A Phase 1, Partially-Blinded, Placebo-Controlled, Randomized, Multiple Ascending Dose Study to Include A Single Dose Food-Effect Study to Evaluate the Safety, Tolerability, and the PK Profile of TBI-223 in Healthy Subjects
Phase: PHASE1
Conditions: Tuberculosis, Tuberculosis, Pulmonary
Sponsor: Global Alliance for TB Drug Development

Protocol TBI-223-CL-002 Version 1.0 
Global Alliance for TB Drug Development 
CONFIDENTIAL 
15 Dec 2020 
Page i 
 
CLINICAL STUDY PROTOCOL 
A Phase 1, Partially-Blinded, Placebo-Controlled, Randomized, Multiple 
Ascending Dose Study to Include A Single Dose Food-Effect Study to 
Evaluate the Safety, Tolerability, and the Pharmacokinetic Profile of 
TBI-223 in Healthy Adult Subjects 
PROTOCOL NUMBER 
TBI-223-CL-002 
VERSION 1.0 DATE 
15 Dec 2020 
 
 
 
CONFIDENTIALITY STATEMENT 
The confidential information in this document is provided to you as an Investigator or 
consultant for review by you, your staff, and the applicable Institutional Review 
Board/Independent Ethics Committee. Your acceptance of this document constitutes 
agreement that you will not disclose the information herein to others without written 
authorization from Worldwide Clinical Trials Early Phase Services, LLC, except to the 
extent necessary to obtain informed consent from persons who participate as subjects in 
this study. 

• 
' 
' 
• 
Protocol TBI-223-CL-002 Version 1.0 
PROTOCOL APPROVAL PAGE 
A Pl1ase 1, Partially-Bli11ded, Placebo-Co11trolled, Rando1nized, Multiple Ascendi11g Dose Study 
to I11clt1de A Si11gle Dose Food-Etlect Study to Evaluate tl1e Safety, Tolerability, and tl1e 
Pl1an11acoki11etic Profile of TBI-223 i11 Healtl1y Adult Subjects 
Protocol Nt1111ber: 
Spo11sor: 
Sponsor Co11tact and 
Medical Mo11itor: 
TBI-223-CL-002 
Global Allia11ce for TB Dn1g Developtnent 
Patil Bruinenberg MD, MBA 
Global Allia11ce for TB Drug Develop1nent 
40 Wall Street, 24t11 Floor 
New York, NY I 0005, U11ited States of America 
Telepl1011e: + 1 646 616 8629 
Mobile:+ 1-201-312-0988 
Facsi111ile: + 1 212 227 7541 
Email: Paul.Bruinenberg@tballia11ce.org 
-DocuSigned by: 
Pmtvw~? 
(} 
Signer Name: Paul Bruinenberg 
Signing Reason: I approve this document 
-+---st 
( 
. 0 !YeW~~B3~5A4BOAAE3;731255B.7116B 
(Date) 
Principal Investigator: 
Suraj Kumar Saggar, MD p O 0 
TKL Research, Inc. 
One Promenade Blvd. Suites 1101 & 1201 
Fair Lawn, New Jersey 07410 
Telephone: 201.587.0500 
Global Alliance for TB Drug Deve]opment 
CONFIDENTIAL 
Page ii 
(Date) 
15 Dec 2020 

Protocol TBI-223 CL-002 Version 1.0 
Global Alliance for TB Drug Development 
CONFIDENTIAL 
15 Dec 2020 
Page iii 
PROTOCOL SYNOPSIS 
Name of Sponsor/Company: Global Alliance for TB Drug Development 
Name of test product: TBI-223  
Name of active ingredient: TBI-223 
Title of study: A Phase 1, Partially-Blinded, Placebo-Controlled, Randomized, Multiple Ascending 
Dose Study to Include A Single Dose Food-Effect Study to Evaluate the Safety, Tolerability, and the 
Pharmacokinetic Profile of TBI-223 in Healthy Adult Subjects 
Principal Investigator: Suraj Kumar Saggar, MD 
Study Center  
TKL Research, Inc. 
One Promenade Blvd. Suites 1101 & 1201 
Fair Lawn, New Jersey 07410 
Study period (maximum duration, from screening to study 
exit): 12 weeks 
Food-effect cohorts: approximately 35 days (from check-in 
[Day -2] through completion of clinical procedures on Day 
26, and a follow-up phone call on Day 33).  
Non-food-effect cohort: approximately 32 days (from check-
in [Day -2] through the completion of clinical procedures on 
Day 23, and a follow-up phone call on Day 30). 
The maximum duration of the study will depend upon the 
final number and timing of each cohort. 
Phase of development: 1 
 
Duration of treatment:  
Cohort 1 and 2 will include single dosing of TBI-223 or 
placebo for TBI-223 as a single dose fasted (1 day) followed 
by TBI-223 or placebo for TBI-223 once daily for 14 days 
under fed conditions. Cohort 3 will be TBI-223 or placebo 
for TBI-223 once daily for 14 days under fed conditions.  
Number of sites enrolling subjects: 1 

Protocol TBI-223 CL-002 Version 1.0 
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15 Dec 2020 
Page iv 
Number of subjects (planned):  
Planned to enroll up to 36 subjects in 3 MAD cohorts, each with 12 subjects (9 to receive active drug 
and 3 to receive placebo). 
Additional cohorts (up to 12 subjects per cohort) may be enrolled if deemed appropriate by the Sponsor 
to study other dose levels, change proposed cohorts, or to study a different dosage formulation. The 
decision on additional cohorts will not take place until the Sponsor, in conjunction with the Principal 
Investigator, has determined that adequate safety, tolerability, and pharmacokinetics from the previous 
cohort have been demonstrated to permit proceeding to the next cohort. The Institutional Review 
Board (IRB) should be immediately notified of dose escalation decisions or any revised approach for 
review and approval. 
Diagnosis and main criteria for inclusion:  
Volunteers will be healthy adult male or female, ages 19 to 50 years (inclusive) at screening, with a 
body mass index (BMI) ≥18.5 and ≤32.0 kg.m2 and body weight of no less than 50.0 kg at the time of 
screening and check-in, who do not use tobacco or nicotine-containing products. Females subjects may 
not be pregnant or lactating. 
Objectives:  
The primary objective of the study is: 
• 
To evaluate the safety and tolerability of multiple doses of TBI-223 in healthy adult subjects  
The secondary objective of the study is: 
• 
To determine the pharmacokinetics (PK) of TBI-223 and its metabolite, M2 after multiple 
ascending doses of TBI-223 in healthy adult subjects when administered after a high-calorie, high-
fat meal 
• 
For the TBI-223 sustained-release (SR1) formulation and for the combination of the SR and 
immediate-release (IR) formulations, to compare the PK profiles of a single dose when 
administered to healthy adult subjects in the fasting state versus after a high-calorie, high-fat meal 
•      To determine the pharmacokinetics (PK) of a single dose of the TBI-223 sustained-release (SR1) 
formulation in healthy adult subjects when administered fasted 
Study design overview: 
This is a partially-blinded, placebo-controlled, randomized multiple ascending dose (MAD) study to be 
conducted at one study center.  
Thirty-six (36) subjects will be enrolled in 3 cohorts with 12 subjects per cohort. Within each cohort, 
9 subjects will be assigned to receive active treatment and 3 subjects will receive placebo. Each subject 
will participate in one dose level.  
The first 2 cohorts (food-effect cohorts) will begin dosing of TBI-223 on Day 1 under fasted 
conditions, followed by a 3 day washout period and then by multiple doses of TBI-223 administered 

Protocol TBI-223 CL-002 Version 1.0 
Global Alliance for TB Drug Development 
CONFIDENTIAL 
15 Dec 2020 
Page v 
after a high-calorie, high-fat meal from Day 4 through Day 17 (total of 14 days). The third cohort (non-
food-effect cohort) will begin dosing of TBI-223 on Day 1 and continue through Day 14, all doses 
administered after a high-calorie, high-fat meal. 
Each subject will be administered TBI-223 tablets (SR1 or IR or a combination of both formulations) 
or placebo once daily for 14 days with corresponding pharmacokinetic measurements. After each dose 
cohort, the Sponsor and Investigator will review the pharmacokinetic and safety data before proceeding 
to the next dose level. 
Dose escalation to the next cohort (i.e., dose level) or decisions regarding changed or additional cohorts 
will not take place until the Sponsor, in conjunction with the Principal Investigator and dose escalating 
committee, has determined that adequate safety, tolerability, and pharmacokinetics from the previous 
cohort(s) have been demonstrated to permit proceeding to the next cohort. The Institutional Review 
Board (IRB) should be immediately notified of the dose escalation or any revised approach for review 
and approval. 
Safety will be assessed throughout the study for all subjects. Safety assessments will include physical 
and detailed neurological examinations, vital signs (blood pressure, pulse rate, respiration rate, 
temperature and pulse oximetry), electrocardiograms (ECGs), cardiac monitoring, adverse events 
(AEs), and clinical laboratory tests (including hematology, serology, serum chemistry, coagulation, and 
urinalysis). 
Blood and urine will be collected for clinical laboratory evaluations. 
The Principal Investigator, in conjunction with the Sponsor may collect additional blood if necessary, 
for repeat laboratory or safety evaluations including AE follow up. 
Female subjects will have blood collected for serum pregnancy testing. Females claiming 
postmenopausal status will have blood collected to measure follicle stimulating hormone (FSH) levels.  
During each cohort, blood samples (trough samples) will be obtained before each dose of study drug, 
and at the time points on the events schedule. Plasma pharmacokinetic samples will be analyzed for 
TBI-223 and M2 using validated analytical methods. Appropriate pharmacokinetic parameters will be 
calculated using non compartmental methods. 
Test product, dosage and mode of administration:  
Cohort 1 and 2 will include single dosing of TBI-223 or placebo for TBI-223 as a single dose fasted 
(1 day) followed by TBI-223 or placebo for TBI-223 once daily for 14 days under fed conditions. 
Cohort 3 will be TBI-223 or placebo for TBI-223 once daily for 14 days under fed conditions. The 
following planned dose levels will be orally administered once daily (QD): 
Cohort 1 (Food-effect cohort):  
Dose Level 1 = 1800 mg TBI-223  
1800 mg (3 x 600 mg SR1 tablets or 3 x Placebo tablets) 
Day 1: TBI-223 or matching placebo (fasted) 
Days 4-17: TBI-223 or matching placebo (fed) 

Protocol TBI-223 CL-002 Version 1.0 
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Cohort 2 (Food-effect cohort):  
Dose Level 2 = 2400 mg TBI-223  
2400 mg (3 x 600 mg SR1 tablets and 1 x 600 mg IR tablets or 4 x Placebo tablets) 
Day 1: TBI-223 or placebo (fasted) 
Days 4-17: TBI-223 or placebo (fed)   
Cohort 3 (Non-food-effect cohort):  
Dose Level 3 = 3000 mg TBI-223  
3000 mg (4 x 600 mg SR1 tablets and 1 x 600 mg IR tablets or 5 x Placebo tablets) 
Days 1-14: TBI-223 or placebo (fed) 
Additional cohorts may be enrolled if deemed appropriate by the Sponsor to repeat a dose level or to 
study another dose level. 

Protocol TBI-223 CL-002 Version 1.0 
Global Alliance for TB Drug Development 
CONFIDENTIAL 
15 Dec 2020 
Page vii 
Criteria for evaluation:  
Safety: Safety assessments will include physical and detailed neurological examinations, vital signs 
(blood pressure, pulse rate, respiration rate, temperature and pulse oximetry), ECGs, cardiac 
monitoring, AEs, and clinical laboratory tests (including hematology, serology, serum chemistry, 
coagulation, and urinalysis). Female subjects will have blood collected for serum pregnancy testing. 
Females claiming postmenopausal status will have blood collected to measure follicle-stimulating 
hormone (FSH) levels. 
Pharmacokinetics: Pharmacokinetic calculations will be performed using appropriate software, e.g. 
Phoenix™ WinNonlin® (Version 8.1 or higher, Pharsight Corporation) and/or SAS® (Version 9.4 or 
higher, SAS Institute Inc.). Pharmacokinetic parameters will be calculated using non-compartmental 
analysis. The following pharmacokinetic parameters will be determined as appropriate for each study 
part. 
AUCExtrap (%) 
The percentage of extrapolated AUC to AUCinf based on extrapolation 
AUCinf 
Area under the concentration-time curve from time-zero extrapolated to infinity; 
calculated as: 
z
last
last
C
AUC
AUC
λ
+
=
inf
 
AUClast 
Area under the concentration-time curve from time-zero to the time of the last 
quantifiable concentration; calculated using the linear trapezoidal rule 
AUCtau 
Area under the concentration-time curve during the dosing interval 
Cavg 
Average steady-state concentration 
Clast 
The last quantifiable concentration determined directly from individual 
concentration-time data 
CL/F 
Apparent total clearance after single administration 
CLss/F 
Apparent total clearance at steady state 
Cmax 
Maximum concentration, determined directly from individual concentration-time 
data 
Cmin 
Minimum concentration 
Ctrough 
Trough plasma concentration 
RAUC 
Accumulation ratio for AUC 
RCmax 
Accumulation ratio for Cmax 
Tlast 
Time of the last quantifiable concentration 

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15 Dec 2020 
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Tmax 
Time of the maximum concentration 
T1/2 
The observed terminal half-life, calculated as: 
z
T
λ
)
2
ln(
2
/
1
=
 
Vz/F 
Apparent volume of distribution in the terminal phase 
λz 
The observed terminal rate constant; estimated by linear regression through at 
least three data points in the terminal phase of the log concentration-time profile 
For the non-food-effect cohorts, PK parameters calculated from plasma concentration of TBI-223 and 
M2 following doses on Days 1 and 14 will include, as appropriate:  
• Day 1: AUCtau, Cmax, C24, Cavg, Tmax. Additionally, AUCinf, AUCextrap, CL/F, Vz/F, λz, and t1/2 
should be included if AUCtau ≥ 70% of AUCinf. 
• Day 14: AUCtau, Cmax, Cmin, Ctrough (i.e., C0), C24, Cavg, Tmax, CL/F, Vz/F, λz, t1/2, RAUC, RCmax 
For the food-effect cohorts, PK parameters calculated from plasma concentration of TBI-223 and M2 
following doses on Days 1, 4, and 17 will include, as appropriate: 
• Day 1: AUCtau, AUCextrap, AUCinf, Cmax, C24, Clast, Tmax, Tlast, CL/F, Vz/F, λz, t1/2. 
• Day 4: AUCtau, Cmax, C24, Cavg, Tmax. Additionally, AUCinf, AUCextrap, CL/F, Vz/F, λz, t1/2 should 
be included if AUCtau ≥ 70% of AUCinf.  
• Day 17: AUCtau, Cmax, Cmin, Ctrough (i.e., C0), C24, Cavg, Tmax, CL/F, Vz/F, λz, t1/2, RAUC, RCmax 
Each parameter will be estimated separately for each participant using plasma concentrations of 
TBI-223 and, as appropriate M2. 
Each day one blood sample will be taken immediately before dosing, to measure Ctrough level and to 
observe the time that steady state is achieved.   
Assessments of food effect will include geometric mean ratios of Cmax and AUCtau between Day 1 
(fasted) and Day 4 (fed), as well as graphical displays of the profiles. Model-based approaches and 
comparisons with results from the single-dose study, TBI-223-CL-001, may also be undertaken. 
Both individual-participant and group summary-statistics (n, mean, median, geometric mean, standard 
deviation, standard error of the mean, coefficient of variation, minimum, maximum) data will be 
reported. Summary statistics will be presented by gender.  All tests will be performed using a 2-sided 
α-level of 0.05, and appropriate confidence intervals will be provided. 
Efficacy: No efficacy evaluations will be performed in this study. 
 

Protocol TBI-223 CL-002 Version 1.0 
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CONFIDENTIAL 
15 Dec 2020 
Page ix 
 
TABLE OF CONTENTS 
PROTOCOL APPROVAL PAGE .............................................................................................. ii 
PROTOCOL SYNOPSIS .......................................................................................................... iii 
TABLE OF CONTENTS ........................................................................................................... ix 
LIST OF TABLES ..................................................................................................................... xi 
LIST OF ABBREVIATIONS....................................................................................................xii 
1 
INTRODUCTION ........................................................................................................... 1 
1.1 
Background Information .................................................................................................. 1 
1.2 
Tuberculosis and Rationale for New Medications ............................................................ 1 
1.3 
Preclinical Studies and Toxicity Studies .......................................................................... 3 
1.4 
Oxazolidinones ................................................................................................................ 4 
1.5 
TBI-223 SAD Study Data ................................................................................................ 5 
1.6 
Adverse Effects, Warnings, and Precautions .................................................................. 13 
1.7 
Overview and Dose Rationale ........................................................................................ 14 
2 
OBJECTIVE ................................................................................................................. 15 
3 
STUDY DESIGN SUMMARY ..................................................................................... 15 
3.1 
Dose Escalation ............................................................................................................. 17 
3.2 
Cohort Stopping Rules for Subjects Receiving Active Drug:.......................................... 18 
4 
IDENTITY OF INVESTIGATIONAL PRODUCT ....................................................... 18 
5 
SUBJECT SELECTION ................................................................................................ 19 
5.1 
Inclusion Criteria ........................................................................................................... 19 
5.2 
Exclusion Criteria .......................................................................................................... 21 
5.3 
Medication and Activity Restrictions ............................................................................. 23 
5.4 
Screening....................................................................................................................... 24 
6 
STUDY PROCEDURES ............................................................................................... 25 
6.1 
Subject Assignment ....................................................................................................... 25 
6.2 
Blinding ........................................................................................................................ 25 
6.2.1 Clinical Research Staff .................................................................................................. 26 
6.2.2 Study Subjects ............................................................................................................... 26 
6.2.3 Bioanalytical Laboratory ............................................................................................... 26 
6.2.4 Pharmacokinetic Analysis .............................................................................................. 26 
6.2.5 Unblinding Procedures .................................................................................................. 26 
6.3 
Check-In Procedures...................................................................................................... 27 
6.4 
Confinement .................................................................................................................. 27 
6.5 
Fasting/Meals/Beverages ............................................................................................... 27 
6.5.1 Fasting/Meals ................................................................................................................ 27 
6.5.2 Beverages ...................................................................................................................... 28 
6.6 
Drug Administration ...................................................................................................... 28 
6.6.1 Administration of TBI-223 Sustained Release and Immediate Release Tablets or Placebo 
Tablets for TBI-223 ....................................................................................................... 28 

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6.7 
Blood Sampling, Processing and Shipment .................................................................... 28 
6.7.1 Pharmacokinetic Sampling Time Windows .................................................................... 30 
6.8 
End-of-Study Procedures ............................................................................................... 31 
6.9 
Safety Monitoring and Procedures ................................................................................. 31 
6.9.1 Adverse Events .............................................................................................................. 31 
6.9.2 Clinical Laboratory Evaluations ..................................................................................... 31 
6.9.3 Vital Signs ..................................................................................................................... 32 
6.9.4 Physical Examinations ................................................................................................... 33 
6.9.5 Neurological Examinations ............................................................................................ 33 
6.9.6 12-Lead Electrocardiograms .......................................................................................... 33 
6.9.7 Other Safety Measures ................................................................................................... 33 
7 
ADVERSE EVENTS .................................................................................................... 34 
7.1 
Definitions ..................................................................................................................... 34 
7.1.1 Adverse Event ............................................................................................................... 34 
7.1.2 Serious Adverse Event ................................................................................................... 34 
7.2 
Attribution/Causality ..................................................................................................... 35 
7.3 
Reporting....................................................................................................................... 37 
7.3.1 Adverse Event ............................................................................................................... 37 
7.4 
Serious Adverse Event Reporting .................................................................................. 37 
7.5 
Follow up of Adverse Events ......................................................................................... 39 
7.6 
Post-Trial Serious Adverse Events ................................................................................. 39 
7.7 
Clinical Laboratory Adverse Events............................................................................... 39 
7.8 
Drug Interaction ............................................................................................................ 40 
7.9 
Pregnancy ...................................................................................................................... 40 
7.10 
Monitoring and Safety for Specific Toxicities ................................................................ 40 
8 
GENERAL CONSIDERATIONS .................................................................................. 41 
8.1 
Basic Principles ............................................................................................................. 41 
8.2 
Institutional Review Board ............................................................................................ 41 
8.3 
Informed Consent .......................................................................................................... 41 
8.4 
Indications for Subject Withdrawal ................................................................................ 41 
8.5 
Termination of the Study ............................................................................................... 42 
8.6 
Documentation .............................................................................................................. 42 
8.7 
Trial Monitoring ............................................................................................................ 42 
8.8 
Reimbursement, Indemnity, and Insurance .................................................................... 42 
9 
PHARMACOKINETIC ANALYSIS ............................................................................. 42 
9.1 
Analytical Methodology ................................................................................................ 42 
9.2 
Pharmacokinetic Analysis .............................................................................................. 43 
9.3 
Statistical Analysis ........................................................................................................ 44 
10 
FACILITIES ................................................................................................................. 45 
11 
DRUG SUPPLIES ......................................................................................................... 45 
12 
ADMINISTRATIVE ISSUES ....................................................................................... 46 

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13 
EVENTS SCHEDULE .................................................................................................. 47 
14 
REFERENCES .............................................................................................................. 52 
APPENDIX 1 PHARMACOKINETIC SAMPLE PROCESSING ............................................. 53 
APPENDIX 2 DESCRIPTION AND COMPOSITION OF TEST PRODUCT .......................... 55 
APPENDIX 3 DIVISION OF MICROBIOLOGY AND INFECTIOUS DISEASE TOXICITY 
TABLE ..................................................................................................................................... 56 
LIST OF TABLES 
Table 1 
Adverse Events, TEAEs by Primary System Organ Class and Preferred Term, Part 1 ..6 
Table 2 
Adverse Events, TEAEs by Primary System Organ Class and Preferred Term, Part 2 10 
Table 3 
Exposures ................................................................................................................. 15 
Table 4 
Dose Cohorts ............................................................................................................ 17 
Table 5 
Identity of Investigational Products ........................................................................... 19 
Table 6 
Total Volume of Blood to be Collected for Testing, Food-Effect Cohorts .................. 29 
Table 7 
Total Volume of Blood to be Collected for Testing, Non-Food-Effect Cohort ........... 30 
Table 8 
Acceptable Pharmacokinetic Sampling Time Windows, Food-Effect Cohorts ........... 30 
Table 9  Acceptable Pharmacokinetic Sampling Time Windows, Non-Food-Effect Cohort ..... 31 
Table 10 Adverse Event Attribution/Causality Ratings ............................................................ 36 
Table 11 Definitions for Adverse Event Severity Gradings ...................................................... 36 
Table 12 Schedule of Assessments (Cohorts 1 and 2) ............................................................... 47 
Table 13 Schedule of Assessments (Cohort 3) ......................................................................... 50 

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CONFIDENTIAL 
15 Dec 2020 
Page xii 
LIST OF ABBREVIATIONS 
AE 
adverse event 
ALP 
alkaline phosphatase  
ALT 
alanine transaminase  
ANOVA 
analysis of variance 
AST 
aspartate transaminase  
AUC 
area under the (plasma concentration vs. time) curve 
AUClast 
area under the curve from time 0 hours to last quantifiable concentration 
AUCinf 
area under the curve from time 0 hours to infinity 
BID 
twice daily 
BMI 
body mass index 
BP 
blood pressure 
BUN 
blood urea nitrogen  
bpm 
beats per minute 
Ca 
calcium  
CFR 
Code of Federal Regulations 
CFU 
colony-forming unit 
CI 
confidence interval 
Cl- 
chloride  
Clast 
last quantifiable drug concentration 
CLIA 
Clinical Laboratory Improvement Amendments 
cm 
centimeter(s) 
Cmax 
maximum concentration 
CNS 
central nervous system 
CRF 
case report form 
CYP 
cytochrome P450 
DMID 
Division of Microbiology and Infectious Disease 
ECG 
electrocardiogram 
FDA 
Food and Drug Administration 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transferase  
HIPAA 
Health Insurance Portability and Accountability Act 
GLP 
Good Laboratory Practice 
HIV 
human immunodeficiency virus 
ICD 
informed consent document 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use  
IND 
Investigational New Drug 
IP 
Investigational Product 

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15 Dec 2020 
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IRB 
institutional review board 
IR 
Immediate-release 
ISF 
Investigator Site File  
IUD 
intrauterine device 
K+ 
potassium  
kg 
kilogram(s) 
K3-EDTA 
ethylenediaminetetraacetic acid 
L 
liter(s) 
lbs 
pounds 
LDH 
lactate dehydrogenase  
m 
meter(s) 
MAO 
monoamine oxidase 
max. 
maximum 
MDR-TB 
multidrug resistant tuberculosis 
mg 
milligram(s) 
MICs 
minimum inhibitory concentrations  
min. 
minute(s) 
mL 
milliliter(s) 
mmHg 
millimeter of mercury 
MPS 
mitochondrial protein synthesis  
msec 
millisecond 
Mtb 
Mycobacterium tuberculosis 
Na+ 
sodium 
NOAEL 
no-observed-adverse-effect level 
OTC 
over-the-counter 
oz 
ounce(s) 
PK 
pharmacokinetic  
PT 
prothrombin time 
rbc 
red blood cell  
SAD 
Single Ascending Dose 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SR 
Sustained-release 
T½ or t½ 
terminal elimination half-life 
TB 
Tuberculosis  
Tlast 
time of the last measurable concentration 
Tmax 
time to reach Cmax 
λz  
apparent elimination rate constant in terminal phase 
°C 
degrees Celsius/Centigrade 

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Page 1 
1 
INTRODUCTION 
1.1 
Background Information 
This study will be conducted in accordance with the protocol, International Good 
Clinical Practice (GCP) Guidelines, the ethical principles that have their origin in the 
Declaration of Helsinki and the applicable regulatory requirement(s). 
A brief overview of available confidential information regarding TBI-223 follows 
below. Unless noted otherwise, the information in this introduction was provided by 
TB Alliance. Details can be found in the TBI-223 Investigator’s Brochure.1  
1.2 
Tuberculosis and Rationale for New Medications 
Tuberculosis (TB) in humans is an infectious disease caused by the bacterium 
Mycobacterium tuberculosis (Mtb), which typically affects the lungs (pulmonary TB) 
but can affect other sites as well (extrapulmonary TB). While incidence rates and 
mortality for TB have been falling, it remains the ninth leading cause of death 
worldwide, the world’s leading cause of death from a single infectious disease, and is 
responsible for more deaths than human immunodeficiency virus (HIV). In 2016, 
6.3 million new cases of TB were reported, with an overall estimated incidence of 
10.4 million (World Health Organization [WHO] Global TB Report 2017).  
The current TB treatment regimens and treatments for drug-sensitive TB are decades 
old and are relatively ineffective. The available treatments have a lengthy duration of 
treatment, can involve multi-drug therapy, many tolerability issues, and require large 
commitments of resources and infrastructure. High rates of noncompliance are 
common, which often results in increased mortality, chronic, infectious, and drug-
resistant cases. The present TB epidemic and treatment conditions demonstrate the 
clear need in patients with drug-sensitive or drug-resistant TB for novel drugs and drug 
regimens that will shorten the current treatment duration and be safe and well tolerated. 
In addition, new TB drugs and regimens should also be affordable, easy to adopt and 
implement, suitable for pediatric use and for co-administration with antiretroviral 
therapy in individuals co-infected with Mtb and HIV. Following the declaration of TB 
as a global emergency by the WHO in 1993, there has been a resurgence of efforts to 
develop improved TB therapies and several promising new agents are presently in or 
approaching clinical evaluation. 
TBI-223 like linezolid (Zyvox®), is a novel oxazolidinone antimicrobial that inhibits 
the growth of Mtb by blocking microbial translation and, thereby, protein synthesis. 
Linezolid, which is licensed for the treatment of complicated skin infections and 
hospital-acquired pneumonia (at an adult dose of 600 mg given twice daily [BID] for 
up to 28 days), has been used to treat difficult cases of multiple drug-resistant and 
extensively drug-resistant TB with apparent clinical benefit. Since bacterial protein 

Protocol TBI-223 CL-002 Version 1.0 
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synthesis is not currently targeted by any of the drugs in the first-line standard of care 
for treatment of TB (isoniazid, rifampin, pyrazinamide, ethambutol), TBI-223, like 
linezolid, has no known pre-existing resistance. Therefore, TBI-223 should be effective 
against multi-drug resistant and extensively drug-resistant forms of TB (MDR-TB and 
XDR-TB) as well.  
The standard dose of linezolid for a multitude of indications is 400 mg or 600 mg BID. 
Doses of linezolid varying from 300 mg to 1200 mg per day were used to treat 
pulmonary TB in combination with other TB drugs in novel regimes over periods of up 
to 20 months with impressive improved outcomes - e.g .in the Nix-TB trial (A Phase 3 
Study Assessing the Safety and Efficacy of Bedaquiline Plus PA-824 (Pretomanid) Plus 
Linezolid in Subjects with Drug Resistant Pulmonary Tuberculosis: NCT02333799), 
but treatments can be impacted with periods of non-compliance and adverse events, 
especially neuropathic and myelosuppressive effects. These adverse events are often 
ameliorated if the dose is reduced or if the drug is discontinued for several weeks and 
then resumed at a lower dose. Although manageable there is a clear need to develop 
effective and tolerable oxazolidinones with a better toxicology profile than linezolid.  
TBI-223 is a drug candidate from TB Alliance’s efforts to develop a safer 
oxazolidinone with the potential to deliver efficacy similar to linezolid, without the 
characteristic bone marrow and neuropathic toxicities of the class. It emerged from a 
scaffold expansion effort based on the linezolid and sutezolid structures. Mammalian 
mitochondrial protein synthesis (MPS) inhibition is presumed to be the reason for the 
side effects associated with long-term administration of linezolid, such as anemia, 
thrombocytopenia, and peripheral neuropathy (Migliori et al., 2009). TBI-223 was 
tested in an MPS inhibition assay and found to have a half maximal inhibitory 
concentration (IC50) of 126 µM (46 µg/mL). This concentration exceeds the expected 
maximum clinical TBI-223 concentration by 2-fold and suggests a lower risk of MPS 
inhibition. In preclinical studies, TBI-223 showed low minimum inhibitory 
concentrations (MICs) against Mtb in vitro and efficacy against mouse models of TB as 
a single agent and in combination with bedaquiline and pretomanid. TBI-223 did not 
show significant myelosuppression in 28-day Good Laboratory Practice (GLP) toxicity 
studies in rats and dogs. 
Current data suggest that TBI-223 could contribute to a new TB treatment, consistent 
with the high-priority target product profile for a novel and universal TB drug regimen. 
A single ascending dose (SAD) study (TBI-223-CL-001) with TBA-223 has been 
finalized and the pharmacokinetic and safety data of TBA-223 oral suspension, TBA-
223 immediate-release and sustained-release tablets, together with the pre-clinical 
safety will form the basis for the dose exposures in the clinical study TBI-223-CL-002. 

Protocol TBI-223 CL-002 Version 1.0 
Global Alliance for TB Drug Development 
CONFIDENTIAL 
15 Dec 2020 
Page 3 
1.3 
Preclinical Studies and Toxicity Studies 
To support IND filing, a nonclinical development plan has been executed based upon 
the ICH M3(R2) guidance document, “Nonclinical Safety Studies for the Conduct of 
Human Clinical Trials and Marketing Authorization for Pharmaceuticals,” 
January 2010.  
A series of in vitro and in vivo studies to evaluate the efficacy of TBI-223 were carried 
out. TBI-223 was evaluated against a large, diverse panel of Mtb clinical isolates, 
consisting of 96 isolates representative of all identified genetic groups of Mtb, broad 
geography and diverse drug-susceptibility profiles. The panel included MDR-TB and 
XDR-TB strains. The MIC of TBI-223 was found to be 1.28 μg/mL for 90% of the 
strains tested with a range of 0.04 to 5. Like linezolid, TBI-223 demonstrated a mild 
bactericidal activity against acute mouse infections of TB as a single agent, good 
activity against chronic mouse infections, including additive activity within the Nix-
like drug combination of bedaquiline, an ATP synthase inhibitor, and pretomanid, a 
nitroimidazole. This combination efficacy demonstrated a strong potential for TBI-223 
to replace linezolid in the Nix trial regimen and deliver a universal treatment shortening 
regimen that is not confined to the XDR-TB population. 
A comprehensive battery of in vitro and in vivo safety pharmacology assessments was 
conducted to characterize the effects of TBI-223 on the function of the nervous, 
respiratory, and cardiovascular systems. The battery included non-GLP studies of 
several cardiac ion channels with TBI-223, a GLP human Ether-à-go-go-Related Gene 
(hERG) assay with TBI-223, a standalone GLP single-dose cardiovascular study. 
Nervous system and respiratory assessments were conducted in rats administered as 
single doses of TBI-223.  
The pharmacokinetics and oral bioavailability of TBI-223 were evaluated in mice, rats, 
dogs and monkeys given single or repeated daily doses of TBI-223. 
In support of planned human studies, the following toxicology studies have been 
completed with TBI-223: 
• Non-GLP, 4-week, repeat-dose, oral toxicity study in mice. 
• Non-GLP, 2- and 4-week, repeat-dose, oral toxicity studies in rats. 
• GLP-compliant, 4-week, repeat-dose, oral toxicity study with recovery in rats. 
• Non-GLP, 5-day and 2-week, repeat-dose, oral toxicity studies in beagle dogs. 
• GLP-compliant, 4-week, repeat-dose, oral toxicity study with recovery in beagle 
dogs. 
• Standard battery of GLP-compliant in vitro and in vivo genetic toxicology studies. 

Protocol TBI-223 CL-002 Version 1.0 
Global Alliance for TB Drug Development 
CONFIDENTIAL 
15 Dec 2020 
Page 4 
Dogs tolerated doses up to 100 mg/kg/day (50 mg/kg BID) for 28 days but showed 
dose- and duration-related nervous system effects at repeated doses ≥200 mg/kg/day. 
There were no correlating histopathology findings in the nervous system in these 
studies. It is unclear whether the nervous system effects are related to the maximum 
concentration (Cmax) or the area under the (plasma concentration vs. time) curve (AUC) 
of TBI-223. 
• In a 5-day study, dogs developed prolonged tremors and two of four dogs were 
found dead after being given 400 mg/kg/day for 3 days. These dogs had previously 
been administered 200 mg/kg/day of TBI-223 without clinical signs. 
• During the first 4 days of dosing of a 14-day DRF study, tremors and emesis were 
observed in dogs administered 200 mg/kg/day, and ataxia, prostration, and 
convulsions were observed in dogs administered 400 mg/kg/day. These dogs were 
given a 2-day washout period and then dosed at 75 mg/kg/day BID or 150 
mg/kg/day QD. Reversible tremors were observed after 8-10 days of dosing at 150 
mg/kg/day (QD or 75 mg/kg BID). In the pivotal 28-day dog GLP study, 2 dogs 
given 200 mg/kg/day (100 mg/kg BID) had continuous tremors after 12 days of 
dosing.  
In ECG evaluation during the pivotal 28-day dog toxicity study, QT prolongation was 
observed.  The findings are detailed below and correlated with similar findings in the 
GLP cardiovascular safety study in dogs, and likely related to inhibition of the hERG 
channel observed in the GLP hERG study. 
• In dogs administered 200 mg/kg/day (100 mg/kg BID) doses of TBI-223, QT 
prolongation was observed in the GLP repeat dose toxicology study. The mean QTc 
interval at 2 to 4 hours post the first daily dose on Day 25 of the dosing phase was 
longer in males by 23 msec (10%) and in females by 27 msec (11%) administered 
200 mg/kg/day compared with the respective controls. Mean uncorrected QT 
interval was also prolonged (up to 42 msec; 22%). The QT and QTc intervals 
returned to baseline during the recovery phase.  
In addition to the above adverse effects, rats had nonadverse abdominal distension 
reported in repeat dose studies with TBI-223, and this was associated with food-filled 
stomach in rats even though they were fasted overnight prior to necropsy.  
1.4 
Oxazolidinones 
The following adverse reactions were noted in more than 1% of adult subjects in a 
study of different drug in the oxazolidinone class, linezolid (marketed as Zyvox®): 
headache, diarrhea, nausea, vomiting, dizziness, rash, anemia, taste alteration, vaginal 
and oral moniliasis, abnormal liver functions tests, fungal infection, tongue 
discoloration, and abdominal pain.2 

Protocol TBI-223 CL-002 Version 1.0 
Global Alliance for TB Drug Development 
CONFIDENTIAL 
15 Dec 2020 
Page 5 
The Zyvox® label carries warnings and precautions for myelosuppression, peripheral 
and optic neuropathy, serotonin syndrome, Clostridium difficile associated diarrhea, 
elevated blood pressure in patients with hypertension, lactic acidosis, convulsions, 
hypoglycemia, and development of drug-resistant bacteria. 2 
1.5 
TBI-223 SAD Study Data 
TBI-223 Single ascending dose (SAD) study (TBI-223-CL-001) 
TBI-223 has been tested in one Phase 1 single-dose ascending dose (SAD) study with 
healthy volunteers. Study TBI-223-CL-001 was a SAD study designed to evaluate the 
safety, tolerability, and pharmacokinetics of TBI-223 in healthy adult subjects using an 
oral suspension, enteric capsule, and Immediate Release (IR) and Sustained Release 
(SR) tablet formulations.  
Part 1 of TBI-223-CL-001 consisted of Cohorts 1-7. Cohorts 1-7 were administered a 
single dose of 50 to 2600 mg of TBI-223 using the oral suspension. In order to test the 
absorption in the gastric duodenum, the same subjects of Cohort 3 returned following 
the completion of Cohort 3 (300 mg suspension), and received TBI-223 as TBI-223 
Oral Suspension in oral enteric capsules (300 mg) in an unblinded fashion. Cohort 5 
received a single 1200 mg dose of TBI-223 suspension under fed and fasted conditions 
over two periods. A total of 60 subjects participated in Part 1 of the study. 
Part 2 of TBI-223-CL-001 consisted of Cohorts 8 and 9. Cohort 8 consisted of 4 arms, 
with 6 subjects per arm:  In Arms 1-3 of Cohort 8, the 3 SR formulations were 
administered under fed conditions at 1800 mg, and in Arm 4 the IR tablet was 
administered under fasting conditions at 2000 mg. In Cohort 9, 6 subjects from Cohort 
8, Arm 4, returned to receive the same 2000 mg of the IR tablet under fed conditions. A 
total of 20 subjects participated in Part 2. 
Safety Overview: 
Part 1 
There were no serious AEs (SAEs) or treatment-emergent adverse event (TEAEs) that 
led to a subject withdrawal or death. 
The most frequently reported TEAE was nausea. There were 5 TEAEs reported by 5 
subjects; 2 TEAEs were reported by 2 (33.3%) subjects who received TBI-223, 2000 
mg and 3 TEAEs were reported by 3 (37.5%) subjects who received TBI-223 2600 mg.  
The second most frequently reported TEAE was dizziness. There were 4 TEAEs 
reported by 4 subjects; 1 TEAE was report by 1 (14.3%) subject who received TBI-223, 
1200 mg (fed), 1 TEAE was reported by 1 (16.7%) subject who received TBI-223, 
2000 mg, and 2 TEAEs were reported by 2 (25.0%) subjects who received TBI-223, 
2600 mg. 

Protocol TBI-223 CL-002 Version 1.0 
Global Alliance for TB Drug Development 
CONFIDENTIAL 
15 Dec 2020 
Page 6 
There were no changes in neurological examinations from baseline to 72 hours. 
The majority of TEAEs were judged by the Investigator as Grade 1 (mild) in severity. 
Four subjects experienced Grade 2 (moderate) TEAEs (vomiting, urticaria, 
hypersensitivity, and blood bilirubin increased).  
Overall, 4 (6.5%) subjects reported TEAEs that were judged by the Investigator as 
probably related to the study treatment, 4 (6.5%) subjects reported TEAEs that were 
judged as possible, 2 (3.2%) subjects reported TEAEs that were judged as unlikely 
related, and 5 (8.1%) subjects reported TEAEs that were judged as not related to the 
study treatment. 
All TEAEs reported during Part 1 are shown in the table below.   
Table 1 
Adverse Events, TEAEs by Primary System Organ Class and Preferred 
Term, Part 1 
MedDRA Primary 
System Organ Class 
Preferred Term 
Statistic 
Placebo 
(N=14) 
TBI-
223 
50 mg 
(N=6) 
TBI-
223 
100 mg 
(N=6) 
TBI-
223 
300 
mg 
(N=6) 
TBI-
223 
300 mg 
Capsule 
(N=6) 
TBI-
223 
600 mg 
(N=6) 
TBI-223 
1200 mg 
(Fasted) 
(N=8) 
TBI-
223 
1200 
mg 
(Fed) 
(N=7) 
TBI-
223 
2000 
mg 
(N=6) 
TBI-
223 
2600 
mg 
(N=8) 
Overall 
(N=62) 
Any TEAE 
N (%), 
No. of 
Events 
4 
(28.6), 
 5 
1 (16.7), 
 1 
2 
(33.3), 
 3 
1 
(16.7), 
 1 
0 
0 
0 
1 
(14.3), 
 1 
3 
(50.0), 
 4 
3 
(37.5), 
 9 
15 
(24.2), 
24 
Gastrointestinal 
disorders 
N (%), 
No. of 
Events 
0 
0 
0 
0 
0 
0 
0 
0 
2 
(33.3), 
 2 
3 
(37.5), 
 5 
5 (8.1), 
 7 
  Nausea 
N (%), 
No. of 
Events 
0 
0 
0 
0 
0 
0 
0 
0 
2 
(33.3), 
 2 
3 
(37.5), 
 3 
5 (8.1), 
 5 
  Vomiting 
N (%), 
No. of 
Events 
0 
0 
0 
0 
0 
0 
0 
0 
0 
2 
(25.0), 
 2 
2 (3.2), 
 2 
Nervous system 
disorders 
N (%), 
No. of 
Events 
0 
0 
0 
0 
0 
0 
0 
1 
(14.3), 
 1 
1 
(16.7), 
 1 
2 
(25.0), 
 3 
4 (6.5), 
 5 
  Dizziness 
N (%), 
No. of 
Events 
0 
0 
0 
0 
0 
0 
0 
1 
(14.3), 
 1 
1 
(16.7), 
 1 
2 
(25.0), 
 2 
4 (6.5), 
 4 
  Headache 
N (%), 
No. of 
Events 
0 
0 
0 
0 
0 
0 
0 
0 
0 
1 
(12.5), 
 1 
1 (1.6), 
 1 
Cardiac disorders 
N (%), 
No. of 
Events 
0 
0 
1 
(16.7), 
 1 
0 
0 
0 
0 
0 
0 
1 
(12.5), 
 1 
2 (3.2), 
 2 
  Tachycardia 
N (%), 
No. of 
Events 
0 
0 
1 
(16.7), 
 1 
0 
0 
0 
0 
0 
0 
1 
(12.5), 
 1 
2 (3.2), 
 2 

Protocol TBI-223 CL-002 Version 1.0 
Global Alliance for TB Drug Development 
CONFIDENTIAL 
15 Dec 2020 
Page 7 
MedDRA Primary 
System Organ Class 
Preferred Term 
Statistic 
Placebo 
(N=14) 
TBI-
223 
50 mg 
(N=6) 
TBI-
223 
100 mg 
(N=6) 
TBI-
223 
300 
mg 
(N=6) 
TBI-
223 
300 mg 
Capsule 
(N=6) 
TBI-
223 
600 mg 
(N=6) 
TBI-223 
1200 mg 
(Fasted) 
(N=8) 
TBI-
223 
1200 
mg 
(Fed) 
(N=7) 
TBI-
223 
2000 
mg 
(N=6) 
TBI-
223 
2600 
mg 
(N=8) 
Overall 
(N=62) 
General disorders and 
administration site 
conditions 
N (%), 
No. of 
Events 
0 
0 
2 
(33.3), 
 2 
0 
0 
0 
0 
0 
0 
0 
2 (3.2), 
 2 
  Energy increased 
N (%), 
No. of 
Events 
0 
0 
1 
(16.7), 
 1 
0 
0 
0 
0 
0 
0 
0 
1 (1.6), 
 1 
  Medical device site 
reaction 
N (%), 
No. of 
Events 
0 
0 
1 
(16.7), 
 1 
0 
0 
0 
0 
0 
0 
0 
1 (1.6), 
 1 
Skin and 
subcutaneous tissue 
disorders 
N (%), 
No. of 
Events 
1 (7.1), 
 1 
1 (16.7), 
 1 
0 
0 
0 
0 
0 
0 
0 
0 
2 (3.2), 
 2 
  Skin discolouration N (%), 
No. of 
Events 
1 (7.1), 
 1 
0 
0 
0 
0 
0 
0 
0 
0 
0 
1 (1.6), 
 1 
  Urticaria 
N (%), 
No. of 
Events 
0 
1 (16.7), 
 1 
0 
0 
0 
0 
0 
0 
0 
0 
1 (1.6), 
 1 
Vascular disorders 
N (%), 
No. of 
Events 
1 (7.1), 
 2 
0 
0 
0 
0 
0 
0 
0 
0 
0 
1 (1.6), 
 2 
  Hypotension 
N (%), 
No. of 
Events 
1 (7.1), 
 2 
0 
0 
0 
0 
0 
0 
0 
0 
0 
1 (1.6), 
 2 
Blood and lymphatic 
system disorders 
N (%), 
No. of 
Events 
1 (7.1), 
 1 
0 
0 
0 
0 
0 
0 
0 
0 
0 
1 (1.6), 
 1 
  Neutropenia 
N (%), 
No. of 
Events 
1 (7.1), 
 1 
0 
0 
0 
0 
0 
0 
0 
0 
0 
1 (1.6), 
 1 
Immune system 
disorders 
N (%), 
No. of 
Events 
1 (7.1), 
 1 
0 
0 
0 
0 
0 
0 
0 
0 
0 
1 (1.6), 
 1 
  Hypersensitivity 
N (%), 
No. of 
Events 
1 (7.1), 
 1 
0 
0 
0 
0 
0 
0 
0 
0 
0 
1 (1.6), 
 1 
Investigations 
N (%), 
No. of 
Events 
0 
0 
0 
1 
(16.7), 
 1 
0 
0 
0 
0 
0 
0 
1 (1.6), 
 1 
  Blood bilirubin 
increased 
N (%), 
No. of 
Events 
0 
0 
0 
1 
(16.7), 
 1 
0 
0 
0 
0 
0 
0 
1 (1.6), 
 1 
Musculoskeletal and 
connective tissue 
disorders 
N (%), 
No. of 
Events 
0 
0 
0 
0 
0 
0 
0 
0 
1 
(16.7), 
 1 
0 
1 (1.6), 
 1 

Protocol TBI-223 CL-002 Version 1.0 
Global Alliance for TB Drug Development 
CONFIDENTIAL 
15 Dec 2020 
Page 8 
MedDRA Primary 
System Organ Class 
Preferred Term 
Statistic 
Placebo 
(N=14) 
TBI-
223 
50 mg 
(N=6) 
TBI-
223 
100 mg 
(N=6) 
TBI-
223 
300 
mg 
(N=6) 
TBI-
223 
300 mg 
Capsule 
(N=6) 
TBI-
223 
600 mg 
(N=6) 
TBI-223 
1200 mg 
(Fasted) 
(N=8) 
TBI-
223 
1200 
mg 
(Fed) 
(N=7) 
TBI-
223 
2000 
mg 
(N=6) 
TBI-
223 
2600 
mg 
(N=8) 
Overall 
(N=62) 
  Back pain 
N (%), 
No. of 
Events 
0 
0 
0 
0 
0 
0 
0 
0 
1 
(16.7), 
 1 
0 
1 (1.6), 
 1 
MedDRA = Medical Dictionary for Regulatory Activities, Version 23.0 
Cardiac Assessments (ECG and Holter)  
Electrocardiograms 
There were no clinically significant findings for ECGs. 
Heart Rhythm and Cardiac Conduction  
In Part 1 of the study, the effect of TBI-223 oral suspension on ECG parameters was 
evaluated using continuous 12-lead ECG (Holter) monitoring. Serial ECGs were 
extracted from the Holter recordings at prespecified time points starting on Day –1 
through 48 hours post-dose. At baseline, data were available from 6 subjects in each of 
the 50, 100, 300, 600 and 2000 mg TBI-223 group, 8 subjects in the 1200 and 2600 mg 
group and from 14 placebo subjects pooled from all cohorts.  
TBI-223 Oral Suspension at the studied doses did not have a clinically relevant effect 
on HR. The pattern across dose groups and relation to the observed PK profile of 
TBI-223 and M2 do not suggest that the drug or metabolite exert a clinically relevant 
effect on HR.  
In the by-time point analysis for QTcF, mean placebo-corrected ΔQTcF (∆∆QTcF) 
ranged from –8.9 ms at 12 hours post-dose in the 600 mg group to 13.3 ms at 5 hours 
post-dose in the 2000 mg dose group. In the 2 highest dose groups (2000 mg and 2600 
mg), mean ∆∆QTcF was 13.1 ms and 13.3 ms at 4 and 5 hours and 12.4 ms at 1 hour 
post-dose, respectively.  
In the concentration-QTc analysis, a full model including TBI-223 and its metabolite 
M2 was selected as the primary model. The estimated population slope of the 
concentration-QTc relationship was 0.0004 ms per μg/L (90% CI: -0.00005 to 0.00093) 
for TBI-223, 0.001 ms per μg/L (90% CI: -0.0010 to 0.0034) for M2 with a treatment 
effect-specific intercept of 1.6 ms (90% CI: -1.01 to 4.16). The predicted effect on 
ΔΔQTcF at the geometric mean Cmax of  TBI-223 and of M2 after a single dose of 1200 
mg, also accounting for the effect of M2 and TBI-223 at the same time points (Tmax of 
TBI-223 and M2, respectively), was 7.47 and 7.16 ms, with an upper bound of the 90% 
CI of 10.06 and 10.20 ms, respectively. In the concentration-QTc analysis with TBI-
223 alone and M2 alone, an effect on ∆∆QTcF can be excluded at TBI-223 and M2 
concentrations up to ~8140 μg/L and ~2040 μg/L, respectively.  

Protocol TBI-223 CL-002 Version 1.0 
Global Alliance for TB Drug Development 
CONFIDENTIAL 
15 Dec 2020 
Page 9 
TBI-223 Oral Suspension at the studied doses did not have a clinically relevant effect 
on cardiac conduction, i.e., the PR and QRS intervals. 
Cardiovascular Summary 
In summary, TBI-223 oral suspension at the studied doses had no clinically relevant 
effects on HR or on cardiac conduction (the PR and QRS intervals). Based on the 
concentration-QTc analysis, a QTcF effect (∆∆QTcF) exceeding 10 ms can be excluded 
for plasma concentrations of TBI-223 and M2 up to ~8000 μg/L and ~2000 μg/L, 
respectively. 
Part 2 
There were no SAEs or TEAEs that led to a subject withdrawal or death.  
The most frequently reported TEAE was vessel puncture site inflammation. There were 
3 TEAEs reported by 3 subjects; 2 TEAEs were reported by 2 (33.3%) subjects who 
received TBI-223, 1800 mg SR Tablet (Prototype 2, fed), and 1 TEAE was reported by 
1 (16.7%) subject who received TBI-223, 2000 mg IR Tablet (fasted). 
The second most frequently reported TEAE was dizziness. There were 3 TEAEs 
reported by 2 subjects; 2 TEAEs were reported by 2 (33.3%) subjects who received 
TBI-223, 2000 mg IR Tablet (fasted) and 1 TEAE was reported by 1 (16.7%) subject 
who received TBI-223, 2000 mg IR Tablet (fed). 
All TEAEs reported during Part 2 were Grade 1 (mild) in severity. 
Overall, 1 (4.2%) subject reported a TEAE that was judged by the Investigator as 
probably related to the study treatment, 3 (12.5%) subjects reported TEAEs that were 
judged as possible, and 4 (16.7%) subjects reported TEAEs that were judged as not 
related to the study treatment. 
There were no TEAEs related to clinically significant out-of-range vital sign 
measurements or laboratory values. 
No clinically significant abnormalities in ECGs were observed.  
There were no changes in neurological examinations from baseline to 48 hours. 
All TEAEs reported during Part 2 are shown in the table below. 

Protocol TBI-223 CL-002 Version 1.0 
Global Alliance for TB Drug Development 
CONFIDENTIAL 
15 Dec 2020 
Page 10 
Table 2 
Adverse Events, TEAEs by Primary System Organ Class and Preferred 
Term, Part 2 
MedDRA Primary System 
Organ Class 
Preferred Term 
Statistic 
TBI-223 
1800 mg 
SR-1 
tablet 
(Fed) 
(N=6) 
TBI-223 
1800 mg 
SR-2 
tablet 
(Fed) 
(N=6) 
TBI-223 
1800 mg 
SR-3 
tablet 
(Fed) 
(N=6) 
TBI-223 
2000 mg 
IR tablet 
(Fasted) 
(N=6) 
TBI-223 
2000 mg 
IR tablet 
(Fed) 
(N=6) 
Overall 
(N=24) 
Any TEAE 
N (%), 
No. of Events 
1 (16.7), 
 1 
2 (33.3), 
 2 
2 (33.3), 
 3 
3 (50.0), 
 6 
2 (33.3), 
 2 
8 (33.3), 
14 
General disorders and 
administration site conditions 
N (%), 
No. of Events 
0 
2 (33.3), 
 2 
2 (33.3), 
 3 
1 (16.7), 
 2 
0 
5 (20.8), 
 7 
  Vessel puncture site 
inflammation 
N (%), 
No. of Events 
0 
2 (33.3), 
 2 
0 
1 (16.7), 
 1 
0 
3 (12.5), 
 3 
  Chest discomfort 
N (%), 
No. of Events 
0 
0 
0 
1 (16.7), 
 1 
0 
1 (4.2), 
 1 
  Vessel puncture site pain 
N (%), 
No. of Events 
0 
0 
1 (16.7), 
 1 
0 
0 
1 (4.2), 
 1 
  Vessel puncture site reaction N (%), 
No. of Events 
0 
0 
1 (16.7), 
 1 
0 
0 
1 (4.2), 
 1 
  Vessel puncture site swelling N (%), 
No. of Events 
0 
0 
1 (16.7), 
 1 
0 
0 
1 (4.2), 
 1 
Nervous system disorders 
N (%), 
No. of Events 
1 (16.7), 
 1 
0 
0 
3 (50.0), 
 3 
1 (16.7), 
 1 
4 (16.7), 
 5 
  Dizziness 
N (%), 
No. of Events 
0 
0 
0 
2 (33.3), 
 2 
1 (16.7), 
 1 
2 (8.3), 
 3 
  Disturbance in attention 
N (%), 
No. of Events 
0 
0 
0 
1 (16.7), 
 1 
0 
1 (4.2), 
 1 
  Headache 
N (%), 
No. of Events 
1 (16.7), 
 1 
0 
0 
0 
0 
1 (4.2), 
 1 
Gastrointestinal disorders 
N (%), 
No. of Events 
0 
0 
0 
1 (16.7), 
 1 
1 (16.7), 
 1 
1 (4.2), 
 2 
  Abdominal pain 
N (%), 
No. of Events 
0 
0 
0 
0 
1 (16.7), 
 1 
1 (4.2), 
 1 
  Nausea 
N (%), 
No. of Events 
0 
0 
0 
1 (16.7), 
 1 
0 
1 (4.2), 
 1 
MedDRA = Medical Dictionary for Regulatory Activities, Version 23.0. 
 
Safety Summary: 
Part 1 
In part 1 of the study all subjects were dosed with TBI-223 oral suspension.  

Protocol TBI-223 CL-002 Version 1.0 
Global Alliance for TB Drug Development 
CONFIDENTIAL 
15 Dec 2020 
Page 11 
Overall, TBI-223 was well-tolerated when administered as an oral suspension and oral 
enteric capsules in healthy subjects under fed and fasted conditions at doses from 
50 mg to 2600 mg. At 2600 mg of the oral suspension, the arithmetic mean Cmax of 
TBI-223 was 16.2 μg/mL. Two of six subjects had Cmax exceeding 20 μg/mL (21.0 and 
22.0 μg/mL). The arithmetic mean AUC0-inf of TBI-223 was 127 μg.h/mL, with the 
maximum value being 190 μg.h/mL.  
Part 2 
In Part 2 of the study all subjects were dosed with TBI-223 Immediate (IR) and 
Sustained (SR) release formulations.  
Overall, the TBI-223 was well-tolerated when administered as a tablet formulation in 
healthy subjects under fed and fasted conditions at doses of 2000 mg (IR) and 1800 mg 
(SR). The highest concentrations of TBI-223 were seen with 2000 mg IR under fed 
conditions, where the arithmetic mean Cmax was 19.7 μg/mL and where two of six 
subjects had Cmax exceeding 20 μg/mL (25.9 and 27.5 μg/mL). That group also 
experienced the highest arithmetic mean AUC0-inf of TBI-223, 100 μg.h/mL, with the 
maximum value being 150 μg.h/mL. 
Pharmacokinetic Summary (Suspension): 
Single Ascending TBI-223 Doses, Cohorts 1-7, Fasted (Part 1) 
After administrations of single TBI-223 oral suspension doses under fasted conditions, 
median TBI-223 Tmax ranged from 1.00 h (Cohort 1, 50 mg) to 2.25 h (Cohort 7, 
2600 mg). TBI-223 exposure (Cmax and AUCs) increased in a nearly dose-proportional 
manner with an increase in dose under fasted conditions dose over the 50 mg to 2600 mg 
dose range. Slope (β1) were close to 1 for each parameter and the 90% confidence 
intervals nearly included 1. Slope estimates and 90% confidence intervals (90% CI) were 
0.9310 (0.8622 - 0.9997) for Cmax, 1.1385 (1.0906 – 1.1863) for AUC0-t, and 1.1338 
(1.0853 – 1.1823) for AUC0-inf. 
Formulation Effect, Cohort 3, 300 mg, Capsule vs. Oral Suspension (Part 1) 
Median TBI-223 Tmax was observed at approximately 3.6 h later for the TBI-223 capsule 
formulation (5.00 h) compared to that after the oral suspension (1.37 h). Maximum 
TBI-223 exposure (Cmax) was approximately 58% lower after administration of the 
capsule formulation compared to that after the oral suspension formulation; total TBI-223 
exposure (AUCs) was similar for capsule and oral suspension formulations. This outcome 
demonstrated uptake in the duodenum and therefore supported evaluating a sustained 
release formulation which could result in more T>MIC Geometric mean ratios and 90% 
CIs for Cmax, AUC0-t, and AUC0-inf were 42.46% (31.57% - 57.10%), 94.43% (90.28% - 
98.76%), and 94.73% (90.58% - 99.06%), respectively. 

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Food Effect, Cohort 5, TBI-223 Oral suspension 1200 mg; (Part 1) 
Median Tmax was 1.50 h after drug administration under fed and fasted conditions. 
Maximum and total TBI-223 exposure (Cmax and AUCs) were similar for fed and fasted 
conditions. Geometric mean ratios and 90% CIs for Cmax, AUC0-t, and AUC0-inf were 
103.34% (87.00% - 122.75%), 103.23% (97.80% - 108.96%), and 102.79% (96.37% - 
109.64%), respectively. 
Food Effect, TBI-223 IR Tablets, 2000 mg; (Part 2) 
Administration of IR tablets with food delayed TBI-223 Tmax by approximately 1 h. 
Administration of TBI-223 IR tablets (2000 mg) with food increased TBI-223 Cmax by 
approximately 51%. TBI-223 AUCs were slightly higher (~16%) under fed conditions 
compared to that under fasted conditions. Geometric mean ratios and 90% CIs for Cmax, 
AUC0-t, and AUC0-inf were 151.24% (127.91% - 178.82%), 115.73% (112.08% - 
119.50%), and 115.70% (112.06% - 119.47%), respectively. 
Different Formulation (Tablets - Immediate and Sustained release) 
Pharmacokinetics: 
Sustained-release (SR) Tablet Prototypes 1, 2, and 3 (Fed), 1800 mg vs. IR Tablets 
2000 mg (Fasted), (Part 2) 
Median TBI-223 Tmax was observed approximately 4.5 to 5.5 h later for the SR prototypes 
administered with food compared to the IR formulation under fasted conditions. 
Maximum TBI-223 exposure (normalized Cmax) was approximately 46%, 28%, and 34% 
lower after administrations of SR-1, SR-2, and SR-3 under fed conditions, compared to IR 
tablet under fasted conditions. Total TBI-223 exposure (normalized AUC0-t and AUC0-inf) 
was approximately 19% lower for SR-1 and SR-2 administered under fed conditions 
compared to IR tablets administered under fasted conditions; AUCs were similar for SR-3 
and IR. 
Geometric mean ratios and 90% CIs for SR-1 normalized Cmax, AUC0-t, and AUC0-inf 
were 53.53% (40.10% - 71.45%), 81.11% (62.92% - 104.56%), and 81.52% (63.26% - 
105.04%), respectively. Geometric mean ratios and 90% CIs for SR-2 normalized Cmax, 
AUC0-t, and AUC0-inf were 71.70% (53.71% - 95.71%), 80.55% (62.49% - 103.84%), and 
80.56% (62.51% - 103.81%), respectively. Geometric mean ratios and 90% CIs for SR-3 
normalized Cmax, AUC0-t, and AUC0-inf were 66.31% (49.67% - 88.53%), 95.71% 
(74.25% - 123.38%), and 95.73% (74.29% - 123.35%), respectively. 
Sustained-release (SR) Tablet Prototypes 1, 2, and 3 (Fed), 1800 mg vs. IR Tablets 
2000 mg (Fed), (Part 2) 
Median TBI-223 Tmax was observed approximately 3.5 to 4.5 h later for the SR 
prototypes compared to the IR formulation under fed conditions. 

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Maximum TBI-223 exposure (normalized Cmax) was approximately 65%, 53%, and 56% 
lower after administrations of SR-1, SR-2, and SR-3 compared to IR tablet under fed 
conditions. Total TBI-223 exposure (normalized AUC0-t and AUC0-inf) was approximately 
17%-30% lower after administrations of SR-1, SR-2, and SR-3 compared to IR tablet 
under fed conditions. 
Geometric mean ratios and 90% CIs for SR-1 normalized Cmax, AUC0-t, and AUC0-inf 
were 35.39% (26.04% - 48.10%), 70.09% (54.10% - 90.81%), and 70.45% (54.40% - 
91.24%), respectively. Geometric mean ratios and 90% CIs for SR-2 normalized Cmax, 
AUC0-t, and AUC0-inf were 47.41% (34.88% - 64.43%), 69.60% (53.72% - 90.18%), 
and 69.62% (53.76% - 90.17%), respectively. Geometric mean ratios and 90% CIs for 
SR-3 normalized Cmax, AUC0-t, and AUC0-inf were 43.85% (32.26% - 59.59%), 82.70% 
(63.83% - 107.15%), and 82.74% (63.88% - 107.15%), respectively. 
1.6 
Adverse Effects, Warnings, and Precautions 
Given the key safety findings in the SAD (TBI-223) study, TBI-223-CL-001 and 
nonclinical safety studies for the cardiovascular system (prolonged QTc) and the 
nervous (CNS) system (tremors), we will implement the following monitoring 
procedures.   
Cardiovascular Monitoring   
Cardiovascular monitoring will be conducted and include the following at both 
protocol-defined time points and whenever deemed necessary by the study investigator.  
Subjects treated with TBI-223 will have their ECGs evaluated prior to treatment and 
during treatment. During treatment, the timing of ECGs will be guided by 
pharmacokinetic (PK) data so that collection occurs around the estimated Tmax. 
ECGs will be interpreted and signed and dated by the Principal Investigator or 
designee. The ECGs will be classified as normal, having a clinically insignificant 
abnormality, or having a clinically significant abnormality. All clinically significant 
abnormalities will be recorded as AEs. In addition, ECG parameters of ventricular rate, 
PQ or PR interval, QRS duration, and QT interval (corrected and uncorrected) will be 
noted on the case report form (CRF). If a patient’s corrected QT interval (QTcF) 
exceeds 500 msec while on treatment or there is a change from baseline exceeding 
60 msec, TBI-223 administration should be stopped, and the patient monitored with 
ECGs and/or telemetry until the QTcF returns to pre-treatment levels.   
Central Nervous System Monitoring  
A detailed neurological exam will be conducted and include the following at both 
protocol-defined time points and whenever deemed necessary by the study 
investigator:  
• 
Mental status – assessment of orientation, speech, and memory   

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• 
Cranial nerves – assessment of cranial nerves II-XII, excluding fundoscopic 
examination   
• 
Motor system – brief assessment of tone and strength   
• 
Sensory system – brief survey for light touch and temperature of the face, neck, 
arms, trunk, and legs   
• 
Reflexes – assessment of deep tendon reflexes and plantar responses (Babinski 
sign)  
• 
Coordination – assessment of upper and lower extremities, including assessment 
for tremor   
• 
Gait – assessment of tandem gait 
1.7 
Overview and Dose Rationale 
TBI-223, as a single agent at 100 mg/kg, demonstrated moderate activity against acute 
murine TB in BALB/c mice, and in a C3HeB/FeJ mouse model of TB. When combined 
with the TB drug bedaquiline and the investigational TB drug pretomanid, TBI-223 at 
100 mg/kg demonstrated bactericidal and sterilizing activity against murine TB in 
BALB/c mice that was similar to that of linezolid at the same dose (100 mg/kg). The 
PK exposure at 100 mg/kg was 179 µg•hr/mL, with T>MIC at 61% (or 14.6 hr/day) in 
the female BALB/c mice. 
A dose fractionation study of TBI-223 in a BALB/c mouse model of TB showed that 
the efficacy drivers were AUC (R2 = 0.92) and T>MIC (R2 = 0.83). The study indicated 
that a 2 Log lung colony-forming unit (CFU) reduction can be achieved with total a 
weekly AUC of 868 µg.hr/mL, or daily AUC0-24hr of 124 µg.hr/mL, with T>MIC of 
34% (T>MIC at 8.2 hours over 24 hours). 
The QD dose regimens in this study were selected to achieve high AUC and T>MIC. 
For the latter objective, the SR formulation introduced in the SAD study (called SR-1 
there) will comprise the majority component of a QD regimen. The SAD study showed 
that such a formulation yields an AUC 70% that of an IR tablet at an equivalent dose 
under fed conditions, while the Cmax ratio is only 35%. The SR dosages planned for this 
study are 1800 and 2400 mg. Tmax for the SR and IR tablet was at 7 and 3 hours, 
respectively. To boost exposure during the prolonged absorption phase of the SR tablet, 
a single 600 mg IR tablet will here be added to each of the SR dosages, yielding total 
doses of 1800, 2400, and 3000 mg. Simulations predict that the steady-state Cmax of the 
average concentration for those three regimens will be 5.7, 7.9, and 9.7 μg/mL, 
respectively, below the lowest preclinical no adverse effect level of 20.2 μg/mL and 
below the highest arithmetic mean Cmax seen in the SAD study, 19.7 μg/mL. Expected 
values of steady-state AUC0-24h are 63.8, 93.9, and 115.2 μg.h/mL, the higher values 
being similar to the highest arithmetic mean AUC0-inf seen in the SAD study, 100 
μg.h/mL. Expected T>MICs are 70, 85, and 93%. If successful, the QD regimens 
produced here by the pairing of SR and IR tablets may be implemented in a single 

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formulation such as a bilayer tablet. Once again, below are the predicted exposures of 
proposed doses in table format (Table 3). 
Table 3 
Exposures 
Cohort 
Dose (QD) 
Cmax 
AUC(0-24hr) 
%T>MIC 
Cohort 1 
1800 mg (3 x 600 mg SR1) 
5.7 µg/mL 
63.8 (h*µg/mL) 
70% 
Cohort 2 
2400 mg (3 x 600 mg SR1 and 1 x 600 mg 
IR) 
7.9 µg/mL 
93.9 (h*µg/mL) 
85% 
Cohort 3 
3000 mg (4 x 600 mg and 1 x 600 mg IR) 
9.7 µg/mL 
115.2 (h*µg/mL) 
93% 
2 
OBJECTIVE 
The primary objective of the study is: 
•
To evaluate the safety and tolerability of multiple doses of TBI-223 in healthy adult
subjects.
The secondary objectives of the study are: 
•
To determine the pharmacokinetics (PK) of TBI-223 and its metabolite M2 after
multiple ascending doses of TBI-223 in healthy adult subjects when administered
after a high-calorie, high-fat meal
•
For the TBI-223 sustained-release (SR) formulation and for a combination of the
SR and immediate-release (IR) formulations, to compare the PK profiles of a single
dose when administered to healthy adult subjects in the fasting state versus after a
high-calorie, high-fat meal
•
To determine the pharmacokinetics (PK) of a single dose of the TBI-223 sustained-
release (SR1) formulation in healthy adult subjects when administered fasted.
3 
STUDY DESIGN SUMMARY 
This is a partially-blinded, placebo-controlled, randomized multiple ascending dose 
(MAD) study to be conducted at one study center.  
Thirty-six (36) subjects will be enrolled in 3 cohorts with 12 subjects per cohort. 
Within each cohort, 9 subjects will be assigned to receive active treatment and 
3 subjects will receive placebo. Each subject will participate in one dose level.  
The first 2 cohorts (food-effect cohorts) will begin dosing of TBI-223 on Day 1 under 
fasted conditions, followed by a 3 day washout period and then followed by multiple 
doses of TBI-223 administered after a high-calorie, high-fat meal from Day 4 through 
Day 17 (total of 14 days). The third cohort (non-food-effect cohort) will begin dosing 
of TBI-223 on Day 1 and continue through Day 14, all doses administered after a high-
calorie, high-fat meal. 

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Each subject will be administered TBI-223 or matching placebo with corresponding 
pharmacokinetic measurements. After each dose cohort, the Sponsor and Investigator 
will review the pharmacokinetic and safety data before proceeding to the next dose 
level. 
Dose escalation to the next cohort (i.e., dose level) or decisions regarding changed or 
additional cohorts will not take place until the Sponsor, in conjunction with the 
Principal Investigator and dose escalating committee, has determined that adequate 
safety, tolerability, and pharmacokinetics from the previous cohort(s) have been 
demonstrated to permit proceeding to the next cohort. The Institutional Review Board 
(IRB) should be immediately notified of the dose escalation or any revised approach for 
review and approval. 
Safety will be assessed throughout the study for all subjects. Safety assessments will 
include physical and detailed neurological examinations, vital signs (blood pressure, 
pulse rate, respiration rate, temperature and pulse oximetry), ECGs, cardiac monitoring, 
adverse events (AEs), and clinical laboratory tests (including hematology, serology, 
serum chemistry, coagulation, and urinalysis). 
Blood and urine will be collected for clinical laboratory evaluations. 
The Principal Investigator, in conjunction with the Sponsor may collect additional 
blood if necessary, for repeat laboratory or safety evaluations including AE follow up. 
Female subjects will have blood collected for serum pregnancy testing. Females 
claiming postmenopausal status will have blood collected to measure follicle 
stimulating hormone (FSH) levels.  
During each cohort, blood samples (trough samples) will be obtained before each dose 
of study drug, and at the time points on the events schedule (Table 6 for food-effect 
cohorts and Table 7 for non-food-effect cohort). Plasma pharmacokinetic samples will 
be analyzed for TBI-223 and M2 using validated analytical methods. Appropriate 
pharmacokinetic parameters will be calculated using non compartmental methods. 
An overview of the dose cohorts is presented in Table 5. 

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Table 4 
Dose Cohorts 
Cohorta  
Dose 
1  
Day 1: Single dose of TBI-223, 1800 mg (n=9) 
(3 x 600 mg SR1 tablets)  
Day 1: Single dose of Placebo, 
1800 mg (n=3) 
(3 x placebo tablets for 600 mg IR 
and SR) 
1 
Day 4: 14 doses (1 per day) of TBI-223, 1800 mg 
(n=9) 
(3 x 600 mg SR1 tablets) 
Day 4: 14 doses (1 per day) of 
Placebo,  
1800 mg (n=3) 
(3 x placebo tablets for 600 mg IR 
and SR) 
2  
Day 1: Single dose of TBI-223, 2400 mg (n=9)  
(3 x 600 mg SR1 tablets and 1 x 600 mg IR 
tablet)  
Day 1: Single dose of Placebo, 
2400 mg (n=3) 
(4 x placebo tablets for 600 mg IR 
and SR) 
2 
Day 4: 14 doses (1 per day) of TBI-223, 
2400 mg (n=9) 
(3 x 600 mg SR1 tablets and 1 x 600 mg IR 
tablet) 
Day 4: 14 doses (1 per day) of 
Placebo, 2400 mg (n=3) 
(4 x placebo tablets for 600 mg IR 
and SR) 
3  
Day 1: Single doses (1 per day) of TBI-223, 
3000 mg (n=9) 
 (4 x 600 mg SR1 tablets and 1 x 600 mg IR 
tablet)  
Day 1: 14 doses (1 per day) of 
Placebo, 3000 mg (n=3) 
(5 x placebo tablets for 600 mg IR 
and SR) 
a) Additional cohorts may be enrolled if deemed appropriate by the Sponsor to repeat a dose level or 
to study another dose level. 
 
3.1 
Dose Escalation 
Dose Escalation Review 
The review of all pertinent safety/tolerability data will include physical examinations, 
ECGs, vital signs, clinical laboratory tests, cardiac monitoring, and adverse events 
(AEs or SAEs) through Day 30 (non-food-effect cohort) or Day 33 (food-effect 
cohorts). Data considered will include data from the current dose cohort and all 
previous cohorts. The Sponsor and Investigator will determine if there is sufficient data 
available from all participating subjects to make a dose escalation decision.  
Any AEs of grade ≥ 2 toxicities (per DMID toxicity table; Appendix 3) must be 
discussed in the determination of escalation to the next dose level. PK analysis will be 
completed only on the active treatment subjects and will be blinded by subject. ECG 

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data will be analyzed in a blinded fashion and unblinded by ECG vendor in order to be 
presented by treatment group in aggregate (reviewers will not be unblinded by subject).  
Upon review of relevant cohort data, the Sponsor, in conjunction with the Investigator, 
may decide to: 
1. Escalate the dose as planned. 
2. Evaluate an intermediate dose level prior to proceeding to the next planned dose 
level based on PK and safety data of preceding groups. 
3. Repeat a given dose level in a new cohort of subjects. 
4. Increase the dose of the next cohort if the PK is lower than expected in the 
previous cohort. 
5. Add a cohort if the PK is lower than expected after a cohort and there are no 
safety concerns. 
6. Halt the study. 
3.2 
Cohort Stopping Rules for Subjects Receiving Active Drug: 
If any of the cohort stopping rules are met, cohort dosing must be stopped until review 
of the data by the Sponsor and the Investigator. 
Rules for stopping dosing of a cohort include the following:  
1. One subject experiences a drug-related SAE.   
2. Two or more subjects develop Grade 3 or higher central nervous system AE 
considered related to drug.  
3. Two or more (≥2) subjects develop QTcF > 500 msec with an increase from 
baseline > 60 msec after completion of repeat testing.  
4. Two or more subjects experience confirmed Grade 3 or Grade 4 cardiac rhythm 
disturbances considered related to drug.  
If any of the cohort stopping rules are met, cohort dosing must be stopped until the 
data has been reviewed by the Sponsor, Investigator and Dose Escalating meeting 
(DEM) before dosing is resumed, or other actions taken, or the decision made to 
discontinue the cohort. Refer to Section 6.2.5 for unblinding procedures. The IRB 
or Ethics committee (EC) should be immediately notified according to their 
regulations. 
4 
IDENTITY OF INVESTIGATIONAL PRODUCT 
The Investigational Medicinal Product (IMP) will be supplied as TBI-223 tablets or 
placebo in the following dose strengths and formulations: TBI-223 SR Tablets, 600 mg 

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(Prototype 1; SR1), TBI-223 IR Tablets, 600 mg (IR), and Placebo Tablets for TBI-223 
IR and SR Tablets, 600 mg (Placebo).   
Refer to Appendix 2 for details regarding the description and composition of TBI-223. 
Table 5 Identity of Investigational Products 
Test Products:  
TBI-223 SR1 Tablet, 600 mg 
Manufactured for Global Alliance for TB Drug Development 
and 
TBI-223 IR Tablet, 600 mg 
Manufactured for Global Alliance for TB Drug Development 
 
 
Control Product: 
Placebo Tablet for TBI-223 IR and SR Tablets, 600 mg 
Manufactured for Global Alliance for TB Drug Development 
 
5 
SUBJECT SELECTION 
5.1 
Inclusion Criteria 
All volunteers must satisfy the following criteria to be considered for study 
participation: 
1. Understands study procedures and voluntarily provides written informed consent 
prior to the start of any study-specific procedures. 
2. Is a healthy adult male or a healthy adult female of non-childbearing potential, 
19 to 50 years of age (inclusive) at the time of screening.  
3. Has a body mass index (BMI) ≥18.5 and ≤32.0 (kg/m2) and a body weight of no 
less than 50.0 kg at the time of screening and check-in. 
4. Is medically healthy with no clinically significant screening results, as determined 
by the Principal Investigator (e.g., laboratory profiles are normal up to and 
including Grade 1 per DMID toxicity tables; Appendix 3), medical history, vital 
signs, ECG, or physical/neurological examination findings. Note: If exclusionary 
lab criteria are met, values may be confirmed by repeat evaluation. 
5. Has not used tobacco- or nicotine-containing products (including smoking 
cessation products), for a minimum of 6 months before dosing.  
6. Females of non-childbearing potential, based on having undergone one of the 
following sterilization procedures at least 6 months before dosing: 
• Hysteroscopic sterilization. 
• Bilateral tubal ligation or bilateral salpingectomy; 
• Hysterectomy; or 

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• Bilateral oophorectomy. 
• Or is postmenopausal with amenorrhea for at least 1 year before the first 
dose with serum FSH levels consistent with postmenopausal status (i.e., 
greater than 40 mIU/mL) at screening.  
Or, if female of childbearing potential, must agree to use an allowable form of 
birth control from screening until 14 days after study completion. The following 
are allowed birth control methods for this study: 
• Vasectomized partner (at least 6 months before dosing); 
• Non-surgical permanent sterilization (e.g., Essure® procedure) at least 
3 months before dosing. 
• Double barrier method (e.g., diaphragm with spermicide; condoms with 
spermicide). 
• Intrauterine device (IUD). 
• Abstinence (and must agree to use a double barrier method if they become 
sexually active during the study); 
• Implanted or intrauterine hormonal contraceptives in use for at least 6 
consecutive months before study dosing; and/or 
• Oral, patch, or injected contraceptives, or vaginal hormonal device (i.e. 
NuvaRing®), in use for at least 3 consecutive months before study dosing. 
7. If a non-vasectomized male (or male vasectomized less than 120 days prior to 
study start) must agree to the following during study participation and for 90 days 
after the last administration of study drug: 
• Use a condom with spermicide while engaging in sexual activity or be 
sexually abstinent  
• Not donate sperm during this time.  
In the event the sexual partner is surgically sterile or postmenopausal, use of a 
condom with spermicide is not necessary. None of the birth control restrictions 
listed above are required for vasectomized males whose procedure was performed 
more than 120 days before study start. 
8. Is willing to answer inclusion and exclusion criteria questionnaire at check-in. 
9. Is able to comply with the protocol and the assessments therein, including all 
restrictions. 

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10. Is willing and able to remain in the study unit for the entire duration of the 
assigned confinement period(s), return for outpatient visit(s), and receive a phone 
call for follow-up questioning about AEs. 
5.2 
Exclusion Criteria 
Volunteers will be excluded from study participation for any of the following: 
1. History or presence of clinically significant cardiovascular, pulmonary, hepatic, 
renal, hematological, gastrointestinal, endocrine, immunologic, dermatologic, 
neurological (including epilepsy), oncologic, or psychiatric disease or any other 
condition that, in the opinion of the Investigator, would jeopardize the safety of 
the subject or the validity of the study results. 
2. Any abnormality on neurologic exam. 
3. History of any illness that, in the opinion of the Investigator, might confound the 
results of the study or pose an additional risk to the subject by their participation 
in the study. 
4. Surgery within the past 90 days prior to dosing as determined by the Investigator 
to be clinically relevant, or any history of cholecystectomy. 
5. History or presence of alcoholism or drug abuse within the past 2 years as 
determined by the Investigator to be clinically relevant. 
6. History of sensitivity or contraindication to use of linezolid, tedizolid, or any 
study investigational products. 
7. Participation in another clinical trial within 30 days prior to dosing. 
8. Female subjects who are pregnant or lactating.  
9. Positive result on a urine drug/alcohol/cotinine screen at Baseline or check-in. 
10. Seated blood pressure is less than 90/40 mmHg or greater than 140/90 mmHg at 
screening. Out-of-range vital signs may be repeated once for confirmation. 
11. Seated heart rate is lower than 40 bpm or higher than 99 bpm at screening. 
Out-of-range vital signs may be repeated once for confirmation. 
12. Any clinically significant ECG abnormality at Screening (as deemed by decision 
of the Investigator and the Sponsor’s Medical Monitor). 
NOTE: The following may be considered not clinically significant without 
consulting the Sponsor’s Medical Monitor: 
• Mild first-degree A-V block (P-R interval <0.23 sec) 
• Right or left axis deviation 

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• Incomplete right bundle branch block 
• Isolated left anterior fascicular block (left anterior hemiblock) in younger 
athletic subjects 
• Early repolarization 
• Tall T waves 
• RSR in V1/V2 consistent with right ventricular conduction delay (with 
acceptable QRS) 
• Sinus rhythm or sinus bradycardia with sinus arrhythmia 
• Minimal or moderate voltage criteria for left ventricular hypertrophy 
(LVH). 
13. QTcF interval >450 msec for males or >470 msec for females at screening, 
Day -1, or Day 1 (predose), or history of prolonged QT syndrome. For the 
triplicate ECGs taken at screening and on Day -1, the average QTcF interval of 
the three ECG recordings will be used to determine qualification. 
14. Family history of long-QT syndrome or sudden death without a preceding 
diagnosis of a condition that could be causative of sudden death (such as known 
coronary artery disease, congestive heart failure, or terminal cancer). 
15. History of any of the following: 
• Serotonin syndrome 
• Seizures or seizure disorders, other than childhood febrile seizures  
• Brain surgery 
• History of head injury in the last 5 years 
• Any serious disorder of the nervous system particularly one that may lower 
the seizure threshold.  
16. Lactose intolerant. 
Specific Treatments 
17. Use of any prescription medication within 14 days prior to dosing. 
18. Use of any of the following medications within 30 days before the first dose of 
study drug or during the study drug treatment period: monoamine oxidase (MAO) 
inhibitors (phenelzine, tranylcypromine), tricyclic antidepressants (amitriptyline, 
nortriptyline, protriptyline, doxepin, amoxapine, etc.), antipsychotics such as 
chlorpromazine and buspirone, serotonin re-uptake inhibitors (fluoxetine, 
paroxetine, sertraline, etc.), bupropion, agents known to prolong the QTc interval 

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(erythromycin, clarithromycin, astemizole, type Ia [quinidine, procainamide, 
disopyramide] and III [amiodarone, sotalol] anti-arrhythmics, carbamazepine, 
sulfonylureas, and meperidine).  
19. Use of any over-the-counter (OTC) medication, including herbal products and 
vitamins, within 7 days prior to dosing, except acetaminophen. Up to 3 grams per 
day of acetaminophen is allowed at the discretion of the Investigator prior to 
dosing. 
20. Use of any drugs or substances known to be significant inhibitors of cytochrome 
P450 (CYP) enzymes and/or significant inhibitors or substrates of P-glycoprotein 
(P-gp) and/or organic anion transporting polypeptides (OATP) within 14 days 
prior to the first dose of study drug. 
21. Use of any drugs or substances known to be inducers of CYP enzymes and/or 
Pgp, including St. John’s Wort, within 30 days prior to the first dose of study 
drug. 
22. Use of any drugs or substance known to lower the seizure threshold. 
Specific Laboratory Abnormalities 
23. Serum magnesium, potassium, or calcium laboratory values outside of the normal 
range at screening. If exclusionary lab criteria are met, values may be confirmed 
by repeat evaluation. 
24. Positive results at screening for human immunodeficiency virus (HIV), hepatitis 
B surface antigen (HBsAg), or hepatitis C antibodies (HCV). 
25. ALT or AST greater than ULN. 
5.3 
Medication and Activity Restrictions 
1. Subject must not donate blood from 56 days or plasma from 7 days prior to the 
first dose of study medication until after the follow-up phone call. It is 
recommended that blood/plasma donations not be made for at least 30 days after 
discharge from the clinic. 
2. Subject must not use tobacco- or nicotine-containing products (including smoking 
cessation products) from 6 months prior to the first dose of study medication until 
after the follow-up phone call. 
3. Subjects must not consume alcohol from 72 hours prior to the first dose of study 
medication until after the follow-up phone call. 
4. Subject must not consume beverages or foods that contain grapefruit or Mandarin 
oranges from 10 days before the first dose of study medication, or poppy seeds, 
broccoli, Brussels sprouts, pomegranate, star fruit, char grilled meat, or 
caffeine/xanthine from 48 hours before the first dose of study medication, until 

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after discharge from the clinic. Subjects will be instructed not to consume any of 
the above products; however, allowance for an isolated single incidental 
consumption may be evaluated and approved by the study Investigator based on 
the potential for interaction with the study drug. 
5. Subject should avoid large quantities of foods or beverages with high tyramine 
content 48 hours prior to the first dose of study medication until discharge from 
the clinic. Quantities of tyramine consumed should be less than 100 mg per meal. 
Foods high in tyramine content include those that may have undergone protein 
changes by aging, fermentation, pickling, or smoking to improve flavor, such as 
aged cheeses (0 to 15 mg tyramine per ounce); fermented or air-dried meats (0.1 
to 8 mg tyramine per ounce); sauerkraut (8 mg tyramine per 8 ounces); and soy 
sauce (5 mg tyramine per 1 teaspoon). The tyramine content of any protein rich 
food may be increased if stored for long periods or improperly refrigerated. 
6. Subject must not engage in strenuous exercise from 48 hours prior to the first dose 
of study medication until after discharge from the clinic. 
7. Subject must be willing to remove any artificial nails (e.g., acrylic, gel) or 
fingernail polish and not use such products for the duration of the study. 
8. Subject must not take any adrenergic/serotonergic agonists, such as 
pseudoephedrine and phenylpropanolamine (frequently found in cold and cough 
remedies), within 7 days before the first dose of study drug or during the study 
drug treatment period. 
5.4 
Screening 
The informed consent documents will be discussed with each potential participant, and 
each individual will sign an informed consent document for the study prior to any 
study-specific procedures being performed. 
Each potential study participant will have the following assessments by the Investigator 
or designee within 28 days prior to study start: 
• Demographic data, including sex, age, race, ethnicity, body weight (kg), height 
(cm), BMI (kg/m2), and smoking habits.  
• Medical history 
• Serology tests for HIV, hepatitis B and C 
• Clinical laboratory tests (hematology, chemistry, and urinalysis) 
• Coagulation test 
• Serum pregnancy (all female subjects) 
• FSH test (female subjects claiming post-menopausal status)  
• Urine test for drugs of abuse, alcohol, and cotinine  

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• Physical and neurological examinations 
• Triplicate 12-lead safety ECGs 
• Vital signs (blood pressure, pulse rate, respiration rate, temperature, and pulse 
oximetry) 
• Concomitant medication review 
Only medically healthy subjects with clinically acceptable laboratory profiles and ECGs 
within the defined parameters who fulfill all other inclusion criteria and meet none of 
the exclusion criteria outlined in the previous sections will be enrolled in the study. 
Subjects will be assigned numbers in an ascending order, based on successful 
completion of the screening process. 
6 
STUDY PROCEDURES 
6.1 
Subject Assignment 
Thirty-six (36) subjects are planned to be enrolled in the study, 12 subjects per cohort. 
Additional subjects may be enrolled if deemed appropriate by the Sponsor to repeat a 
dose level or to study another dose level. The number of subjects for each cohort is 
expected to provide sufficient safety and tolerability data to evaluate whether escalation 
to the next dose level is warranted. This study has not been formally powered. 
Each subject will receive an assigned treatment (active or placebo) based on the 
randomization schedule prepared by the unblinded statistician. The unblinded pharmacy 
staff will ensure compliance with the randomization schedule. 
6.2 
Blinding 
All subjects and clinical staff (except for the unblinded pharmacy staff) will be blinded 
to treatment. An unblinded pharmacy staff will be required at the Clinical Site to 
comply with the study’s randomization and blinding requirements. At the Clinical Site, 
prior to study initiation, the Principal Investigator will be responsible for designating a 
qualified pharmacy staff to serve as the unblinded pharmacy staff in the study. 
Unblinded pharmacy staff may dose subjects but may not participate in any subject 
assessments.  
Throughout the study, the designated unblinded pharmacy staff will be responsible for 
all drug accountability issues, including preparing, labeling, dispensing, and dosing 
study drug according to the randomization code provided, yet remain independent of all 
subject assessments. The pharmacy staff will follow the Standard Operating Procedures 
and Work Instructions related to pharmacy services and protocol-specific requirements. 
Randomization codes will be provided to the unblinded pharmacy staff. Confirmation of 
receipt of the randomization code will be required by the Sponsor. The unblinded 

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pharmacy staff will be responsible for maintaining the blind, consistent with protocol 
design, throughout the study. All documentation is to be filed in the Pharmacy Manual. 
Access to this manual by study personnel will be restricted to the unblinded pharmacy 
staff.  
The subjects, Principal Investigator, and all other study personnel involved with subject 
assessments will remain blinded to the actual treatment assignments of the subjects. The 
Principal Investigator will be ultimately responsible for ensuring that the integrity of the 
blind is maintained throughout the study, and will be required to notify the Sponsor in 
the event of any breaking of the blind for any reason.  
6.2.1 
Clinical Research Staff 
All observers who evaluate any reported adverse event, laboratory abnormalities, ECGs, 
and changes in the ECGs will be blinded as to what treatment sequence each subject is 
assigned. 
6.2.2 
Study Subjects 
All subjects will be blinded as to which treatment they are receiving at any dose. 
6.2.3 
Bioanalytical Laboratory  
All samples will be sent to the bioanalytical laboratory for analysis. The bioanalytical 
laboratory will be unblinded and only run the analysis on active treatment subjects. 
6.2.4 
Pharmacokinetic Analysis 
Pharmacokinetic analysis will be completed only on the active treatment subjects and 
will be blinded by subject for interim assessments. 
6.2.5 
Unblinding Procedures 
As data from each cohort is informative for dose escalation decisions in subsequent 
cohorts, review of unblinded data will be conducted after completion of each cohort by 
2 experienced individuals not directly involved in the study, one of whom must be a 
physician. Per protocol, the dose escalation meeting and decision require PK data 
through the morning of Day 15 and approximately 21 days of safety data, depending on 
the turnaround time of the bioanalysis. Upon completion of the review, they will 
communicate to the study team modifications, if any, that should be implemented for 
subsequent cohorts. 
The treatment assignment should be unblinded at the clinic only in the case of an 
emergency, when knowledge of the study drug assignment is absolutely necessary for 
the clinical management or welfare of the subject. Breaking of the blind at the clinic 
under any other circumstances will be considered a protocol violation.  
The Investigator is strongly encouraged to contact the Sponsor before unblinding the 
study drug assignment prior to the scheduled assessment of tolerance and safety data. If 
the blind is broken for any reason, the Investigator must notify the Sponsor within 

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1 day, and an SAE form must be completed, if appropriate. In addition, the Investigator 
will record the date and reason for revealing the blinded study drug assignment for that 
subject in the source documents and appropriate CRF page(s). 
6.3 
Check-In Procedures 
Subjects will check into the clinic on Day -2.  
At check-in, all subjects will be evaluated to confirm they continue to meet all the 
inclusion criteria (Section 5.1) and none of the exclusion criteria (Section 5.2). Subjects 
will undergo the following assessments during the confinement period prior to dosing: 
• 
Physical and neurological examinations 
• 
Vital signs (temperature, respirations, blood pressure, pulse, and pulse oximetry) 
• 
Triplicate 12-lead ECG 
• 
Urine drug, alcohol, and cotinine screens – results must be negative for the 
subject to continue study participation 
• 
Serum pregnancy test (all female subjects) – results must be negative for the 
subject to continue study participation 
• 
Concomitant medication review 
• 
AE review 
6.4 
Confinement 
Subjects will be admitted to the research center on Day -2. 
Subjects in the food-effect cohorts will remain confined until after completion of the 
Day 20 procedures and will return for follow-up outpatient visits on Days 21-26. 
Subjects will receive a follow up phone call on Day 33 (+1 day). 
Subjects in the non-food-effect cohort will remain confined until after completion of the 
Day 17 procedures and will return for follow-up outpatient visits on Days 18-23. 
Subjects will receive a follow up phone call on Day 30 (+1 day). 
6.5 
Fasting/Meals/Beverages 
6.5.1 
Fasting/Meals  
An optional meal may be served the evening of check-in.  
All subjects in the food-effect cohorts will be required to fast for at least 10 hours 
before the first dose on Day 1. The subjects will fast for 4 hours thereafter.  
For Days 4-17 in the food-effect cohorts and Days 1-14 for the non-food-effect cohort, 
all subjects will then be required to fast for at least 10 hours before consuming a 
required FDA standard high-fat, high-calorie breakfast. Subjects will receive the 
required FDA standard high-fat, high-calorie breakfast to begin 30 minutes before 

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scheduled administration of the dose and to end (last bite taken) within 5 minutes before 
dosing. The subjects will fast for 4 hours thereafter. An FDA standard high-fat 
(approximately 50% of total caloric content of the meal), high-calorie (approximately 
1000 calories) breakfast consists of: 
2 eggs fried in butter 
2 strips of bacon 
2 slices of toast with butter 
4 ounces of hash brown potatoes 
8 ounces of whole milk 
This meal contains approximately 150 protein calories, 250 carbohydrate calories, and 
500-600 fat calories. An equivalent meal may be substituted with documentation of the 
menu and caloric contents. 
Standard meals will be provided at approximately 4 and 10 hours after drug 
administration and at appropriate times thereafter.  
6.5.2 
Beverages 
Except for 200 mL of the room temperature water provided with the study treatment, 
no water may be consumed for 1 hour prior to each dose through 1 hour after each 
dose.  
At other times, subjects will be encouraged to drink water ad libitum. 
6.6 
Drug Administration 
6.6.1 
Administration of TBI-223 Sustained Release and Immediate Release Tablets or 
Placebo Tablets for TBI-223  
Each subject will receive the oral dose of the assigned study treatment with 
approximately 200 mL of room temperature water. Subjects must swallow the study 
medication intact. The medication should NOT be crushed or chewed. A hand and 
mouth check will be performed immediately after dose to ensure that the medication has 
been appropriately swallowed. 
The subjects will remain seated, except as otherwise required for study procedures or 
personal needs, for the first 4 hours after dosing. Should the need to move about occur 
during the first 4 hours after each dose, subjects may be escorted to such procedures or 
activities by research personnel as deemed medically necessary. Subjects will not be 
allowed to lie down, except as directed by clinical staff secondary to AEs, for the first 
4 hours after dosing. 
6.7 
Blood Sampling, Processing and Shipment 
Blood samples will be collected as detailed in Appendix 1. 

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Refer to the Schedule of Events for specific blood collection time points. The Principal 
Investigator, in conjunction with the Sponsor, may collect additional blood if necessary 
for repeat laboratory or safety evaluations including AE follow-up. 
After Day -1, blood for clinical labs and coagulation testing should be collected 
6-7 hours postdose. 
For the food-effect cohorts, a total of 60 mL (15 x 4 mL samples) will be collected 
from each subject for plasma predose trough pharmacokinetic analysis. A total of 
204 mL (51 x 4 mL samples) will be collected from each subject for plasma postdose 
pharmacokinetic analysis. Approximately 144.2 mL of blood will be collected for the 
clinical laboratory evaluations. The total volume of blood collected from each subject 
will not exceed approximately 408.2 mL.  
Table 6 
Total Volume of Blood to be Collected for Testing, Food-Effect Cohorts 
Reason for Collection 
Number of 
Samples 
Volume per 
Sample (mL) 
Total Volume (mL) 
Clinical labs at screening 
1 
12.5 
12.5 
Clinical labs during study (Days -1, 1, 2, 3, 4, 
5, 6, 10, 14, 17, 20 and 26/end-of-study) 
12 
8.5 
102 
Coagulation (screening and Days -1, 1, 3, 4, 
6, 10, 14, 17, 20, and 26) 
11 
2.7 
29.7 
Pharmacokinetic analysis (predose, trough) 
15 
4.0 
60.0 
Pharmacokinetic analysis (postdose) 
51 
4.0 
204.0 
Total 
408.2 
For the non-food-effect cohort, a total of 56 mL (14 x 4 mL samples) will be collected 
from each subject for plasma predose trough pharmacokinetic analysis. A total of 
208 mL (52 x 4 mL samples) will be collected from each subject for plasma postdose 
pharmacokinetic analysis. Approximately 90.9 mL of blood will be collected for the 
clinical laboratory evaluations. The total volume of blood collected from each subject 
will not exceed approximately 274.9 mL.  

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Table 7 
Total Volume of Blood to be Collected for Testing, Non-Food-Effect Cohort 
Reason for Collection 
Number of 
Samples 
Volume per 
Sample (mL) 
Total Volume (mL) 
Clinical labs at screening 
1 
12.5 
12.5 
Clinical labs during study (Days -1, 1, 3, 6, 
10, 14, and 23/end-of-study) 
7 
8.5 
59.5 
Coagulation (screening and Days -1, 1, 6, 10, 
14, and 23) 
7 
2.7 
18.9 
Pharmacokinetic analysis (predose, trough) 
14 
4.0 
56.0 
Pharmacokinetic analysis (postdose) 
32 
4.0 
128 
Total 
274.9 
The Principal Investigator, in conjunction with the Sponsor, may collect additional 
blood if necessary for repeat laboratory or safety evaluations including AE follow-up. 
6.7.1 
Pharmacokinetic Sampling Time Windows 
Blood samples collected within the time windows listed below will not be considered 
deviations. Note: The 24-hour sample of Day 1 must be collected prior to the Day 2 
dose. 
Table 8 
Acceptable Pharmacokinetic Sampling Time Windows, Food-Effect Cohorts 
Investigation and examination 
Allowable Time Window 
Postdose 
≤24 hours 
˃24 hours to 
≤Day 20 
>Day 20
Plasma sample collection for pharmacokinetic assessment 
± 2 minutesa 
± 5 minutes 
± 10 minutes 
a: The 24-hour sample of Day 1 must be collected prior to the Day 2 dose; the 2-minute window does not apply. 

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Table 9 
Acceptable Pharmacokinetic Sampling Time Windows, Non-Food-Effect Cohort 
Investigation and examination 
Allowable Time Window 
Postdose 
≤24 hours 
˃24 hours to 
≤Day 17 
>Day 17
Plasma sample collection for pharmacokinetic assessment 
± 2 minutesa 
± 5 minutes 
± 10 minutes 
a: The 24-hour sample of Day 1 must be collected prior to the Day 2 dose; the 2-minute window does not apply. 
6.8 
End-of-Study Procedures 
On the day of study discharge (Day 23 for non-food-effect cohort and Day 26 for the 
food-effect cohorts), the following procedures will be conducted: 
•
Physical and neurological examinations
•
Vital signs measurements (blood pressure, pulse, temperature, respirations, and pulse
oximetry)
•
Clinical laboratory tests (hematology, chemistry, urinalysis)
•
Coagulation
•
Triplicate 12-lead ECG
•
Concomitant medication review
•
AE assessment
Subjects will receive a follow up phone call on Day 30 (non-food-effect cohort) or Day
33 (food-effect cohorts) (+1 day).
6.9 
Safety Monitoring and Procedures 
6.9.1 
Adverse Events 
Subjects will be instructed to inform the study physician and/or research personnel of 
any AEs that occur at any time during the study. Subjects will be monitored for AEs 
from the first dose through the end-of-study visit.  
Refer to Section 7 for details regarding AE reporting. 
6.9.2 
Clinical Laboratory Evaluations 
Clinical laboratory evaluations will be performed at the times noted on the events 
schedule (Table 6 for food-effect cohorts and Table 7 for non-food-effect cohort). A 
Clinical Laboratory Improvement Amendments (CLIA) certified laboratory will 
perform all clinical laboratory tests for this study. If exclusionary lab criteria are met, 
values may be confirmed by repeat evaluation. 

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•
Hematology: hemoglobin, hematocrit, total and differential leukocyte count, red
blood cell count (RBC), and platelet count.
•
Serum Chemistry: albumin, blood urea nitrogen (BUN), creatinine, total bilirubin,
alkaline phosphatase (ALP), aspartate transaminase (AST), alanine transaminase
(ALT), sodium (Na+), potassium (K+), chloride (Cl-), lactate dehydrogenase
(LDH), calcium (Ca), uric acid, glucose, gamma-glutamyltransferase (GGT), and
magnesium.
•
Serology: hepatitis B surface antigen, hepatitis C antibody, and HIV.
•
Coagulation: prothrombin time (PT), partial thromboplastin time (PTT), and
international normalized ratio (INR).
•
Urinalysis - The following will be evaluated by an automated or manual urine
“dipstick” method: pH, specific gravity, protein, glucose, ketones, bilirubin, blood,
nitrite, leukocyte esterase, and urobilinogen. If protein, occult blood, nitrite, or
leukocyte esterase values are out of range, a microscopic examination will be
performed.
•
Urine Drug, Cotinine, and Alcohol Screens: drugs of abuse (amphetamines,
benzodiazepines, barbiturates, cannabinoids, cocaine, opiates), alcohol, and
cotinine.
•
Pregnancy test (all female subjects).
•
Follicle-stimulating hormone (female subjects claiming post-menopausal status).
6.9.3 
Vital Signs 
Vital signs (blood pressure, pulse rate, and respiration rate, pulse oximetry, and 
temperature) will be measured performed at the times noted on the events schedule 
(Table 6 for food-effect cohorts and Table 7 for non-food-effect cohort). 
NOTE: Blood pressure and pulse rate will be captured simultaneously. Blood pressure 
and pulse rate should be measured after subjects are in a seated position for 2 minutes 
and then again after standing for 1 minute, except when they are supine or semi-reclined 
because of study procedures and/or adverse events, or as deemed necessary by the 
Investigator. 
For purposes of qualifying any given subject for study participation, out-of-range vital 
signs may be repeated once.  
Predose vital signs will be assessed by the Principal Investigator or designee (e.g., a 
medically qualified Sub-Investigator) prior to each study drug administration. The 
Principal Investigator or designee will verify the eligibility of each subject with 
out-of-range vital signs and document approval prior to dosing. 

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Additional vital signs measurements may be performed as deemed medically necessary 
by research personnel.   
6.9.4 
Physical Examinations 
Physical examinations, including height and weight measurements, will be conducted 
at the times noted on the events schedule (Table 6 for food-effect cohorts and Table 7 
for non-food-effect cohort). 
6.9.5 
Neurological Examinations 
Detailed neurological examinations will be conducted at the times noted on the events 
schedule (Table 6 for food-effect cohorts and Table 7 for non-food-effect cohort) and at 
unscheduled time points as deemed necessary by the Investigator. Each neurological 
exam will assess the following: 
•
Mental Status – orientation, speech, and memory
•
Cranial Nerves – excluding fundoscopic examination
•
Muscle tone and strength
•
Sensory System – brief survey for light touch and temperature of the face, neck,
arms, trunk, and legs
•
Reflexes –deep tendon reflexes and plantar responses (Babinski sign)
•
Coordination – upper and lower extremities, including tremor
• Gait – tandem gait
6.9.6 
12-Lead Electrocardiograms 
Safety 12-lead ECGs will be recorded and printed for on-site review by the Principal 
Investigator or designee at the times noted on the events schedule (Table 6 for food-
effect cohorts and Table 7 for non-food-effect cohort).  
The predose ECG should be completed within 20 minutes prior to the predose blood 
draw. 
All safety ECGs will be performed after the subject has been in supine position for a 
minimum of 5 minutes.   
If a subject experiences a post-dosing QTcF >500 msec or a change-from-baseline 
QTcF ≥60 msec, after repeat testing, additional ECGs should be recorded until 
normalization or return to baseline. 
6.9.7 
Other Safety Measures 
Medical emergency personnel trained in advanced cardiac life support will be on site to 
monitor subjects during the confinement period in the research center. Emergency 

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medical equipment including but not limited to intubation equipment and pulse 
oximetry shall be maintained on site to administer appropriate medical care should it be 
required.  
Procedures will be completed as specified in this protocol unless contraindicated due to 
a reported AE. 
7 
ADVERSE EVENTS 
The Investigator or a suitably medically qualified designee are responsible for eliciting 
adverse events by observing and questioning the subject and recording all adverse 
events observed by him/her or reported by the subject during the trial. 
7.1 
Definitions 
7.1.1 
Adverse Event 
Any untoward medical occurrence in a clinical investigation participant, temporally 
associated with the use of a trial treatment whether or not considered related to trial 
treatment. An adverse event can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of a trial treatment, whether or not related to the trial 
treatment. 
7.1.2 
Serious Adverse Event  
Any untoward medical occurrence that at any dose: 
• Results in death; 
• Is life threatening (any event in which the participant was at risk of death at the time 
of the event; it does not refer to an event, which hypothetically might have caused 
death if it were more severe); 
• Requires inpatient hospitalization or prolongation of existing hospitalization; In 
general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the 
physician’s office or outpatient setting. Complications that occur during 
hospitalization are AEs. If a complication prolongs hospitalization or fulfills any 
other serious criteria, the event is serious. When in doubt as to whether 
“hospitalization” occurred or was necessary, the AE should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE; 
• Results in persistent or significant disability/incapacity; the term disability means a 
substantial disruption of a person’s ability to conduct normal life functions. This 

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definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g., sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption; 
• Is a congenital anomaly/birth defect; or 
• Is a medically important event. 
Note:  Medical and scientific judgment should be exercised in deciding which is a 
medically important event that may not be immediately life-threatening or result in 
death or hospitalization, but may jeopardize the participant or may require medical or 
surgical intervention to prevent one of the outcomes listed above. Examples of such 
events are intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization, or 
the development of drug dependency or drug abuse.  A “suspected transmission of 
infectious agent by a medicinal product” is also considered a serious adverse event 
under the SAE criterion “Other medically important condition”.  
7.2 
Attribution/Causality 
An adverse reaction, the nature or severity of which is not consistent with the 
applicable product information (e.g., Investigator’s Brochure for an unapproved 
investigational product). 
• The investigator is obligated to assess the relationship between trial treatment and 
each occurrence of each AE/SAE. 
• The investigator will use clinical judgment to determine the relationship. 
• Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to trial treatment 
administration will be considered and investigated. 
• The investigator will also consult the Investigator’s Brochure and/or Product 
Information, for marketed products, in his/her assessment. 
• For each AE/SAE, the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality. 
• There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to the Sponsor/designee. 
However, it is very important that the investigator always make an assessment of 
causality for every event before the initial transmission of the SAE data to the 
Sponsor/designee. 

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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. 
Table 10 Adverse Event Attribution/Causality Ratings 
Relatedness Rating 
Definition 
Not Related 
An adverse event, which is not related to the use of the drug. 
Unlikely 
An adverse event for which an alternative explanation is more likely, e.g., 
concomitant drug(s) or concomitant disease(s), and/or the relationship in time 
suggests that a causal relationship is unlikely. 
Possible 
An adverse event, which might be due to the use of the drug.  An alternative 
explanation, e.g., concomitant drug(s) or concomitant disease(s), is inconclusive.  
The relationship in time is reasonable; therefore, the causal relationship cannot be 
excluded. 
Probable 
An adverse event, which might be due to the use of the drug.  The relationship in 
time is suggestive, e.g., confirmed by dechallenge.  An alternative explanation is 
less likely, e.g., concomitant drug(s) or concomitant disease(s). 
Certain 
An adverse event, which is listed as a possible adverse reaction and cannot be 
reasonably explained by an alternative explanation, e.g., concomitant drug(s) or 
concomitant disease(s).   
 
Table 11 Definitions for Adverse Event Severity Gradings 
Grade 
Severity Rating 
Definition 
GRADE 1 
Mild 
Transient or mild discomfort (< 48 hours); no medical 
intervention/therapy required. 
GRADE 2 
Moderate 
Mild to moderate limitation in activity - some assistance may be 
needed; no or minimal medical intervention/therapy required. 
GRADE 3 
Severe 
Marked limitation in activity, some assistance usually required; 
medical intervention/therapy required, hospitalizations possible. 
GRADE 4 
Potentially Life-
Threatening 
Extreme limitation in activity, significant assistance required; 
significant medical intervention/therapy required, hospitalization or 
hospice care probable. 
See Appendix 3 for full DMID Toxicity Tables. The above ratings should be used to 
estimate the grade for abnormalities NOT found elsewhere in the Toxicity Tables. Lab 
results within the testing facility’s normal range will not be considered AEs when 
referenced to the DMID assessment/grading scale (Appendix 3). 
Laboratory abnormalities and cardiovascular findings of hypertension or hypotension 
Grade 2 or above on the DMID toxicity tables will be considered AEs. 

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7.3 
Reporting 
7.3.1 
Adverse Event 
Adverse Events will be collected by the Investigator or qualified designee(s) from the 
time a subject signs the Informed Consent Form through the follow-up phone calls 
(Day 14 for the Single Ascending Dose Cohort and Day 28 for the Multiple Ascending 
Dose Cohorts). 
Any AE (serious or non-serious) observed by the Investigator (or a suitably medically 
qualified designee) or reported by the subject will be recorded on the Adverse Event 
Case Report Form. The Investigator will review each AE and assess its relationship to 
drug treatment based on all available information at the time of the completion of the 
CRF. The following information will be recorded for each Adverse Event reported: 
• Diagnosis of the AE, if possible. In the case where an overall diagnosis cannot be 
made, each specific sign and/or symptom will be recorded as individual AEs; 
• Date of onset; 
• Stop date (with duration, if applicable); 
• Severity;   
• Action taken with IMP; 
• Other action taken; 
• Outcome; 
• Relationship to IMP; 
• Occurrence; 
• Seriousness 
7.4 
Serious Adverse Event Reporting 
The Investigator or designee will notify the appropriate Sponsor contact immediately 
after the SAE detection, observation, or report of occurrence (regardless of the 
relationship to test article). The Sponsor contact information for SAE reporting is 
provided below: 
TB Alliance Pharmacovigilance 
Email: AE_inbox@tballiance.org 
Questions relative to SAE processing may also be sent to the above mentioned email 
address. If there is ever any email failure upon trying to report an SAE, please call Dr. 
Bruinenberg at +1.201.312.0988 and he will notify the safety team at TB Alliance. 
Medical questions relative to AEs and SAEs can be directed to: 

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Paul Bruinenberg MD, MBA 
Global Alliance for TB Drug Development 
40 Wall Street, 24th Floor 
New York, NY  10005, United States of America 
Telephone: +1 646.616.8629 
Mobile: +1 201.312.0988 
Facsimile: +1 212.227.7541 
Email: Paul.Bruinenberg@tballiance.org 
These SAE reports must contain the following information: 
A. Study name/number (for EU also the Eudract number) 
B. Study drug 
C. Investigator details (name, phone, fax, e-mail) 
D. Subject number 
E. Subject demographics 
F. Clinical event: 
1) Description 
2) Date of onset 
3) Treatment (drug, dose, dosage form) 
4) Adverse event relationship to study drug 
5) Action taken regarding study drug in direct relationship to the AE 
G. If the AE was fatal or life-threatening 
H. If applicable, cause of death (whether or not the death was related to study drug) 
I. If applicable, autopsy findings (if available) 
Any new SAE that occurs within one month after the study period and is considered to 
be possibly related to the Investigational Product (IP) should be recorded and reported 
immediately to the Sponsor.  
The person responsible for the study shall take care that the study has been carried out 
in accordance with pharmacovigilance local regulations. 
All serious event reporting will adhere to U.S. Code of Federal Regulations 
(21 CFR Part 312.32) for IND drugs and 21 CFR 314.80 for marketed drugs (15-day 
alerts). The Institutional Review Board (IRB) will be notified of the alert reports per 
Food and Drug Administration (FDA) regulations. 
All AEs, including SAEs, will be followed to resolution when possible. All AEs and 
treatment administered will be recorded on the case report form (CRF). 

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The Sponsor will be responsible for processing and reporting any SAEs (and their 
relevant updates) to the FDA or other applicable regulatory agency. 
7.5 
Follow up of Adverse Events 
All AEs will be followed until: 
• Satisfactory clinical resolution or stabilization; or 
• End of the follow-up period; and  
• All queries on these AEs have been resolved.   
Certain long-term AEs cannot be followed until resolution within the setting of this 
protocol. In these cases, follow-up will be the responsibility of the treating physician. 
However, this will have to be agreed upon with the Sponsor Medical Monitor. 
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor or 
representative to elucidate the nature and/or causality of the AE or SAE as fully as 
possible. This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other health care professionals.  
Investigator should contact sponsor/designee to discuss appropriate medical follow-up 
if consultation required.  
If a participant dies during participation in the trial or during a recognized follow-up 
period, the investigator will provide sponsor/representative with a copy of any post-
mortem findings including histopathology. 
New or updated information on an SAE will be recorded in the originally completed 
CRF and submitted to sponsor within 24 hours of the information becoming known per 
SAE reporting guidelines. 
7.6 
Post-Trial Serious Adverse Events 
Any new SAEs reported by the subject to the Investigator that occur up to 30 days after 
last contact, and are determined by the Principal Investigator to be possible, probable or 
very likely related to the use of the IMP, will be reported to the Sponsor, IRB and FDA 
on an expedited basis as required in accordance with local requirements and ICH 
guidelines for GCP. 
7.7 
Clinical Laboratory Adverse Events 
Changes in the results of the Clinical Laboratory assessment results which the 
Investigator feels are clinically significant will be reported as adverse events. It is the 
Investigators’ responsibility to review the results of all laboratory tests as they become 
available. This review must be documented by the Investigators’ dated signature on the 
laboratory report. For each abnormal laboratory test result, the Investigator needs to 

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15 Dec 2020 
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ascertain and document if this is a clinically significant change from baseline for that 
individual participant. This determination, however, does not necessarily need to be 
made the first time an abnormal value is observed. The Investigator may repeat the 
laboratory test or request additional tests to verify the results of the original laboratory 
tests.  If this laboratory value is determined by the Investigator to be a clinically 
significant change from baseline for that participant, it is considered to be an adverse 
event. 
7.8 
Drug Interaction 
If the Investigator becomes aware that the subject has experienced a drug interaction 
which has resulted in an adverse event, it will be recorded as an adverse event.  
7.9 
Pregnancy 
The Investigator will immediately notify the Sponsor of any pregnancy that is 
discovered during the clinical trial. Pregnancy forms will be completed for all 
pregnancies reported during the study or in the 30 days after completion of the IMP. In 
addition, the Investigator will report to the Sponsor follow up information regarding the 
outcome of the pregnancy, including perinatal and neonatal outcome.  Infants should be 
followed for 6 months.   
If pregnancy is suspected while the subject is receiving IMP, the IMP will be withheld 
immediately until the result of the pregnancy test is known.  If pregnancy is confirmed, 
the IMP will be permanently discontinued in an appropriate manner and the subject 
withdrawn from the trial. Protocol-required procedures for trial discontinuation and 
follow up will be performed unless contraindicated by the pregnancy. 
If the Investigator becomes aware the female partner of a male subject becomes 
pregnant during the study or in the 30 days after the completion of IMP, consent will be 
requested from the female partner for collection of information on her pregnancy 
history and for information on the current pregnancy and birth. 
7.10 
Monitoring and Safety for Specific Toxicities 
During preclinical testing, issues with increased heart rate and lowering of blood 
pressure were detected. Therefore, heart rate and blood pressure changes should be 
monitored carefully. When abnormalities are detected both blood pressure and pulse 
rate should be captured simultaneously 

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15 Dec 2020 
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8 
GENERAL CONSIDERATIONS 
8.1 
Basic Principles 
This research will be carried out in accordance with the protocol, the International 
Council for Harmonisation (ICH), Guideline for Good Clinical Practice: Consolidated 
Guidance (E6), and applicable regulatory requirements(s) including clinical research 
guidelines established by the Basic Principles defined in the U.S. 21 CFR Parts 50, 56, 
and 312 and the principles enunciated in the Declaration of Helsinki (revised version 
Fortaleza 2013). 
8.2 
Institutional Review Board 
This protocol will be reviewed by an appropriate IRB and study enrollment will not 
commence until the Board has approved the protocol or a modification thereof. The 
Board is constituted and operates in accordance with the principles and requirements 
described in 21 CFR Part 56. 
8.3 
Informed Consent 
Written informed consent will be obtained from each subject prior to performing any 
baseline study-specific evaluations. The informed consent document is prepared by the 
Investigator or designee, subject to review and approval by the Sponsor, and forwarded 
to a qualified IRB for final review and approval. The IRB-approved document must 
contain, at minimum, the eight basic elements of informed consent. Only the most 
recently IRB-approved Informed Consent Document must be used to consent 
prospective study subjects. One copy of the signed and dated informed consent 
document will be given to the subject and the original retained by the Investigator/site.  
8.4 
Indications for Subject Withdrawal 
Subjects will be free to withdraw at any time for any reason, or they may be withdrawn 
if necessary, to protect their health and safety or the integrity of the study data.  
The final report will include reasons for withdrawals. In the event of an early 
termination, subjects will undergo the procedures described in Section 6.8. 
Subjects who experience emesis may be replaced if the emesis could potentially impact 
drug absorption and therefore the pharmacokinetic data. Cases of emesis will be 
evaluated by the Sponsor and Principal Investigator to determine if subject replacement 
is needed. 

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8.5 
Termination of the Study 
The Principal Investigator reserves the right to terminate the study in the interest of 
subject safety and welfare. The Sponsor reserves the right to terminate the study at any 
time for administrative reasons. 
8.6 
Documentation 
All documents pertaining to the study, including a copy of the approved protocol, copy 
of the informed consent document and Health Insurance Portability and Accountability 
Act (HIPAA) documents, completed CRFs (where applicable), drug accountability and 
retention records, and other study related documents will be retained in the permanent 
archives of the study site. These will be available for inspection at any time by the 
Sponsor or the FDA. Per 21 CFR 312, record retention for this study is required for a 
period of two years following the date on which this study agent is approved by the 
FDA for the marketing purposes that were the subject of this investigation; or, if no 
application is to be filed or if the application is not approved for such indication, until 
two years following the date on which the entire study is completed, terminated, or 
discontinued, and the FDA is notified. 
Subject records will be kept private except when ordered by law. The following 
individuals will have access to study subject records: Principal Investigator and 
designees, study Sponsor, monitors, and auditors, the FDA, other government offices, 
and the IRB. 
8.7 
Trial Monitoring 
Sponsor personnel (or designees) will be responsible for monitoring the study to ensure 
compliance with the protocol and GCP. Compliance may be verified by one or more of 
the following methods: on-site visits, frequent communication with the Investigator, 
and/or review of CRFs and source documents. The Investigator agrees to permit such 
monitoring as well as audits or reviews by regulatory authorities and the IRB. 
8.8 
Reimbursement, Indemnity, and Insurance 
Reimbursement, indemnity, and insurance shall be addressed in a separate agreement 
on terms agreed upon by the parties. 
9 
PHARMACOKINETIC ANALYSIS 
9.1 
Analytical Methodology  
Plasma samples will be analyzed for TBI-223 and M2 using validated assays. Plasma 
samples from subjects who receive placebo for TBI-223 will not be analyzed. 

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9.2 
Pharmacokinetic Analysis 
Pharmacokinetic calculations will be performed using appropriate software, e.g. 
Phoenix™ WinNonlin® (Version 8.1 or higher, Pharsight Corporation) and/or SAS® 
(Version 9.4 or higher, SAS Institute Inc.). 
Pharmacokinetic parameters will be calculated using non-compartmental analysis. The 
following pharmacokinetic parameters will be determined as appropriate as detailed 
below. 
AUCExtrap 
(%) 
The percentage of AUCinf based on extrapolation 
AUCinf 
Area under the concentration-time curve from time-zero extrapolated to infinity; 
calculated as: 
z
last
last
C
AUC
AUC
λ
+
=
inf
 
AUClast 
Area under the concentration-time curve from time-zero to the time of the last 
quantifiable concentration; calculated using the linear trapezoidal rule 
AUCtau 
Area under the concentration-time curve during the dosing interval 
Cavg 
Average steady-state concentration 
Clast 
The last quantifiable concentration determined directly from individual 
concentration-time data 
CL/F 
Apparent total clearance after single administration 
CLs/F 
Apparent total clearance at steady state 
Cmin 
Minimum concentration 
Cmax 
Maximum concentration, determined directly from individual 
concentration-time data 
Ctrough 
Trough plasma concentration 
RAUC 
Accumulation ratio for AUC 
RCmax 
Accumulation ratio for Cmax 
Tlast 
Time of the last quantifiable concentration 
Tmax 
Time of the maximum concentration 
T1/2 
The observed terminal half-life, calculated as: 
z
T
λ
)
2
ln(
2
/
1
=
 

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15 Dec 2020 
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Vz/F 
Apparent volume of distribution in the terminal phase 
λz 
The observed terminal rate constant; estimated by linear regression through at 
least three data points in the terminal phase of the log concentration-time profile 
For the non-food-effect cohorts, PK parameters calculated from plasma concentration 
of TBI-223 and M2 following doses on Days 1 and 14 will include, as appropriate:  
• Day 1: AUCtau, Cmax, C24, Cavg, Tmax. Additionally, AUCinf, AUCextrap, CL/F, Vz/F, 
λz, and t1/2 should be included if AUCtau ≥ 70% of AUCinf. 
• Day 14: AUCtau, Cmax, Cmin, Ctrough (i.e., C0), C24, Cavg, Tmax, CL/F, Vz/F, λz, t1/2, 
RAUC, RCmax 
For the food-effect cohorts, PK parameters calculated from plasma concentration of 
TBI-223 and M2 following doses on Days 1, 4, and 17 will include, as appropriate: 
• 
Day 1: AUCtau, AUCextrap, AUCinf, Cmax, C24, Clast, Tmax, Tlast, CL/F, Vz/F, λz, t1/2. 
• 
Day 4: AUCtau, Cmax, C24, Cavg, Tmax. Additionally, AUCinf, AUCextrap, CL/F, Vz/F, 
λz, t1/2 should be included if AUCtau ≥ 70% of AUCinf.  
• 
Day 17: AUCtau, Cmax, Cmin, Ctrough (i.e., C0), C24, Cavg, Tmax, CL/F, Vz/F, λz, t1/2, 
RAUC, RCmax 
Each parameter will be estimated separately for each participant using plasma 
concentrations of TBI-223 and, as appropriate M2. 
Each day one blood sample will be taken immediately before dosing, to measure Ctrough 
level and to observe the time that steady state is achieved.   
Assessments of food effect will include geometric mean ratios of Cmax and AUCtau 
between Day 1 (fasted) and Day 4 (fed), as well as graphical displays of the profiles. 
Model-based approaches and comparisons with results from the single-dose study, TBI-
223-CL-001, may also be undertaken. 
Both individual-participant and group summary-statistics (n, mean, median, geometric 
mean, standard deviation, standard error of the mean, coefficient of variation, 
minimum, maximum) data will be reported. Summary statistics will be presented by 
gender.  All tests will be performed using a 2-sided α-level of 0.05, and appropriate 
confidence intervals will be provided. 
9.3 
Statistical Analysis 
Statistical analyses will be performed using appropriate software, e.g. Phoenix™ 
WinNonlin® (Version 8.1 or higher, Pharsight Corporation) and SAS® (Version 9.4 or 
higher, SAS Institute Inc.). 

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Pharmacokinetic parameters will be summarized by cohort using descriptive statistics. 
Summary statistics will also be presented by gender within each cohort. 
Dose proportionality will be assessed using a power model approach. 
10 
FACILITIES 
CLINICAL TRIAL SITE 
TKL Research, Inc. 
One Promenade Blvd. Suites 1101 & 1201  
Fair Lawn, New Jersey 07410 
Telephone: 201.587.0500 
CLINICAL LABORATORIES 
Quest Diagnostics 
One Malcolm Avenue 
Teterboro, New Jersey 07608 
Telephone: 888.604.5770  
Fax: 551.256.8833  
ANALYTICAL LABORATORY 
Alliance Pharma, Inc. 
Project Manager: Duxi Zhang 
Contact for Sample Shipment: Ruth Guan 
17 Lee Boulevard 
Malvern, PA 19355 
Phone: 610.296.3152 
Fax: 610.296.3153 
Email: dzang@alliancepharmaco.com; samples@alliancepharmaco.com 
Web: www.alliancepharmaco.com 
11 
DRUG SUPPLIES 
Global Alliance for TB Drug Development will supply sufficient a quantity of the study 
drug, TBI-223 SR1 tablets, TBI-223 IR tablets, and Placebo for TBI-223 IR and SR1 
tablets 600 mg. Study drug will be shipped to TKL Research, Inc. pursuant to site 
standard operating procedures. Upon receipt of the study drug products, the supplies 
will be inventoried and stored in an environmentally controlled and secure, limited 
access area. The lot numbers of the drugs along with the expiration dates (where 
available) will be recorded and copies of the Certificate of Analysis (where available) 
will be maintained on file. Records will be maintained of the receipt and dispensation 
of the drugs supplied. At the conclusion of the study, any unused study drug will be 

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15 Dec 2020 
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returned to the sponsor or destroyed by the site pursuant to written authorization by the 
sponsor and applicable federal and state regulations.  
12 
ADMINISTRATIVE ISSUES 
The Investigator is referred to the Investigator Brochure, or information provided 
during the study initiation visit, information provided by the study monitor, and ICH 
Guidelines for Good Clinical Practice for information regarding the study drug, details, 
or general considerations to be followed during the course of this study. 

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13 
EVENTS SCHEDULE  
Table 12 Schedule of Assessments (Cohorts 1 and 2) 
 
SCREEN CHECK-
INa 
Fasted dosing 
Day 1  
and washout 
Day 2-3 
TREATMENT 
(14 Days) 
Day 18-19 Follow-up 
CHECK 
OUT 
FOLLOW-UP 
EARLY 
WITHDRAWAL 
DAY 
-28 to -2 
-2 
-1 
1 
2 
3 
4 5-10 
11 
12-17 18-19 
20 
21-25 
26 
33 
(+1) 
 
EVENT 
 
Informed consent and 
medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Check-in questions 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height, weight 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV/ hepatitis B, C 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy 
testb 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FSHb 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine 
drug/alcohol/cotinine 
screen 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety Labs 
(hematology, 
chemistry)c 
X 
 
X 
X X X 
X Xc 
 
Xc 
 
X 
 
X 
 
X 
Coagulationd 
X 
 
X 
X  
X 
X Xd 
 
Xd 
 
X 
 
X 
 
X 
Urinalysise 
X 
 
X 
X  
X 
X Xe 
 
Xe 
 
X 
 
X 
 
 
Physical and 
neurological examsf 
X 
X 
X 
X X X 
X Xf 
 
Xf 
 
 
 
X 
 
X 
Vital signs (blood 
pressure, pulse, 
temperature, respiration 
rate, and pulse 
oximetry)g 
X 
X 
 
X X X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
Concomitant 
medication reviewh 
 
---------------------------------------------------------------X----------------------------------------------------------- 
Adverse eventsi 
 
---------------------------------------------------------------X----------------------------------------------------------- 

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15 Dec 2020 
Page 48 
 
SCREEN CHECK-
INa 
Fasted dosing 
Day 1  
and washout 
Day 2-3 
TREATMENT 
(14 Days) 
Day 18-19 Follow-up 
CHECK 
OUT 
FOLLOW-UP 
EARLY 
WITHDRAWAL 
DAY 
-28 to -2 
-2 
-1 
1 
2 
3 
4 5-10 
11 
12-17 18-19 
20 
21-25 
26 
33 
(+1) 
 
EVENT 
 
Dosej 
 
 
 
X  
 
X 
X 
X 
X 
 
 
 
 
 
 
12-lead safety ECGsk 
X 
X 
X 
X  
 
X 
X 
 
X 
X 
X 
 
X 
 
X 
Plasma for predose 
trough PKl, m 
 
 
 
X  
 
X 
X 
X 
X 
 
 
 
 
 
 
Plasma for Postdose 
PKn 
 
 
 
X X X 
X 
 
 
X 
X 
X 
 
 
 
 
ECG = electrocardiogram; FSH = follicle-stimulating hormone; HIV = human immunodeficiency virus; PK = pharmacokinetic. 
a. 
Confinement to start at Check-in (evening of Day -2) and continue until 72 hours after dosing on Day 17. 
b. 
Serum pregnancy test at screening and at check-in for females only. FSH completed for postmenopausal females only.  
c. 
Blood will be collected for safety labs (hematology and chemistry) at Screening and Day -1 and at 6-7 hours postdose on Days 1, 2, 3, 4, 6, 10, 14, 17, 
and on Days 20 and 26 
d. 
Blood for coagulation testing will be collected at Screening and Day -1, and 6-7 hours postdose on Days 1, 3, 4, 6, 10, 14, 17, and on Days 20 and 26. 
e. 
Urinalysis testing at Screening and Days -1, 1, 3, 4, 6, 10, 14, 17, and on Days 20 and 26. 
f. 
Neurological exam: Performed at Screening, Day -2 and Day -1 around 6-7 hours postdose and prior to blood collection for safety labs on Days 1, 4, 6, 
10, 14, 17, and on Day 26.   
g. 
Vital signs (blood pressure, heart rate [pulse], temperature, and respiration rate) should be measured at screening, check-in, and while subjects are in 
confinement. Vital sign measurements should be taken within 90 minutes prior to dosing and within 15 minutes of the remaining defined time points 
in flowchart at study hours 0, 1, 6, and 12 on Days 1 and 17. Furthermore, vital signs will be taken once daily on Days 1 through Day 20 (6 hours after 
dosing) and once daily on Days 18 through 26 and at early withdrawal (must be done within 15 minutes before review of medication and collection of 
adverse experiences). Both blood pressure and heart rate should be captured simultaneously. Blood pressure and heart rate should be measured after 
subjects are in a seated position for 2 minutes and again after standing for 1 minute, except when they are supine or semi-reclined because of study 
procedures and/or adverse events, or as deemed necessary by the Investigator.  
h. 
On Day 33 (+1 day), follow-up questioning on concomitant medications will be completed by a phone call.  
i. 
Subjects will be monitored for treatment-emergent adverse events to be monitored from the time of dosing and throughout the study via safety 
assessments, observation and participant reporting. Specific adverse event questions will be posed daily throughout the study until Day 26. The inquiry 
to collect adverse events using non-leading questions will be performed after all other procedures are conducted for the specified time points. On Day 
33 (±1 day), follow-up questioning on adverse events will be completed by a phone call.  
j. 
TBI-223 SR1 and IR tablets and placebo for TBI-223 will be administered orally followed by approximately 200 mL of water. Note: Dosing on Day 1 
will be fasted. Dosing on Days 4-17 to occur following a high-fat, high-calorie breakfast to begin 30 minutes prior to dose and to end (last bite taken) 
within 5 minutes prior to dosing   
k. 
12-lead safety ECGs will be printed and reviewed on-site by the Principal Investigator or designee. Triplicate ECGs will be completed at screening, 
Day -2, Day -1, and on Day 26 or upon early withdrawal. All other time points will be single ECG readings. ECGs may be done within 2 hours prior 

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to time of dosing and at 3, 6, 12 and 16 hours postdose on Days 1, 4, 8, 10, 12, 14, 17, and on Days 18 and 20.  Another single ECG reading will be 
performed on the morning of Day 20 before discharge. The predose ECG should be completed within 20 minutes prior to the predose blood draw. If a 
subject experiences a post-dosing QTcF >500 msec with a change-from-baseline QTcF >60 msec, after repeat testing, additional ECGs should be 
recorded until normalization or return to baseline  
l. 
Predose trough blood samples will be drawn on Day 1 and daily starting on Day 4.  
m. Duplicate plasma samples will be generated from all blood pharmacokinetic samples.  
n. 
Postdose blood plasma samples will be drawn at the following timepoints:  
• 
Day 1: 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 12, 16, 20, 24, 30, 36, 42, 48, 54, 60, and 72 hours. The 72-hour sample is the predose sample of Day 4. 
• 
Day 4: 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 12, 16, 20, and 24 hours. The 24-hour sample is the predose sample of Day 5. 
• 
Day 17:  0.5, 1, 2, 3, 4, 5, 6, 7, 8, 12, 16, 20, 24, 30, 36, 42, 48, 54, 60, and 72 hours  
 

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Table 13 Schedule of Assessments (Cohort 3) 
 
SCREEN 
CHECK-
INa 
 
TREATMENT 
CHECK 
OUT 
FOLLOW-UP 
EARLY 
WITHDRAWAL 
DAY 
-28 to -2 
-2 
-1 
1 
2 - 6 
7 
8-13 
14 
15-16 
17 
18-22 
23 
30 
(+1) 
 
EVENT 
 
 
Informed consent and 
medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Check-in questions 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Height, weight 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV/ hepatitis B, C 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy testb 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
FSHb 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine 
drug/alcohol/cotinine 
screen 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Safety Labs 
(hematology, chemistry)c 
X 
 
X 
X 
Xc 
 
Xc 
X 
 
 
 
X 
 
X 
Coagulationd 
X 
 
X 
X 
Xd 
 
Xd 
X 
 
 
 
X 
 
X 
Urinalysise 
X 
 
X 
X 
Xe 
 
Xe 
X 
 
 
 
X 
 
 
Physical and 
neurological examsf 
X 
X 
X 
X 
Xf 
 
Xf 
X 
 
 
 
X 
 
X 
Vital signs (blood 
pressure, pulse, 
temperature, respiration 
rate, and pulse oximetry)g 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Concomitant 
medication reviewh 
 
---------------------------------------------------------------X------------------------------------------------------ 
Adverse eventsi 
 
 
 
-------------------------------------------------X------------------------------------------------ 
Dosej 
 
 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
12-lead safety ECGsk 
X 
X 
X 
X 
X 
 
X 
 
 
X 
 
X 
 
X 
Plasma for predose 
trough PKl, m 
 
 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
Plasma for Postdose 
PKn 
 
 
 
X 
 
 
 
X 
X 
X 
 
 
 
 
ECG = electrocardiogram; FSH = follicle-stimulating hormone; HIV = human immunodeficiency virus; PK = pharmacokinetic. 

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a. 
Confinement to start at Check-in (evening of Day -2) and continue until 24 hours after dosing on Day 14. 
b. Serum pregnancy test at screening and at check-in for females only. FSH completed for postmenopausal females only.  
c. 
Blood will be collected for safety labs (hematology and chemistry) at Screening and Day -1 and at 6-7 hours postdose on Days 1, 3, 6, 
10, 14, and on Day 23. 
d. Blood for coagulation testing will be collected at Screening and Day -1, and 6-7 hours postdose on Days 1, 6, 10, 14, and on Day 23. 
e. 
Urinalysis testing at Screening and Days -1, 1, 6, 10, 14, and 23. 
f. 
Neurological exam: Performed at Screening, Day -2 and Day -1 and 6-7 hours postdose and prior to blood collection for safety labs on 
Days 1, 3, 6, 10, 14, and on Day 23.   
g. Vital signs (blood pressure, heart rate [pulse], temperature, and respiration rate) should be measured at screening, check-in, and while 
subjects are in confinement. Vital sign measurements should be taken within 90 minutes prior to dosing and within 15 minutes of the 
remaining defined time points in flowchart at study hours 0, 1, 6, and 12 on Days 1 and 14. Furthermore, vital signs will be taken once 
daily on Day 2 through Day 14 (6 hours after dosing) and once daily on Days 15 through 23 and at early withdrawal (must be done 
within 15 minutes before review of medication and collection of adverse experiences). Both blood pressure and heart rate should be 
captured simultaneously. Blood pressure and heart rate should be measured after subjects are in a seated position for 2 minutes and then 
again after standing for 1 minute, except when they are supine or semi-reclined because of study procedures and/or adverse events, or 
as deemed necessary by the Investigator.  
h. On Day 30 (+1 day), follow-up questioning on concomitant medications will be completed by a phone call.  
i. 
Subjects will be monitored for treatment-emergent adverse events to be monitored from the time of dosing and throughout the study via 
safety assessments, observation and participant reporting. Specific adverse event questions will be posed daily throughout the study 
until Day 23. The inquiry to collect adverse events using non-leading questions will be performed after all other procedures are 
conducted for the specified time points. On Day 30 (±1 day), follow-up questioning on adverse events will be completed by a phone 
call.  
j. 
TBI-223 SR1 and IR1 tablets and placebo for TBI-223 will be administered orally followed by approximately 200 mL of water. Note: 
Dosing to occur following a high-fat, high-calorie breakfast to begin 30 minutes prior to dose and to end (last bite taken) within 5 
minutes prior to dosing   
k. 12-lead safety ECGs will be printed and reviewed on-site by the Principal Investigator or designee. Triplicate ECGs will be completed 
at screening, Day -2, Day -1, and on Day 23 or upon early withdrawal. All other time points will be single ECG readings. ECGs may be 
done within 2 hours prior to time of dosing and at 3, 6, 12, and 16 hours postdose on Days 1, 2, 3, 8, 12.  Another single ECG reading 
will be performed on the morning of Day 17 before discharge. The predose ECG should be completed within 20 minutes prior to the 
pre-dose blood draw. If a subject experiences a post-dosing QTcF >500 msec with a change-from-baseline QTcF >60 msec, after repeat 
testing, additional ECGs should be recorded until normalization or return to baseline  
l. 
Predose trough blood samples will be drawn daily starting on Day 1.  
m. Duplicate plasma samples will be generated from all blood pharmacokinetic samples.  
n. Postdose blood plasma samples will be drawn at the following timepoints:  
• 
Day 1: 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 12, 16, 20, and 24 hours. The 24-hour sample is the predose sample of Day 2.    
• 
Day 14-17:  0.5, 1, 2, 3, 4, 5, 6, 7, 8, 12, 16, 20, 24, 30, 36, 42, 48, 54, 60, and 72 hours 

Protocol TBI-223 CL-002 Version 1.0 
Global Alliance for TB Drug Development 
CONFIDENTIAL 
15 Dec 2020 
Page 52 
14 
REFERENCES 
1. Investigator’s Brochure for TBI-223 
2. Prescription Monograph for Linezolid 
3. FDA Guidance for Industry, Estimating the Maximum Safe Starting Dose in Initial 
Clinical Trials for Therapeutics in Adult Healthy Volunteers 

Protocol TBI-223 CL-002 Version 1.0 
Global Alliance for TB Drug Development 
CONFIDENTIAL 
15 Dec 2020 
Page 53 
APPENDIX 1 PHARMACOKINETIC SAMPLE PROCESSING 
A. Collection and Processing 
A more detailed description of plasma sample preparation requirements may be provided by the 
analytical laboratory. If such a description is provided, the method of sample preparation 
provided by the laboratory shall supersede those provided in this protocol and appropriate 
documentation shall be placed in the Investigator Site File (ISF). 
Processing Instructions 
1 
Samples will be collected via direct venipuncture at the time points delineated in the 
appropriate Events Schedule (Section 13).  
2 
Blood will be drawn into pre-chilled 4 mL evacuated tubes containing K3-EDTA and 
immediately placed on wet ice and then processed to plasma within 60 minutes.  
3 
Samples will be centrifuged at 1500 g at approximately 4°C (± 10 degrees) for 
10 minutes. After centrifugation, two aliquots of plasma (the first containing at least 
0.5 mL and the second containing the remainder of the plasma) will be removed and 
placed in appropriately labeled 5 mL polypropylene vials.  
4 
The aliquots will be immediately placed on dry ice. Within 90 minutes of collection, 
the aliquots will be stored in a freezer set at -20°C ± 10°C and remain in the freezer 
until transferred for analysis.  
5 
Samples will be transferred at the agreed upon intervals. 
6 
The aliquots will be transferred on dry ice to the Alliance Pharma, Inc. bioanalytical 
laboratory for the determination of plasma concentrations of TBI-223 and TBI-
223-M2, using a validated procedure at Alliance Pharma. 
7 
Blood sampling, plasma processing, and storage time will be documented in the study 
records. 
Labeling of aliquot tubes 
Labels will contain at least the following information: 
a) Study number 
b) Subject number 
c) Period or dosing phase; sampling time (relative to dosing) 
d) Aliquot letter (A or B)  

Protocol TBI-223 CL-002 Version 1.0 
Global Alliance for TB Drug Development 
CONFIDENTIAL 
15 Dec 2020 
Page 54 
Shipment 
1. The samples will be transferred to the analytical laboratory after completion of the 
study or at mutually agreed upon time points during the clinical conduct of the study. 
The second set of samples will be shipped after the bioanalytical laboratory confirms 
receipt of the first set of samples. 
2. Samples will be packaged into cryoboxes and sorted by subject and time point. 
3. Prior to shipment, the samples will be appropriately packed in a cooler containing 
dry ice. Sufficient dry ice will be added to ensure that the samples will remain frozen 
for at least 72 hours.  
4. An electronic manifest will be provided in advance. The shipment will be 
accompanied by documentation containing the following information: name of the 
study drug product, protocol number, number of subjects, and number of samples 
included in the shipment. Expected samples that are not present will be identified. 
5. All frozen pharmacokinetic samples will be transferred with accompanying 
documentation to: 
Alliance Pharma, Inc. 
17 Lee Blvd 
Malvern, PA 19355 
Telephone:  610.296.3152 
Fax:  610.296.3153 
Contact name: Ruth Guan 
Contact e-mail: dzang@alliancepharmaco.com; samples@alliancepharmaco.com   
 
 
 
 
 

Protocol TBI-223 CL-002 Version 1.0 
Global Alliance for TB Drug Development 
CONFIDENTIAL 
15 Dec 2020 
Page 55 
APPENDIX 2 DESCRIPTION AND COMPOSITION OF TEST PRODUCT 
Description of the Dosage Form 
TBI-223 tablets are supplied as immediate release (IR) or sustained release (SR) or placebo. The 
description of the tablets and strengths are as follows: 
TBI-223 IR tablets 600 mg (IR) 
White to off-white, capsule shaped tablets, debossed with “TBA” on one side and “22” on the 
other 
TBI-223 SR Tablets, 600 mg (Prototype 1) (SR1) 
White to off-white, capsule shaped tablets, debossed with “TBA” on one side and “11” on the 
other 
Placebo Tablets for TBI-223 IR and SR Tablets 600 mg (Placebo) 
White to off-white, capsule shaped tablets, debossed with “TBA” on one side and “17” on the 
other 
Composition of the Drug Product 
The composition of the tablets is as follows: 
TBI-223 IR tablets, 600 mg 
TBI-223, microcrystalline cellulose, hypromellose, crospovidone, colloidal silicon dioxide, 
magnesium stearate 
 TBI-223 SR Tablets, 600 mg (Prototype 1) (SR1) 
TBI-223, lactose monohydrate, microcrystalline cellulose, hypromellose, colloidal silicon 
dioxide, magnesium stearate 
Placebo Tablets for TBI-223 IR and SR Tablets 600 mg 
Microcrystalline cellulose, hypromellose, crospovidone, colloidal silicon dioxide, magnesium 
stearate. 
Container and Closure System 
TBI-223 IR Tablets, TBI-223 SR Tablets, and Placebo Tablets are packaged as 30-count in 100 
cc round high-density polyethylene (HDPE) bottles and closed with aluminum foil lined heat 
induction seals and 38 mm polypropylene (PP) child resistant closures (CRC). 

Protocol TBI-223 CL-002 Version 1.0 
Global Alliance for TB Drug Development 
CONFIDENTIAL 
15 Dec 2020 
Page 56 
APPENDIX 3 DIVISION OF MICROBIOLOGY AND INFECTIOUS DISEASE 
TOXICITY TABLE 
Division of Microbiology and Infectious Disease (DMID) Toxicity Table 
Source:  U.S. National Institute of Allergy and Infectious Diseases, DMID, November 2007 
(Draft) 
ABBREVIATIONS:  Abbreviations utilized in the Table: 
ULN = Upper Limit of Normal 
LLN = Lower Limit of Normal 
Rx = Therapy 
Req = Required 
Mod = Moderate 
IV = Intravenous 
ADL = Activities of Daily Living 
Dec = Decreased 
 
ESTIMATING SEVERITY GRADE 
For abnormalities NOT found elsewhere in the Toxicity Tables use the scale below to estimate 
grade of severity: 
Grade 
Severity Rating 
Definition 
GRADE 1 
Mild 
Transient or mild discomfort (< 48 hours); no medical 
intervention/therapy required. 
GRADE 2 
Moderate 
Mild to moderate limitation in activity - some assistance may be 
needed; no or minimal medical intervention/therapy required. 
GRADE 3 
Severe 
Marked limitation in activity, some assistance usually required; 
medical intervention/therapy required, hospitalizations possible. 
GRADE 4 
Potentially Life-
threatening 
Extreme limitation in activity, significant assistance required; 
significant medical intervention/therapy required, hospitalization or 
hospice care probable. 
 
SERIOUS OR LIFE-THREATENING AEs 
ANY clinical event deemed by the clinician to be serious or life-threatening should be 
considered a grade 4 event. Clinical events considered to be serious or life-threatening include, 
but are not limited to: seizures, coma, tetany, diabetic ketoacidosis, disseminated intravascular 
coagulation, diffuse petechiae, paralysis, acute psychosis, severe depression. 
COMMENTS REGARDING THE USE OF THESE TABLES 
• Standardized and commonly used toxicity tables (Division of AIDS, NCI’s Common 
Toxicity Criteria (CTC), and World Health Organization (WHO)) have been adapted for use 
by the Division of Microbiology and Infectious Diseases (DMID) and modified to better 
meet the needs of Patients in DMID trials. 
• For parameters not included in the following Toxicity Tables, sites should refer to the “Guide 
For Estimating Severity Grade” located above. 

Protocol TBI-223 CL-002 Version 1.0 
Global Alliance for TB Drug Development 
CONFIDENTIAL 
15 Dec 2020 
Page 57 
• Criteria are generally grouped by body system. 
• Some protocols may have additional protocol specific grading criteria, which will supersede 
the use of these tables for specified criteria. 
HEMATOLOGY 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Hemoglobin 
9.5 - 10.5 gm/dL 
8.0  - 9.4gm/dL 
6.5 - 7.9 gm/dL 
< 6.5 gm/dL 
Absolute Neutrophil 
Count 
1000-1500/mm3 
750-999/mm3 
500-749/mm3 
<500/mm3 
Platelets 
75,000-99,999/mm3 
50,000-74,999/mm3 
20,000-49,999/mm3 
<20,000/mm3 
WBCs 
11,000-13,000/ 
mm3 
13,000-15,000 
/mm3 
15,000-30,000/mm3 
>30,000 or <1,000 
/mm3 
% Polymorphonuclear 
Leucocytes + Band 
Cells 
> 80% 
90 – 95% 
>95% 
---------- 
Abnormal Fibrinogen 
Low: 
100-200 mg/dL 
High: 
400-600 mg/dL 
Low: 
<100 mg/dL 
High: 
>600 mg/dL 
Low: 
< 50 mg/dL 
 
---------- 
Fibrinogen 
associated with 
gross bleeding or 
with disseminated 
coagulation 
Fibrin Split Product 
20-40 mcg/ml 
41-50 mcg/ml 
51-60 mcg/ml 
> 60 mcg/ml 
Prothrombin Time (PT) 
1.01 - 1.25 x ULN 
1.26-1.5 x ULN 
1.51 -3.0 x ULN 
>3 x ULN 
Activated Partial 
Thromboplastin (APPT) 
1.01 -1.66 x ULN 
1.67 - 2.33 x ULN 
2.34 - 3 x ULN 
> 3 x ULN 
Methemoglobin 
5.0 - 9.9 % 
10.0 - 14.9 % 
15.0 - 19.9% 
> 20.0 % 
 
CHEMISTRIES 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Hyponatremia 
130-135 mEq/L 
123-129 mEq/L 
116-122 mEq/L 
< 116 mEq/L or abnormal 
sodium with mental status 
changes or seizures 
Hypernatremia 
146-150 mEq/L 
151-157 mEq/L 
158-165 mEq/L 
> 165 mEq/L or abnormal 
sodium with mental status 
changes or seizures 
Hypokalemia 
3.0 - 3.4 mEq/L 
2.5 - 2.9 mEq/L 
2.0 - 2.4 mEq/L or 
intensive 
replacement 
therapy or 
hospitalization 
required 
< 2.0 mEq/L or abnormal 
potassium with paresis, ileus 
or life-threatening arrhythmia 

Protocol TBI-223 CL-002 Version 1.0 
Global Alliance for TB Drug Development 
CONFIDENTIAL 
15 Dec 2020 
Page 58 
CHEMISTRIES 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Hyperkalemia 
5.6 - 6.0 mEq/L 
6.1 - 6.5 mEq/L 
6.6 - 7.0 mEq/l 
> 7.0 mEq/L or abnormal 
potassium with life-
threatening arrhythmia 
Hypoglycemia 
55-64 mg/dL 
40-54 mg/dL 
30-39 mg/dL 
<30 mg/dL or abnormal 
glucose with mental status 
changes or coma 
Hyperglycemia 
(non-fasting and no 
prior diabetes) 
116 - 160 mg/dL 
161- 250 mg/dL 
251 - 500 mg/dL 
> 500 mg/dL or abnormal 
glucose with ketoacidosis or 
seizures 
Hypocalcemia 
(corrected for 
albumin) 
8.4 - 7.8 mg/dL 
7.7 - 7.0 mg/dL 
6.9 - 6.1 mg/dL 
< 6.1 mg/dL or abnormal 
calcium with life threatening 
arrhythmia or tetany 
Hypercalcemia 
(correct for albumin) 
10.6 - 11.5 mg/dL 
11.6 - 12.5 
mg/dL 
12.6 - 13.5 mg/dL 
> 13.5 mg/dL or abnormal 
calcium with life threatening 
arrhythmia 
Hypomagnesemia 
1.4 - 1.2 mEq/L 
1.1 - 0.9 mEq/L 
0.8 - 0.6 mEq/L 
< 0.6 mEq/L or abnormal 
magnesium with life-
threatening arrhythmia 
Hypophosphatemia 
2.0 - 2.4 mg/dL 
1.5 -1.9 mg/dL 
or replacement 
Rx required 
1.0 -1.4 mg/dL 
intensive therapy or 
hospitalization 
required 
< 1.0 mg/dL or abnormal 
phosphate with life-
threatening arrhythmia 
Hyperbilirubinemia 
(when accompanied 
by any increase in 
other liver function 
test) 
1.1 - <1.25 x ULN 
1.25 - <1.5 x 
ULN 
1.5 – 1.75 x ULN 
> 1.75 x ULN 
Hyperbilirubinemia 
(when other liver 
function are in the  
normal range) 
1.1 - <1.5 x ULN 
1.5 - <2.0 x ULN 
2.0 – 3.0 x ULN 
> 3.0 x ULN 
BUN 
1.25 - 2.5 x ULN 
2.6 - 5 x ULN 
5.1 - 10 x ULN 
> 10 x ULN 
Hyperuricemia (uric 
acid) 
7.5 – 10.0 mg/dL 
10.1 – 12.0 
mg/dL 
12.1 – 15.0 mg/dL 
>15.0 mg/dL 
Creatinine 
1.1 - 1.5 x ULN 
1.6 - 3.0 x ULN 
3.1 - 6 x ULN 
> 6 x ULN or dialysis 
required 
 
ENZYMES 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
AST (SGOT) 
1.1 - <2.0 x ULN 
2.0 – <3.0 x ULN 
3.0 – 8.0 x ULN 
> 8 x ULN 
ALT (SGPT) 
1.1 - <2.0 x ULN 
2.0 – <3.0 x ULN 
3.0 – 8.0 x ULN 
> 8 x ULN 

Protocol TBI-223 CL-002 Version 1.0 
Global Alliance for TB Drug Development 
CONFIDENTIAL 
15 Dec 2020 
Page 59 
ENZYMES 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
GGT 
1.1 - <2.0 x ULN 
2.0 – <3.0 x ULN 
3.0 – 8.0 x ULN 
> 8 x ULN 
Alkaline Phosphatase 
1.1 - <2.0 x ULN 
2.0 – <3.0 x ULN 
3.0 – 8.0 x ULN 
> 8 x ULN 
Amylase 
1.1 - 1.5 x ULN 
1.6 - 2.0 x ULN 
2.1 - 5.0 x ULN 
> 5.1 x ULN 
Lipase  
1.1 - 1.5 x ULN 
1.6 - 2.0 x ULN 
2.1 - 5.0 x ULN 
> 5.1 x ULN 
 
URINALYSIS 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Proteinuria 
1+ or 200 mg - 1 
gm loss/day 
2-3+ or 1- 2 gm 
loss/day 
4+ or 2-3.5 gm 
loss/day 
nephrotic syndrome 
or > 3.5 gm 
loss/day 
Hematuria* 
microscopic only 
<10 rbc/hpf 
gross, no clots >10 
rbc/hpf 
gross, with or 
without clots, OR 
red blood cell casts 
obstructive or 
required transfusion 
*Assessment does not apply if a subject is on menses. 
CARDIOVASCULAR 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Cardiac Rhythm 
 
asymptomatic, 
transient signs, no 
Rx required 
recurrent/persistent; 
symptomatic Rx 
required 
unstable 
dysrythmia; 
hospitalization and 
treatment required 
Hypertension 
transient increase 
> 20 mm/Hg; no 
treatment1 
recurrent, chronic 
increase > 
20mm/Hg. 
/treatment required 
acute treatment 
required; outpatient 
treatment or 
hospitalization 
possible 
end organ damage 
or hospitalization 
required 
Hypotension 
transient 
orthostatic 
hypotension with 
heart rate 
increased by <20 
beat/min or 
decreased by <10 
mm Hg systolic 
BP, No treatment 
required1 
symptoms due to 
orthostatic 
hypotension or BP 
decreased by <20 
mm Hg systolic; 
correctable with oral 
fluid treatment 
requires IV fluids; no 
hospitalization 
required 
mean arterial 
pressure <60mm/ 
Hg or end organ 
damage or shock;   
requires 
hospitalization and 
vasopressor 
treatment 

Protocol TBI-223 CL-002 Version 1.0 
Global Alliance for TB Drug Development 
CONFIDENTIAL 
15 Dec 2020 
Page 60 
CARDIOVASCULAR 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Pericarditis 
minimal effusion 
mild/moderate 
asymptomatic 
effusion, no 
treatment 
symptomatic 
effusion; pain; EKG 
changes 
tamponade; 
pericardiocentesis 
or surgery required 
Hemorrhage, Blood 
Loss 
microscopic/occult 
mild, no transfusion 
gross blood loss; 1-2 
units transfused 
massive blood 
loss; > 3 units 
transfused 
 
 
RESPIRATORY 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Cough 
Transient - no 
treatment 
persistent cough; 
treatment responsive 
Paroxysmal cough; 
uncontrolled with 
treatment 
-------------------- 
Bronchospasm, 
Acute 
transient; no 
treatment; 70% - 
80% FEV1 of peak 
flow 
requires treatment; 
normalizes with 
bronchodilator; FEV1 
50% - 70% (of peak 
flow) 
no normalization with 
bronchodilator;FEV1 
25% - 50% of peak 
flow; or  retractions 
present 
cyanosis: FEV1 < 
25% of peak flow 
or intubation 
necessary 
Dyspnea 
dyspnea on exertion 
dyspnea with normal 
activity 
dyspnea at rest 
dyspnea requiring 
Oxygen therapy 
 
GASTROINTESTINAL 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Nausea 
mild or transient; 
maintains 
reasonable intake 
moderate 
discomfort; intake 
decreased 
significantly; some 
activity limited 
no significant 
intake; requires IV 
fluids 
hospitalization 
required; 
Vomiting 
1 episode in 24 
hours 
2-5 episodes in 24 
hours 
>6 episodes in 24 
hours or needing IV 
fluids 
physiologic 
consequences 
requiring 
hospitalization or 
requiring parenteral 
nutrition 
Constipation 
requiring stool 
softener or dietary 
modification 
requiring laxatives 
obstipation 
requiring manual 
evacuation or 
enema 
obstruction or toxic 
megacolon 
Diarrhea 
mild or transient; 3-
4 loose stools/day 
or mild diarrhea 
moderate or 
persistent; 5-7 loose 
stools/day or 
>7 loose stools/day 
or bloody diarrhea; 
or orthostatic 
hypotensive shock 
or physiologic 
consequences 

Protocol TBI-223 CL-002 Version 1.0 
Global Alliance for TB Drug Development 
CONFIDENTIAL 
15 Dec 2020 
Page 61 
GASTROINTESTINAL 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
last < 1 week 
diarrhea lasting >1 
week 
hypotension or 
electrolyte 
imbalance or >2L 
IV fluids required  
requiring 
hospitalization   
Oral 
Discomfort/Dysphagia 
mild discomfort; no 
difficulty swallowing 
some limits on 
eating/drinking 
eating/talking very 
limited; unable to 
swallow solid foods 
unable to drink 
fluids; requires IV 
fluids 
 
NEUROLOGICAL 
 
Grade 1  
Grade 2  
Grade 3  
Grade 4  
Neuro-Cerebellar 
slight 
incoordination 
dysdiadochokinesis 
intention tremor, 
dysmetria, slurred 
speech; nystagmus 
locomotor ataxia 
incapacitated 
Psychiatric 
mild anxiety or 
depression 
moderate anxiety or 
depression; therapy 
required; change in 
normal routine 
severe mood 
changes requiring  
therapy; or suicidal 
ideation;  or 
aggressive ideation 
acute psychosis 
requiring 
hospitalization;  or 
suicidal 
gesture/attempt or 
hallucinations 
Muscle Strength 
Subjective 
weakness no 
objective 
symptoms/ signs 
mild objective 
signs/symptoms no 
decrease in function 
objective weakness 
function limited 
paralysis 
Paresthesia (burning, 
tingling, etc.) 
mild discomfort; no 
treatment  required 
moderate 
discomfort; non-
narcotic analgesia 
required 
severe discomfort; 
or narcotic 
analgesia required 
with symptomatic 
improvement 
incapacitating; or 
not responsive to 
narcotic analgesia 
Neuro-sensory 
mild impairment in 
sensation 
(decreased 
sensation, e.g., 
vibratory, pinprick, 
hot/cold in great 
toes) in focal area 
or symmetrical 
distribution; or 
change in taste, 
smell, vision and/or 
hearing 
moderate 
impairment (mod 
decreased 
sensation, e.g., 
vibratory, pinprick, 
hot/cold to ankles) 
and/or joint position 
or mild impairment 
that is not 
symmetrical 
severe impairment 
(decreased or loss 
of sensation to 
knees or wrists) or 
loss of sensation of 
at least mod 
degree in multiple 
different body 
areas (i.e., upper 
and lower 
extremities) 
sensory loss 
involves limbs and 
trunk; paralysis;  or 
seizures 
 
 
 

Protocol TBI-223 CL-002 Version 1.0 
Global Alliance for TB Drug Development 
CONFIDENTIAL 
15 Dec 2020 
Page 62 
MUSCULOSKELETAL 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Arthralgia (joint pain) 
mild pain not 
interfering with 
function 
moderate pain, 
analgesics and/or 
pain interfering with 
function but not with 
activities of daily 
living 
severe pain; pain 
and/or analgesics 
interfering with 
activities of daily 
living 
disabling pain 
Arthritis 
mild pain with 
inflammation, 
erythema or joint 
swelling – but not 
interfering with 
function 
moderate pain with 
inflammation, 
erythema or joint 
swelling – interfering 
with function, but not 
with activities of 
daily living 
severe pain with 
inflammation, 
erythema or joint 
swelling –and 
interfering with 
activities of daily 
living 
permanent and/or 
disabling joint 
distruction 
Myalgia 
myalgia with no 
limitation of activity 
muscle tenderness 
(at other than 
injection site) or with 
moderate 
impairment of 
activity 
severe muscle 
tenderness with 
marked impairment 
of activity 
frank 
myonecrosis 
 
SKIN 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Mucocutaneous 
erythema; pruritus 
diffuse, maculo 
papular rash, dry 
desquamation 
vesiculation or moist 
desquamation or 
ulceration 
exfoliative dermatitis, 
mucous membrane 
involvement or 
erythema, 
multiforme or 
suspected Stevens-
Johnson or  necrosis 
requiring surgery 
Induration 
< 15mm  
15-30 mm 
>30mm 
 
Erythema 
< 15mm  
15-30 mm 
>30mm 
 
Edema 
< 15mm  
15-30 mm 
>30mm 
 
Rash at Injection 
Site 
< 15mm  
15-30 mm 
>30mm 
 
Pruritus 
slight itching at 
injection site 
moderate itching at 
injection extremity 
itching over entire 
body 
 
 
 

Protocol TBI-223 CL-002 Version 1.0 
Global Alliance for TB Drug Development 
CONFIDENTIAL 
15 Dec 2020 
Page 63 
SYSTEMIC 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Allergic Reaction 
pruritus without rash 
localized urticaria 
generalized urticaria; 
angioedema 
anaphylaxis 
Headache 
mild, no treatment 
required 
transient, moderate; 
treatment required 
severe; responds to 
initial narcotic 
therapy 
intractable; requires 
repeated narcotic 
therapy 
Fever: oral 
37.7 - 38.5 C or 
100.0 - 101.5 F 
38.6 - 39.5 C or 
101.6 - 102.9 F 
39.6 - 40.5 C or 103 
- 105 F 
> 40 C or > 105 F 
Fatigue 
normal activity 
reduced < 48 hours 
 normal activity 
decreased 25- 50% 
> 48 hours 
normal activity 
decreased > 50% 
can’t work 
unable to care for 
self