sputum collection, one or more of the above procedures can
 
 on a 2nd overnight sputum collected during the Day -7 
to -3 screening period if the patient is domiciled at the site for both  
8. Vital sign and body weight recording. The following 5 vital sig s will be recor ed: axillary body temperature (BT), respiratory rate (RR), heart rate
(HR), systolic blood pressure, (SBP), diastolic blood pressure (DBP). Body weight (BW) will also be recorded with vital signs. Vital signs and body 
weight will be recorded as follows:
x Screening Phase: vital signs and BW once in the mo ning at appr
tely the same time the 1st daily dose study drug will be administered. SBP, 
DBP and HR can be repeated twice if exclus n criteria are 
t.
x Study Treatment Phase: vital signs and BW once e ery morning (Days 1 to 14) before administration of the 1st daily dose of study drug; in addition, 
on Days 1, 4, 7, 10 and 14 vital signs will also collected 2.5h, 10.5h and 16.5h after the time of 1st daily dose of study drug (see Table 4 of the 
protocol).
x Follow-up Phase: vital signs and BW on Day 15 in the morning before 1st daily dose of SoC medication; on Days 28 and 42 during the visit.
x EWV: vital signs and BW if the participant withdraws from the study between Day 1 and 14.
At each time point BT, RR and BW will be measured once, whereas HR, SBP and DBP will be measured twice as follows: after 10 min supine 
(“manual, supine”) and after 2 (±0.5) min standing (“manual, 2-min standing”). When ECG, vital signs and/or blood/serum samples are to be 
obtained at the same time point, the following order must be followed: ECG, vital signs, blood/serum sample, within 5 min of each other.
9. ECG recording. 12-lead ECG will be recorded once at each time point after at least 10 minutes of supine rest as follows:
x Screening Phase: once in the morning at approximately the same time the 1st daily dose study drug will be administered.
x Study Treatment Phase: on Days 1, 4, 7, 10 and 14 before administration of the 1st daily dose of study drug and 2.5h, 10.5h and 16.5h thereafter
(see Table 4 of the protocol).
x Follow-up Phase: on Day 15 in the morning before 1st daily dose of standard of care medication; on Days 28 and 42 during the visit.
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can b  
nducted
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or both. . 
tal signs will be recorded: a
ns will be record
pressure (DBP). Body weight
e (DBP). Body 
n the mo ning at approxima
n the mo ning at appr
xclus n criteria are met.
s n criteria are met.
BW once e ery mornin
once e ery morn
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also collected 2.5
o collected 2.5
5 in 


Gates_MRI-TBD03-20 l_Statistical Analysis Plan_ 04Oct2022 
Vault eTMF Document Number: VV-TMF-29915 I 1.0 
TBA-7371 
Bill & Melinda Gates Medical Research Institute 
04-October-2022 
Statistical Analysis Plan: Gates MRI-TBD03-201 
• EWV: if the participant withdraws from the study between Day 1 and 14. 
10.Eye assessment. A trained staff member will assess: i) eye symptoms using a standardized script {Section 10.5, Appendix 5 of the protocol), ii) visual 
acuity by means of the Rosenbaum Pocket Eye Screener, iii) color vision by means of the Waggoner Computerized Color Vision Test and as follows: 
• 
Screening Phase: once in the AM. 
• 
Study Treatment Phase: Days 1, 4, 7, 10, and 14, 2.Sh after 1st daily dose of study drug (see Table 4 of the protocol). 
• 
Follow-up Phase: Days 15, 28 and 42 during the visit. 
• 
EWV: if the participant withdraws from the study between Days 1 and 14. 
11. Study drug (IMP) administration. Study drug (TBA-7371 or HRZE) will be administered fro 
ay 1 to Day 14 based on the randomization list by an 
authorized and trained site staff member. The 1st dose of study drug will be administered ~t ,t.e same time each Day for the individual participant. 
Subsequent doses will be administered as follows (see Table 4 of the protocol): 
• Twice daily (BID) schedules: 12h after 1st dose 
• Three times (TID) daily schedule: 7h and 14h after 1st dose 
Fasting must occur at least 2 hours before dosing and at least 1 hour after dosing. Study drug administration will be followed by 200 ml water. 
12. Overnight sputum collection for EBA assessment and exploratory measurements. Overnigti• sputum will be collected from 3 PM to 7 AM of the 
following Day (16 hours) on Days -2 and -1 during Screening Phase and on 14 consecutive Days during the Study Treatment Phase (Days 1 to 14) for 
EBA assessment. The last collection will finish at 7 AM of D , 15. 
, l"' ;u_ 
tibility t - sting for isoniazid and rifam 
MIC of TBA-7371 will be erformed o ~,ther of Da -2 or Da -1 and again on Day 14. 
13. 
14. Recording of AE, SAE (including serious AOR) and "ES,; recor" ing of concomitant treatments. Adverse events (AE), serious adverse events {SAE), 
including serious adverse drug reactions (A "R), adverse ev nts of special interest (AESI) and concomitant treatments will be recorded from the t ime 
each participant has signed the informed con ent torr (ICF) until he/she has completed the last follow- up visit (Day 42) or the Early Withdrawal 
Visit {EWV). 
15. Blood/serum sample collection for PK measurements. WILL BE CONDUCTED ONLY IN PARTICIPANTS RANDOMIZED TO TBA-7371. Timing of 
sampling will be as follows: 
16. 
• Study Treatment Phase: Days 1, 2, 4, 7 and 14 before administration of the 1st daily dose of study drug; in addition, on Days 1, 7 and 14 samples 
will also collected 30 min(+/- 5 min) and at 1h, 2.Sh, 3h, 4h, 6h, 7h, 10.Sh, 12h, 16.Sh (+/- 15 min) after 1st daily dose of study drug. (see Table 4 of 
the protocol). Patients assigned to BID dosing will not have collections at 16.Sh, and the 12h sample will be taken prior to the second daily dose. 
Patients assigned to TID dosing will not have collections at 10.Sh, 12h and 16.Sh, and the 7h sample will be taken prior to the second daily dose. 
When timing coincides, samples must always be taken after recording of ECG and vital signs. 
Confidential 
Page 45 of53 


TBA-7371
Bill & Melinda Gates Medical Research Institute
Statistical Analysis Plan: Gates MRI-TBD03-201
04-October-2022
Confidential
Page 46 of 53
Coronavirus Disease (COVID-19) / Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2 Testing). COVID-19 testing will be conducted via 
PCR using a test product authorized by SAHPRA at an accredited public or private sector laboratory. A specimen will be collected during the screening 
period between Day-7 to Day -3, and a negative result must be confirmed prior to randomization. For safety monitoring purposes, testing will also be 
performed at Day 7 (±2 Days), on Day 14 OR Day 15 before discharge, and/or at any other time that infection is suspected.
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$SSURYHG


Appendix 2 Imputation Rules for Missing or Partial Dates for AEs 
Date
Situation
Imputation Rule
AE Start Date
Only month and year are known and 
month is prior to first dose date 
Use the first day of the month
Only month and year are known and 
month is the same as first dose date
Use the first dose date
Only month and year are known and 
month is after first dose date
Use the first day of the month
Only year is known and year is after first 
dose date
Use Jan 1 of that year
AE End Date
Only month and year are known and 
month is prior to last dose date 
Use the last day of the month
Only month and year are known and 
month is the same as last dose date
Use the last dose date
Only month and year are known and 
month is after last dose date
Use the first day of the month
Only year is known and year is before 
last dose date
Use Dec 31 of that year
The estimated stop date is before a 
complete or imputed AE start date
Use the last day of the month of 
the AE start date
AE = adverse event
Note: The imputation of end date must be later than start date.
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n and 
Use t
U
G
ar is before
befor
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HG
e is before a 
efore a 
d AE start date
start d
Y
e later than start date.
r than start 
R
S


TBA-7371
Bill & Melinda Gates Medical Research Institute
Statistical Analysis Plan: Gates MRI-TBD03-201
04-October-2022
Confidential
Page 48 of 53
Appendix 3 Imputation Rules for Missing or Partial Dates for Concomitant 
Medications
Imputation rules for missing or partial dates (D=day, M=month, Y=year, T=time)
Parameter
Missing
Additional conditions
Imputation Rule
Start date 
D only
M and Y same as M and Y of first 
dose of study drug
Date of first dose of study 
drug
M and/or Y not same as M and Y 
of first dose of study drug
First day of month
M and D
Y same as Y of first dose of study 
drug
Date of first dose of study 
drug
Y not same as Y of first dose of 
study drug
Use Jan 01 of Y
M, D and Y
None--date completely missing
Date of first dose of study 
drug
Stop date 
D only
M and Y same as M and Y of end 
of study
Date of end of study
M and/or Y not same as M and Y 
of nd of study
Last day of month
M and D
Y same as Y of end of study
Date of last dose of study 
drug
Y not same as Y of end of study
Use Dec 31 of Y
M, D and Y
Medications that are not marked 
as ongoing - date completely 
missing
Date of end of study
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of s
first dose of 
se 
U
G
mpletely missing
etely missi
YH
nd Y same as M an
ame 
f study
dy
UR
M and/or Y not s
and/or Y not
of f
nd of stud
nd of stud
SS
$
D
Y same as 
Y same as 
$S
$
Y no
Y
$


Gates_MRI-TBD03-20 l_Statistical Analysis Plan_ 040ct2022 
Vault eTMF Document Number: VV-TMF-29915 I 1.0 
TBA-7371 
Statistical Analysis Plan: Gates MRI-TBD03-201 
Bill & Melinda Gates Medical Research Institute 
04-October-2022 
Appendix 4 SAS Code 
SAS code for computing 95% confidence interval for single propo1iion based on the mid-P 
method: 
proc freq data=<dataset > order=freq; 
tabl es category/ b i nomia l 
(CL=MIDP) alpha=0 . 05; 
wei ght Count; 
run; 
SAS code for response-exposure Ema.x model: 
ods output fitstatistics=<Data with aic>; 
ods output parameterestimates=<Data wi t h slope estimates> ; 
proc nlmixed data=<dataset> ; 
by <treatment group> ; 
parms Emax=<numeric> 
EC50=<numeric> 
s2=<numeric>; 
mu= (Emax*Cmax)/(ECSO+Cmax) ; 
model <Avg . Slope(0- 14)> ~ nor mal (mu,s2) ; 
run; 
SAS code for bilinear regression model with kar a as one of the parameters: 
ods output fitstatistics=<TJat a with aic>; 
ods output parametercstimates=<Data with slope estimates> ; 
ods output additionalestimates=<Data with BA( 0- 14) estimate>; 
run; 
proc nlmixed data=<dataset> ; 
by <subject ID> ; 
betal=-0.3 t o 0.3 by 0.05 
parms alpha=4 to 8 by 0.5 
beta2=-0.3 to 0.3 by 0.05 
by 0.05 / best=l ; 
kappa=2 t o 10 by 1 
s2=0.05 to 0.3 
bounds a l pha >0 , 
1 <kappa< 14 , 
s2>0; * Add constraints to 
parameters to improve convergence; 
if day<= kappa then mu= alpha+ betal*day; 
e l se if day> kappa then mu= a l pha + betal*kappa + 
beta2*(day- kappa) ; 
model l ogCFU ~ norma l (mu,s2) ; 
esti mate 'BAcfu (0-14) ' 
(kappa*betal + (t last-
kappa) *beta2) /t l ast ; *Estimate BA(0-14); 
run; 
Confidential 
Page 49 of53 


Gates_MRI-TBD03-20 l_Statistical Analysis Plan_ 040ct2022 
Vault eTMF Document Number: VV-TMF-29915 I 1.0 
TBA-7371 
Statistical Analysis Plan: Gates MRI-TBD03-201 
Bill & Melinda Gates Medical Research Institute 
04-October-2022 
SAS code for bilinear regression model with kappa fixed at 2: 
ods output fitstatistics=<Data with aic>; 
ods output parameterestimates=<Data with slope estimates>; 
proc nlmixed data=<dataset>; 
by <subject ID>; 
parms alpha=4 to 8 by 0.5 
betal=-0.3 t o 0.3 by 0.05 
beta2=-0.3 to 0.3 by 0.05 s2=0.05 t o 0.3 by 0.05 / best=l ; 
bounds alpha >0 , 
s2>0; * Add constrai nts to parame t e r s t o 
improve convergence; 
if day<= 2 then mu= alpha+ betal*day; 
else if day> 2 then mu= alpha+ betal*2 + beta2*(day-2); 
model l ogCFU ~ normal (mu,s2); 
run; 
SAS code for simple regression model: 
ods output fitstatistics=<Data with aic>; 
ods output parameterestimates=<Data with slope estimates>; 
proc nlmixed data=<dataset>; 
by <subject ID>; 
parms alpha=4 to 8 by 0.5 
betal =-0.3 t o 0.3 by 0.05 
s2=0.05 
to 0.3 by 0.05 
/ best=l ; 
mu= alpha+ betal*day; 
model l ogCFU ~ normal (mu,s2); 
run; 
SAS code for ANCOVA (lsmeans statement used to estimate 90% Cls, lsmestimate 
statements used for one-sided 5% p-values, 1:It = u·eatment group with HRZE as reference): 
proc mixed data=<dataset>; 
class <treatment group>(ref=HRZE) ; 
model <Avg . Slope(0- 14)> = <treatment group>+ <screening 
logCFU> / 
* LSmeans used to obtain 90 Cis ; 
lsmeans <treatment group>/ cl alpha=0 . 1; 
* 6 LSMestimate stat ement s used to obtain 1- s i ded p- values -
NOTE : HRZE will r efer to #6 bel ow if used as reference, t he #1 - 5 wi l l 
be as indi cated in model ;; 
lsmestimate <trt> ' t r t #1' 1 0 0 0 0 0 I lower alpha = 0 . 05 ; 
lsmestimate <trt> 
'trt #2 ' 0 1 0 0 0 0 I lower alpha = 0 . 05; 
lsmestimate <trt> 
'trt #3 ' 0 0 1 0 0 0 I lower alpha = 0 . 05; 
lsmestimate <trt> 
'trt #4 ' 0 0 0 1 0 0 I lower alpha = 0 . 05 ; 
lsmestimate <trt> 
'trt #5 ' 0 0 0 0 1 0 I lower alpha = 0 . 05; 
lsmestimate <trt> 
' trt #6 ' 0 0 0 0 0 1 I lower alpha = 0 . 05 ; 
run; 
Confidential 
Page 50 of53 


TBA-7371 
Gates_MRI-TBD03-20 l_Statistical Analysis Plan_ 040ct2022 
Vault eTMF Document Number: VV-TMF-29915 I 1.0 
Statistical Analysis Plan: Gates MRI-TBD03-201 
Bill & Melinda Gates Medical Research Institute 
04-October-2022 
SAS code for random intercepts and slopes model (day = relative to baseline study day, 1:It = 
u·eatment group with HRZE as reference): 
proc mixed data=<da t a s e t> ; 
c l ass <treatment g r oup>( ref=HRZE) <subject>; 
model l ogCFU = <da y> + <tr t> + <day*trt > + <screening logCFU> ; 
random int day/ subj ect=<subj ect> t ype=un; 
* The firs t 6 estimat e statements used to obtai n correct 1- s i ded p -
values -
NOTE : HRZE will r efer t o #6 bel ow if used as ref e r e nce , t he 
#1 - 5 will be as indi cated in model ; 
estimate "Avg slope Tr 1 " day 1 trt*day 1 0 0 0 0 0 / c l l ower 
alpha =0 . 05 ; 
esti mate "Avg s l ope Tr 2" day 1 t rt*day O _ l. 0 0 0 / cl l ower a l pha 
=0 . 05 ; 
esti mate "Avg s l ope Tr 3" 
day 1 trt*day O O 1 0 0 0 / cl l ower alpha 
=0 . 05 ; 
esti mate "Avg s l ope Tr 4" day 1 t rt*day O O O 1 0 0 / cl l ower a l pha 
=0 . 05 ; 
esti mate "Avg s l ope Tr 5" day 1 t rt-A;d-:y O O O O 1 0 / cl l ower a l pha 
=0 . 05 ; 
esti mate "Avg s l ope Tr 6" 
day 1 t r t*day O O O O O 1 / cl l ower alpha 
=0 . 05 ; 
* The next 
6 e sti mat e stat e ments used to obtai n cor rect 
90% Ci s ; 
esti mate "Avg s l ope Tr 1 II day 1 trt*day 1 0 0 0 0 0 I cl a l pha =0 . 1 ; 
esti mate "Avg s l ope Tr 2 " day 1 trt*day 0 1 0 0 0 0 I cl a l pha =0 . 1 ; 
esti mate "Avg s l ope Tr 3 " 
day 1 trt*day 0 0 1 0 0 0 I cl a l pha =0 .1; 
esti mate "Avg s l ope Tr 4 ,. day 1 trt*day 0 0 0 1 0 0 I cl a l pha =0 . 1 ; 
esti mate "Avg s l ope Tr 5 " day 1 t rt*day 0 0 0 0 1 0 I cl a l pha =0 . 1 ; 
esti mate "Avg s l ope Tr 6" 
day 1 trt*day 0 0 0 0 0 1 I cl a l pha =0 .1; 
run; 
Confidential 
Page 51 of 53 


Gates_MRI-TBD03-20 l_Statistical Analysis Plan_ 040ct2022 
Vault eTMF Document Number: VV-TMF-29915 I 1.0 
Appendix 5 Document History 
DOCUMENT HISTORY 
Document 
Original SAP 
Amendment 1 
Amendment 2 
Changes in Amendment 1: 
Modifications were made to the following sections of the SAP: 
Section 4.0 futroduction 
• 
Revise text with respect to the protocol amendment 
Section 5.2 Objectives and Endpoint 
• 
Revise text with respect to the protocol amendment 
Section 6 Study Design Considerations 
• 
Revise text with respect to the protocol amendment 
Section 7 Study Population 
• 
Remove completer population 
Section 9 Overall Statistical Considerations 
• 
Define baseline values of vital signs 
Section 10 Statistical Analysis Methods 
Date 
22 Nov 2019 
23 Aug 2021 
27 June 2022 
0 
• 
Add drng susceptibilities and MIC of TBA-73 71 to summaiy of baseline characteristics 
Section 11 
• 
Add description for computing CFU/mL 
Section 12 Safety Analyses 
• 
Clarify determination of AEs of special interest per fuvestigator discretion 
• 
Add line plots of mean of intraday and daily heaii rate, SBP, and DBP in supine and standing position 
• 
Add line plots of mean of 01ihostatic change in intraday and daily hea1i rate, SBP, and DBP 
• 
Add boxplots of intraday and daily values of QTcF 
• 
Revise analyses for eye symptoms, visual acuity, and color vision test 


TBA-7371
Bill & Melinda Gates Medical Research Institute
Statistical Analysis Plan: Gates MRI-TBD03-201
04-October-2022
Confidential
Page 53 of 53

Add summary of COV-19/SARS-CoV-2 test

Add summary of drug susceptibilities and MIC of TBA-7371
Section 16 References

Update references
Changes in Amendment 2:
Modifications were made to the following sections of the SAP:
Section 2 Signature Page

Author of SAP changed from
to

Approval changed from
 to
Section 7.1  Population for Analyses 

Randomized population definition added.

Clarity added for the timing of PK samples to the PK population definition.
Section 11.1.1 Primary Analysis 

Clarity added for starting values for the bili
ar regression model

Clarity added regarding equations, refined definition of BAcfu(0-14) for bilinear model

Clarity added to use of PROC NLMIXED for both linear and bilinear models
Section 11.1.2 Secondary Analysis

Clarity added to bilinear models used for secondary analysis.
Section 11.1.3 Sensitivity Analysis

Updated the use of Bayesian model to ANCOVA using averaged change from baseline, as well as a mixed model
Section 11.3 Subgroups

Added HIV status at Baseline as a subgroup.
Section 13.2 Pharmacokinetic analyses

Clarity added regarding models and statistics used for reporting
Appendix

Updated SAS code in appendix according to updates in Sections 11.1 – 11.3
*DWHVB05,7%'B6WDWLVWLFDO $QDO\VLV 3ODQB2FW
9DXOW H70) 'RFXPHQW 1XPEHU 9970) _ 
$SSURYHG
 the PK population defin
PK populat
he bilinear regression mod
near regressi
 refined definition of BA
ed definition o
NLMIXED for both line
MIXED for both
odels used for second
s used for secon
odel to A
del


Gates_MRI-TBD03-20 l_Statistical Analysis Plan_ 04Oct2022 
Vault eTMF Document Number: VV-TMF-29915 I 1.0 
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