Clinical trial NCT03758612
Conditions: Tuberculosis Tuberculosis, Pulmonary
Keywords: TB Tuberculosis TBI-223 Pulmonary Tuberculosis
Sponsor: Global Alliance for TB Drug Development
Start date: 2019-01-16; Completion date: 2020-03-15
Enrollment: 86 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Partially-Blinded, Placebo-Controlled, Randomized, Single Ascending Dose (SAD) with a Food Effect Cohort to Evaluate the Safety, Tolerability, and Pharmacokinetics of TBI-223 in Healthy Adults.

Detailed description:
This study was a partially-blinded, placebo-controlled, randomized SAD study conducted at one study center. The primary objective of the study was to evaluate the safety and tolerability of single doses of TBI-223 oral suspension, TBI-223 oral enteric capsules, and TBI-223 tablet formulations in healthy adult subjects. The secondary objectives of the study were to determine the PK of TBI-223 and its metabolite M2 after single doses of TBI-223 oral suspension, TBI-223 oral enteric capsules, and TBI-223 tablet formulations in healthy adult subjects, and to compare the rate and extent of absorption of a single dose of TBI-223 oral suspension and TBI-223 tablet formulations when administered in healthy adult subjects either after a high-calorie, high-fat meal or in the fasting state.

Safety was assessed throughout the study for all subjects. Safety assessments included physical examinations, vital signs, serial ECGs, cardiac monitoring, adverse events (AEs), and clinical laboratory tests (including hematology, serum chemistry, coagulation, and urinalysis).

Arms: arm 1: Cohort 1, single dose of TBI-223 50 mg dosed under fasted conditions arm 2: Cohort 2, single dose of TBI-223 100 mg dosed under fasted conditions arm 3: Cohort 3a, Period 1 - gave a single dose of TBI-223 300 mg oral suspension dosed under fasted conditions.

Cohort 3b, Period 2 - participants in cohort 3a were invited after a washout period to return for an additional single dose of TBI-223 300 mg enteric capsule dosed under fasted conditions arm 4: Cohort 4, single dose of TBI-223 600 mg dosed under fasted conditions arm 5: Cohort 5, Period 1, single dose of TBI-223 1200 mg dosed under fasted conditions.

Cohort 5, Period 2, participants were invited to return after a washout period to continue in period 2 and receive a single dose of TBI-223 1200 mg dosed under fed conditions arm 6: Cohort 6, single dose of TBI-223 2000 mg dosed under fasted conditions arm 7: Cohort 7, single dose of TBI-223 2600 mg dosed under fasted conditions arm 8: Period 1 Single dose matching placebo for TBI-223 under fasted conditions for cohorts 1 to 7

Period 2 Placebo participants in cohort 5 were invited to return after a washout period and were administered a single dose matching placebo for TBI-223 1200mg under fed conditions arm 9: Cohort 8, arm 1 - Single dose TBI-223 of 1800 mg (3 x 600 mg) sustained release (SR) tablet formulation 1 under fed conditions arm 10: Cohort 8, arm 2 - Single dose TBI-223 of 1800 mg (3 x 600 mg) sustained release (SR) tablet formulation 2 under fed conditions arm 11: Cohort 8, arm 3 - Single dose TBI-223 of 1800 mg (2 x 900 mg) sustained release (SR) tablet formulation 3 under fed conditions arm 12: Cohort 8, arm 4 - Single dose TBI-223 of 2000 mg (2 x 1000 mg) immediate release (IR) tablet under fasted conditions

Cohort 9 - Participants from cohort 8 arm 4 were invited to return and were administered a single dose TBI-223 of 2000 mg (2 x 1000 mg) immediate release (IR) tablet under fed conditions
Interventions: intervention 1: TBI-223 oral suspension intervention 2: TBI-223 enteric capsule intervention 3: TBI-223 SR Tablet Prototype 1 intervention 4: TBI-223 SR Tablet Prototype 2 intervention 5: TBI-223 SR Tablet Prototype 3 intervention 6: TBI-223 IR Tablet intervention 7: Placebo suspension
Intervention descriptions: intervention 1: TBI-223 oral suspension, orally administered. intervention 2: TBI-223 enteric capsules filled with 150 mg of TBI-223 powder, orally administered. intervention 3: TBI-223 600 mg sustained-release (SR) tablet Prototype 1, orally administered. intervention 4: TBI-223 600 mg SR tablet Prototype 2, orally administered. intervention 5: TBI-223 900 mg SR tablet Prototype 3, orally administered. intervention 6: TBI-223 1000 mg immediate release (IR) tablet, orally administered intervention 7: Placebo for TBI-223 oral Suspension; orally administered.

Protocol documents:
Prot_000.pdf: 
Protocol TBI-223-CL-001 Final Version 3.0 
Global Alliance for TB Drug Development 
CONFIDENTIAL 
21 Jan 2020 
Page i 
 
CLINICAL STUDY PROTOCOL 
A Phase 1, Partially-Blinded, Placebo-Controlled, Randomized Single 
Ascending Dose (SAD) with a Food Effect Cohort Study to Evaluate the 
Safety, Tolerability, and Pharmacokinetics of TBI-223 in Healthy Adult 
Participants 
PROTOCOL NUMBER 
TBI-223-CL-001 
Version: 3.0 
21 Jan 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-001 Final Version 3.0 
Global Alliance for TB Drug Development 
CONFIDENTIAL 
21 Jan 2020 
Page ii 
PROTOCOL APPROVAL PAGE 
 
A Phase 1, Partially-Blinded, Placebo-Controlled, Randomized, Single 
Ascending Dose (SAD)with a Food Effect Cohort Study to Evaluate the 
Safety, Tolerability, and Pharmacokinetics of TBI-223 in Healthy Adult 
Participants 
 
Protocol Number: 
TBI-223-CL-001  
Sponsor: 
Global Alliance for TB Drug Development 
Sponsor Contact and 
Medical Monitor: 
 
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 
 
 
 
 
 
 
 
 
(Signature) 
(Date) 
 
Principal Investigator: Cynthia A. Zamora, MD 
 
Worldwide Clinical Trials Early Phase Services, LLC 
 
2455 N.E. Loop 410, Suite 150 
 
San Antonio, Texas 78217 
 
Telephone: 210.635.1500 
 
Fax: 210.635.1646 
 
 
 
 
 
 
 
 
 (Signature) 
(Date) 
21-Jan-2020 | 16:12:01 GMT
21-Jan-2020 | 10:51:14 EST


Protocol TBI-223-CL-001 Final Version 3.0 
Global Alliance for TB Drug Development 
CONFIDENTIAL 
21 Jan 2020 
Page iii 
SUMMARY OF CHANGES 
 
 
The primary reasons for this amendment are to incorporate the changes from the protocol 
clarification letter dated 18 Oct 2019 regarding subject replacement of subjects who experience 
emesis, how replacement subjects will be numbered, and that replacement subjects will receive 
the same dose allocation of study drug.  
This amendment also includes clarifying Part 1 and Part 2 and updates whereby Part 1 captures 
adding a capsule cohort (3b, TBI-223, 300 mg), updating the dose of cohort 7 (TBI-223, 
2600 mg) and whereby Part 2 consists of 2 additional cohorts (Cohort 8 and 9) that will be added 
to the study in relation to evaluating tablet formulations of TBI-223. 
Part 1: (TBI-223 oral suspension) 
Cohort 3b: Is a cohort that was added to evaluate a capsule formulation of TBI-223 150 mg in 
oral enteric capsules, dosed at 300 mg 
Cohort 7: Is the final TBI-223 oral suspension cohort at a dose of 2600 mg  
Part 2: (TBI-223 tablet formulation) 
Cohort 8:  Is a single dose cohort that investigates 3 different TBI-223 Sustained Release (SR) 
tablet formulations (Prototypes 1, 2, and 3) and one TBI-223 Immediate Release (IR) tablet 
formulation. The cohort includes 4 arms with 6 subjects per arm. The 3 SR tablet formulations 
(Prototypes 1, 2, and 3) will be evaluated under fed conditions (Arms 1-3) and the IR tablet 
formulation will be evaluated under fasting conditions (Arm 4). 
Cohort 9: 6 subjects from Cohort 8, Arm 4, who received the IR tablet formulation will be 
brought back following a 7-day washout and receive the IR tablet formulation under fed 
conditions. If more than 2 subjects of these 6 subjects from Cohort 8 drop-out, they will be 
replaced by healthy volunteers (a minimum of 4 subjects are needed to complete Cohort 9). 
Additional minor changes to format, grammar, and spelling have been applied.   
The sections of protocol version 2.0 dated 12 Jul 2019 affected by these changes are indicated 
below. 
Section 
Number 
(s) 
Section Title(s) 
Description of Change (s) 
Synopsis 
Study period 
(maximum 
duration, from 
screening to 
study exit): 
From: 
Single ascending dose (SAD) cohort (fasting): 40 days 
Food-effect cohort: 50 days 
The maximum duration of the study will depend upon the final number and 
timing of each cohort. 


Protocol TBI-223-CL-001 Final Version 3.0 
Global Alliance for TB Drug Development 
CONFIDENTIAL 
21 Jan 2020 
Page iv 
Section 
Number 
(s) 
Section Title(s) 
Description of Change (s) 
 
To: 
Part 1:  
Single ascending dose (SAD) cohort (fasting): 40 days 
Food-effect cohort: 50 days 
Part 2:  
Cohort 8: Single dose cohort of the 4 TBI-223 tablet formulations 
(Prototypes 1, 2, and 3 SR tablet formulations under fed conditions and 
one IR tablet formulation under fasting conditions): Duration 40 days. 
Cohort 9: The IR tablet formulation will be evaluated under fed 
conditions  
Single dose: 40 days 
The maximum duration of the study will depend upon the final number and 
timing of each cohort. 
Synopsis 
Duration of 
treatment 
From: 
Fasting cohorts: One single dose of TBI-223 oral suspension or placebo for 
TBI-223 oral suspension 
Food-effect cohort: Two single doses of TBI-223 oral suspension or placebo 
for TBI-223 oral suspension separated by a washout period of at least 7 days 
To: 
Part 1: 
Fasting cohorts: One single dose of TBI-223 oral suspension or placebo for 
TBI-223 oral suspension 
Food-effect cohort: Two single doses of TBI-223 oral suspension or placebo 
for TBI-223 oral suspension separated by a washout period of at least 7 days 
Part 2: 
Cohort 8: Single dose cohort of 4 TBI-223 tablet formulations (three SR 
tablet formulations as prototypes 1, 2, and3 and one IR tablet 
formulation). The SR tablet formulations will be evaluated under fed 
conditions and the IR tablet formulation will be evaluated under fasting 
conditions  
Cohort 9: The IR tablet formulation will be evaluated under fed 
conditions  
Synopsis 
Number of 
subjects 
(planned) 
From: 
Fasting Cohorts: Planned to enroll up to 48 subjects in a total of 6 single 
ascending dose (SAD) cohorts of 8 subjects each (6 to receive active drug 


Protocol TBI-223-CL-001 Final Version 3.0 
Global Alliance for TB Drug Development 
CONFIDENTIAL 
21 Jan 2020 
Page v 
Section 
Number 
(s) 
Section Title(s) 
Description of Change (s) 
and 2 to receive placebo). 
Food-effect Cohort:  1 cohort with 10 subjects (8 active and 2 placebo) who 
will receive TBI-223 or placebo under both fasting and fed conditions.   
Additional cohorts may be enrolled if deemed appropriate by the Sponsor to 
repeat a dose level or to study another dose level. These decisions 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 this revised approach. 
To: 
Part 1: 
Fasting Cohorts: Planned to enroll up to 48 subjects in a total of 6 single 
ascending dose (SAD) cohorts of 8 subjects each (6 to receive active drug 
and 2 to receive placebo). 
Food-effect Cohort: 1 cohort with 10 subjects (8 active and 2 placebo) who 
will receive TBI-223 or placebo under both fasting and fed conditions.   
Part 2: 
Cohort 8: Planned to enroll 24 subjects in a total of 4 arms with 
6 subjects in each. Subjects will receive a single dose of 1 of the 3 
prototypes of TBI-223 SR tablets under fed conditions (Arms 1-3) or a 
single dose of TBI-223 IR tablets under fasted conditions (Arm 4). 
Cohort 9: Plan to bring back the 6 subjects from Cohort 8, Arm 4, who 
received the IR tablet formulation, following a 7-day washout to receive 
the IR tablet formulation under fed conditions. 
If more than 2 subjects of these 6 subjects from Cohort 8 drop-out, they 
will be replaced by heathy volunteers (a minimum of 4 subjects are 
needed to complete Cohort 9). 
Additional cohorts may be enrolled if deemed appropriate by the Sponsor to 
repeat a dose level or to study another dose level. These decisions 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 this revised approach. 
Synopsis 
and 2 
Objective 
From: 
The primary objective of the study is: 


Protocol TBI-223-CL-001 Final Version 3.0 
Global Alliance for TB Drug Development 
CONFIDENTIAL 
21 Jan 2020 
Page vi 
Section 
Number 
(s) 
Section Title(s) 
Description of Change (s) 
• 
To evaluate the safety and tolerability of single ascending doses of TBI-
223 oral suspension in healthy adult subjects.  
The secondary objectives of the study are: 
• 
To determine the pharmacokinetics of TBI-223 and its metabolite M2 
after single doses of TBI 223 oral suspension in healthy adult subjects; and 
• 
To compare the rate and extent of absorption of a single dose of TBI-223 
oral suspension when administered in healthy adult subjects either after a 
high-calorie, high-fat meal or in the fasting state. 
To: 
The primary objective of the study is: 
• 
To evaluate the safety and tolerability of single ascending doses of TBI-
223 oral suspension, TBI-223 oral enteric capsules, and TBI-223 
tablet formulations in healthy adult subjects.  
The secondary objectives of the study are: 
• 
To determine the pharmacokinetics of TBI-223 and its metabolite M2 
after single doses of TBI-223 oral suspension, TBI-223 oral enteric 
capsules, and TBI-223 tablet formulations in healthy adult subjects; 
and 
• 
To compare the rate and extent of absorption of a single dose of TBI-223 
oral suspension, TBI-223 oral enteric capsules, and TBI-223 tablet 
formulations when administered in healthy adult subjects either after a 
high-calorie, high-fat meal or in the fasting state. 
Synopsis 
Section before 
Test product, 
dosage and 
mode of 
administration 
From: 
This is a partially-blinded, placebo-controlled, randomized SAD study with a 
food effect cohort. The study will be conducted at one study center in the 
United States.  
This study will have up to 6 planned dose levels. Based on interim 
pharmacokinetic data obtained during the dose escalation, a dose cohort will 
be selected to return for additional dosing after a high-calorie, high-fat meal 
(food-effect cohort). 
Sentinel Cohort: The first cohort will be separated into 2 groups. A sentinel 
group of 3 subjects (2 active and 1 placebo) will be dosed at least 24 hours 
before the remaining 5 subjects (4 active and 1 placebo). The remaining 
cohorts will be dosed in 2 groups of 4 subjects each (3 active and 1 placebo), 
at least 24 hours apart. 


Protocol TBI-223-CL-001 Final Version 3.0 
Global Alliance for TB Drug Development 
CONFIDENTIAL 
21 Jan 2020 
Page vii 
Section 
Number 
(s) 
Section Title(s) 
Description of Change (s) 
Food-effect Cohort: Based on exposure levels, subjects in one of the dose 
levels will return after a 7-day minimum washout or 5 half-lives of the drug 
(whichever is longer) to receive the same dose under fed conditions. 
Safety will be assessed throughout the study for all subjects. 
Blood will be collected for pharmacokinetic analysis. Plasma samples will be 
analyzed for TBI-223 and TBI-223 metabolite (M2).  
Dose escalation to the next cohort (i.e., dose level) 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 has been demonstrated to permit proceeding to the next cohort. 
Additional cohorts may be enrolled if deemed appropriate (e.g. if 
bioavailability is lower than expected) by the Sponsor to repeat a dose level, 
to study other dose levels, change proposed cohorts, or to study a different 
dosage formulation. These 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 have been 
demonstrated to permit proceeding to the next cohort. The Institutional 
Review Board (IRB) should be immediately notified of this revised approach 
for review and approval. 
To:  
This is a partially-blinded, placebo-controlled, randomized SAD study with a 
food effect cohort. The study will be conducted at one study center in the 
United States. 
Safety will be assessed throughout the study for all subjects. 
Blood will be collected for pharmacokinetic analysis. Plasma samples will be 
analyzed for TBI-223 and TBI-223 metabolite (M2).  
Part 1: 
There will be up to 6 planned dose levels. Based on interim pharmacokinetic 
data obtained during the dose escalation, a dose cohort will be selected to 
return for additional dosing after a high-calorie, high-fat meal (food-effect 
cohort). 
Sentinel Cohort: The first cohort will be separated into 2 groups. A sentinel 
group of 3 subjects (2 active and 1 placebo) will be dosed at least 24 hours 
before the remaining 5 subjects (4 active and 1 placebo). The remaining 
cohorts will be dosed in 2 groups of 4 subjects each (3 active and 1 placebo), 
at least 24 hours apart. 
Food-effect Cohort: Based on exposure levels, subjects in one of the dose 


Protocol TBI-223-CL-001 Final Version 3.0 
Global Alliance for TB Drug Development 
CONFIDENTIAL 
21 Jan 2020 
Page viii 
Section 
Number 
(s) 
Section Title(s) 
Description of Change (s) 
levels will return after a 7-day minimum washout or 5 half-lives of the drug 
(whichever is longer) to receive the same dose under fed conditions. 
Dose escalation to the next cohort (i.e., dose level) 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 has been demonstrated to permit proceeding to the next cohort. 
Cohort 8: 
There will be 4 arms each consisting of 6 subjects. Subjects will be 
assigned to one of the following arms and dose:  
• 
Arm 1 – TBI-223 SR Tablets (Prototype 1) - 1800 mg dose (3 x 
600 mg tablets), under fed conditions 
• 
Arm 2 – TBI-223 SR Tablets (Prototype 2) - 1800 mg dose (3 x 
600 mg tablets), under fed conditions 
• 
Arm 3 – TBI-223 SR Tablets (Prototype 3) - 1800 mg dose (2 x 
900 mg tablets), under fed conditions 
• 
Arm 4 – TBI-223 IR Tablets - 2000 mg dose (2 x 1000 mg tablets), 
under fasting conditions   
Cohort 9:  
The 6 subjects from Cohort 8, Arm 4, who were received IR tablet 
formulation will be brought back following a 7-day washout – TBI-223 
IR Tablets – 2000 mg (2 x 1000 mg tablets), under fed conditions. 
If more than 2 subjects of these 6 subjects from Cohort 8 drop-out, they 
will be replaced by heathy volunteers (a minimum of 4 subjects are 
needed to complete Cohort 9). 
Additional cohorts may be enrolled if deemed appropriate (e.g. if 
bioavailability is lower than expected) by the Sponsor to repeat a dose level, 
to study other dose levels, change proposed cohorts, or to study a different 
dosage formulation. These 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 have been 
demonstrated to permit proceeding to the next cohort. The Institutional 
Review Board (IRB) should be immediately notified of this revised approach 
for review and approval. 
Synopsis 
Test product, 
dosage and 
mode of 
From: 
TBI-223 oral suspension, orally administered 
Dose level 1 = single dose of 50 mg TBI-223 


Protocol TBI-223-CL-001 Final Version 3.0 
Global Alliance for TB Drug Development 
CONFIDENTIAL 
21 Jan 2020 
Page ix 
Section 
Number 
(s) 
Section Title(s) 
Description of Change (s) 
administration 
Dose level 2 = single dose of 100 mg TBI-223 
Dose level 3 = single dose of 300 mg TBI-223 
Dose level 4 = single dose of 600 mg TBI-223 
Dose level 5 = single dose of 1200 mg TBI-223 
Dose level 6 = single dose of 2000 mg TBI-223 
Additional cohorts may be enrolled if deemed appropriate by the Sponsor to 
repeat a dose level or to study another dose level or a different dosage 
formulation. 
To: 
Part 1: 
TBI-223 oral suspension, orally administered 
Dose level 1 = single dose of 50 mg TBI-223 
Dose level 2 = single dose of 100 mg TBI-223 
Dose level 3 = single dose of 300 mg TBI-223 
Dose level 3 includes a Cohort 3a with TBI-223 (oral suspension) and the 
same subjects participated in Cohort 3b with TBI-223 within oral enteric 
capsules 
Dose level 4 = single dose of 600 mg TBI-223 
Dose level 5 = single dose of 1200 mg TBI-223 
Dose level 6 = single dose of 2000 mg TBI-223 
Dose level 7= Single dose of 2600 mg TBI-223 
 
Additional cohorts may be enrolled if deemed appropriate by the Sponsor to 
repeat a dose level or to study another dose level or a different dosage 
formulation. 
Part 2: 
Cohort 8: 
Arm 1 - TBI-223 SR Tablets 600 mg (Prototype 1). Dose of 1800 mg (3 
tablets of 600 mg), under fed conditions 
Arm 2 - TBI-223 SR Tablets 600 mg (Prototype 2). Dose of 1800 mg (3 
tablets of 600 mg), under fed conditions 
Arm 3 - TBI-223 SR Tablets 900 mg (Prototype 3). Dose of 1800 mg 
(2 tablets of 900 mg), under fed conditions  
Arm 4 - TBI-223 IR Tablets 1000 mg. Dose of 2000 mg (2 tablets of 


Protocol TBI-223-CL-001 Final Version 3.0 
Global Alliance for TB Drug Development 
CONFIDENTIAL 
21 Jan 2020 
Page x 
Section 
Number 
(s) 
Section Title(s) 
Description of Change (s) 
1000 mg), under fasting conditions  
Cohort 9:  
TBI-223 IR Tablets 1000 mg. Dose of 2000 mg (2 tablets of 1000 mg), 
under fed conditions.  
Additional cohorts may be enrolled if deemed appropriate by the 
Sponsor to repeat a dose level or to study another dose level or a 
different dosage formulation. 
Synopsis 
Control product, 
dosage and 
mode of 
administration: 
Add the following to the beginning of the section: 
Part 1 only: 
Synopsis 
Criteria of 
evaluation  
Second paragraph. Delete the following pharmacokinetic parameters and 
definitions: 
• 
AUCtau – area under the concentration time curve during the dosing 
interval 
• 
Cavg – average stead state concentration  
• 
CLss/F - apparent total clearance at steady state 
• 
Cmin minimum concentration  
• 
Ctrough- trough plasma concentration 
• 
RAUC accumulation ration for AUC 
• 
RCmax- accumulation ratio for Cmax 
 
Add the following to the definitions of CL/F and Vz/F 
(TBI-223 only) 
 
Delete the third paragraph: 
Noncompartmental pharmacokinetic parameters of AUClast, AUCinf, Cmax, 
Tmax, CL/F, Vz/F, λz, and T1/2 will be calculated from plasma concentrations 
of TBI-223 and M2. Additional pharmacokinetic parameters may be 
calculated if deemed appropriate. 
Add the following to the fourth paragraph from:  
Food Effect: The effect of food will be assessed comparing pharmacokinetic 
parameters under fed versus fasting conditions using an analysis of variance 
(ANOVA) approach. 


Protocol TBI-223-CL-001 Final Version 3.0 
Global Alliance for TB Drug Development 
CONFIDENTIAL 
21 Jan 2020 
Page xi 
Section 
Number 
(s) 
Section Title(s) 
Description of Change (s) 
 
To: 
Food Effect: The effect of food will be assessed comparing pharmacokinetic 
parameters (Cmax, AUCs) under fed versus fasting conditions using an 
analysis of variance (ANOVA) approach. 
 
3 
Study Design 
Summary 
Add the following before the first paragraph of the section 
Part 1: 
 
Add the following to the end of the section, after Table 2 
Part 2:  
Cohort 8: A minimum of 24 subjects in 4 dosing arms are planned to be 
enrolled; within each arm, 6 subjects will be assigned to receive a single 
dose treatment. Subjects will be assigned to one of the following arms 
and dose:  
• 
Arm 1 – TBI-223 SR Tablets (Prototype 1) - 1800 mg dose (3 x 
600 mg tablets), under fed conditions 
• 
Arm 2 – TBI-223 SR Tablets (Prototype 2) -1800 mg dose (3 x 
600 mg tablets), under fed conditions 
• 
Arm 3 – TBI-223 SR Tablets (Prototype 3) - 1800 mg dose (2 x 
900 mg tablets), under fed conditions 
• 
Arm 4 – TBI-223 IR Tablets - 2000 mg dose (2 x 1000 mg tablets), 
under fasting conditions   
Procedures and analyses will be conducted as outlined in Appendix 6.  
Cohort 9: 
The 6 subjects from Cohort 8, Arm 4, who received the IR tablet 
formulation fasted will return after a 7-day washout and receive a single 
dose of TBI-223 IR Tablets, 2000 mg dose (2 x 1000 mg tablets), under 
fed conditions.  
If more than 2 subjects of these 6 subjects from Cohort 8 drop-out, they 
will be replaced by heathy volunteers (a minimum of 4 subjects are 
needed to complete Cohort 9). 
Procedures and analyses will be conducted as outlined in Appendix 6. 
3.1 
Dose Escalation 
Change the title of the section from: 


Protocol TBI-223-CL-001 Final Version 3.0 
Global Alliance for TB Drug Development 
CONFIDENTIAL 
21 Jan 2020 
Page xii 
Section 
Number 
(s) 
Section Title(s) 
Description of Change (s) 
Dose Escalation  
To: 
Part 1 Dose Escalation 
3 (pg 12 
Table 2 
Update Table 2 
From: 
Table 2 presents the planned dose cohorts for the study. 
Table 2 Planned Dose Cohorts 
Cohorta 
(Groupb) 
Dosec 
1 (sentinel 
group) 
Single dose of 50 mg TBI-223 (n=2) 
Placebo (n=1) 
1 (remainder of 
cohort) 
Single dose of 50 mg TBI-223 (n=4) 
Placebo (n=1) 
2 (Group 1) 
Single dose of 100 mg TBI-223 
(n=3)  
Placebo (n=1) 
2 (Group 2) 
Single dose of 100 mg TBI-223 
(n=3)  
Placebo (n=1) 
3 (Group 1) 
Single dose of 300 mg TBI-223 
(n=3)  
Placebo (n=1) 
3 (Group 2) 
Single dose of 300 mg TBI-223 
(n=3)  
Placebo (n=1) 
4 (Group 1) 
Single dose of 600 mg TBI-223 
(n=3)  
Placebo (n=1) 
4 (Group 2) 
Single dose of 600 mg TBI-223 
(n=3)  
Placebo (n=1) 
5 (Group 1) 
Single dose of 1200 mg TBI-223 
(n=3)  
Placebo (n=1) 
5 (Group 2) 
Single dose of 1200 mg TBI-223 
(n=3)  
Placebo (n=1) 
6 (Group 1) 
Single dose of 2000 mg TBI-223 
(n=3)  
Placebo (n=1) 
6 (Group 2) 
Single dose of 2000 mg TBI-223 
(n=3)  
Placebo (n=1) 
 
To: 


Protocol TBI-223-CL-001 Final Version 3.0 
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CONFIDENTIAL 
21 Jan 2020 
Page xiii 
Section 
Number 
(s) 
Section Title(s) 
Description of Change (s) 
Table 2 presents the actual dose cohorts for Part 1 of the study. 
Table 2 Actual Dose Cohorts for Part 1 
Cohorta 
(Groupb) 
Dosec 
1 (sentinel 
group) 
Single dose of 50 mg TBI-223 (n=2) 
Placebo (n=1) 
1 (remainder of 
cohort) 
Single dose of 50 mg TBI-223 (n=4) 
Placebo (n=1) 
2 (Group 1) 
Single dose of 100 mg TBI-223 
(n=3)  
Placebo (n=1) 
2 (Group 2) 
Single dose of 100 mg TBI-223 
(n=3)  
Placebo (n=1) 
3a (Group 1) 
Single dose of 300 mg TBI-223 
(n=3)  
Placebo (n=1) 
3a (Group 2) 
Single dose of 300 mg TBI-223 
(n=3)  
Placebo (n=1) 
3b (Capsule 
cohort) 
Single dose of 300 mg (TBI oral in 
oral enteric) (n=4) 
N/A 
4 (Group 1) 
Single dose of 600 mg TBI-223 
(n=3)  
Placebo (n=1) 
4 (Group 2) 
Single dose of 600 mg TBI-223 
(n=3)  
Placebo (n=1) 
5 (Group 1) 
Single dose of 1200 mg TBI-223 
(n=3)  
Placebo (n=1) 
5 (Group 2) 
Single dose of 1200 mg TBI-223 
(n=3)  
Placebo (n=1) 
6 (Group 1) 
Single dose of 2000 mg TBI-223 
(n=3)  
Placebo (n=1) 
6 (Group 2) 
Single dose of 2000 mg TBI-223 
(n=3)  
Placebo (n=1) 
7 (Group 1) 
Single dose of 2600 mg TBI-223 
(n=3)  
Placebo (n=1) 
7 (Group 2) 
Single dose of 2600 mg TBI-223 
(n=3)  
Placebo (n=1) 
4 
Identity of 
Investigational 
Add the following to Table 3, Identify of Investigational Product  


Protocol TBI-223-CL-001 Final Version 3.0 
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CONFIDENTIAL 
21 Jan 2020 
Page xiv 
Section 
Number 
(s) 
Section Title(s) 
Description of Change (s) 
Product 
From: 
Test Product:  
TBI-223 oral suspension 25 mg/mL 
Manufactured for Global Alliance for TB 
Drug Development 
Control 
Product: 
Placebo for TBI-223 oral suspension  
Manufactured for Global Alliance for TB 
Drug Development 
To: 
Part 1 
Test Product:  
TBI-223 oral suspension 25 mg/mL 
Manufactured for Global Alliance for TB 
Drug Development 
Control 
Product: 
Placebo for TBI-223 oral suspension  
Manufactured for Global Alliance for TB 
Drug Development 
Test Product: 
Cohort 3b 
TBI-223 Oral Enteric Capsules, 150 mg 
Manufactured for Global Alliance for TB 
Drug Development 
Part 2 
Test 
Products: 
Cohort 8 
(Arms 1-4) 
TBI-223 SR Tablets 600 mg (Prototype 1) 
Manufactured for Global Alliance for TB 
Drug Development by Piramal Enterprise 
Limited 
TBI-223 SR Tablets 600 mg (Prototype 2) 
Manufactured for Global Alliance for TB 
Drug Development by Piramal Enterprise 
Limited 
TBI-223 SR Tablets 900 mg (Prototype 3) 
Manufactured for Global Alliance for TB 
Drug Development by Piramal Enterprise 
Limited 
TBI-223 IR Tablets 1000 mg 
Manufactured for Global Alliance for TB 
Drug Development by Piramal Enterprise 
Limited 
Test 
Products: 
Cohort 9 
TBI-223 IR Tablets 1000 mg 
Manufactured for Global Alliance for TB 
Drug Development by Piramal Enterprise 
Limited 


Protocol TBI-223-CL-001 Final Version 3.0 
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CONFIDENTIAL 
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Page xv 
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6.1 
Subjects 
Assignment 
From: 
Up to 50 subjects are planned to be enrolled in the study. 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 selected for the study 
was based on the adequate number considered to provide sufficient safety 
data. 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.  
Note: the repeat cohort using a different dosage formulation will be non-
randomized and unblinded; see Appendix 5. 
To: 
For Part 1, up to 50 subjects are planned to be enrolled in the study. 
Additional subjects may be enrolled if deemed appropriate by the Sponsor to 
repeat a dose level or to study another dose level. For Part 2, Cohort 8, 24 
subjects will be enrolled. For Part 2, Cohort 9, the 6 subjects from 
Cohort 8 who received the IR tablet formulation fasted will return after 
a 7-day washout and receive the IR tablet formulation under fed 
conditions. If more than 2 subjects of these 6 subjects from Cohort 
8 drop-out, they will be replaced by heathy volunteers (a minimum 
of 4 subjects are needed to complete Cohort 9). 
The number of subjects selected for the study was based on the adequate 
number considered to provide sufficient safety data. This study has not been 
formally powered. 
For Part 1, 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.  
Note: the repeat cohort using a different dosage formulation in Part 1 and 
subjects in Part 2 will be non-randomized and unblinded; see Appendix 5 
and Appendix 6. 
6.3 
Check-in 
Procedures 
Update the first sentence from:  
Subjects will check into the clinic on Day -2.  
To: 
Subjects will check into the clinic on Day -2 for Part 1 and Day -1 for Part 
2.  


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Add the following to the last bullet point: 
(Part 1 only) 
6.4 
Confinement  
First paragraph, change from: 
Fasting cohorts: Subjects will be admitted to the research center on Day -2 
and remain confined until after completion of the 48-hour procedures on Day 
3. Subjects will return for a follow-up visit approximately 72 hours after 
dosing (Day 4) and receive a follow up phone call on Day 11 (+1 day). 
To: 
Part 1 fasting cohorts and Part 2, Cohort 8, Arm 4 only: Subjects will be 
admitted to the research center on Day -2 (Part 1) or Day -1 (Part 2) and 
remain confined until after completion of the 48-hour procedures on Day 3. 
Subjects will return for a follow-up visit approximately 72 hours after dosing 
(Day 4) and receive a follow up phone call on Day 11 (+1 day). 
Second paragraph, change from: 
Food-effect cohort: Subjects will be admitted to the research center on Day -2 
of Period 1 and Period 2 and remain confined until after completion of the 
48-hour procedures on Day 3 of each study period. Subjects will return for a 
follow-up visit approximately 72 hours after dosing (Day 4) in each study 
period. Subjects will receive a follow up phone call on Day 11 (+1 day) of 
Period 2. 
To: 
Part 1 food-effect cohort, Part 2, Cohort 8, Arms 1-3 and Cohort 9: 
Subjects will be admitted to the research center on Day -2 of Period 1 and 
Period 2 (Part 1) or Day -1 (Part 2) and remain confined until after 
completion of the 48-hour procedures on Day 3 of each study period. 
Subjects will return for a follow-up visit approximately 72 hours after dosing 
(Day 4) in each study period. Subjects will receive a follow up phone call on 
Day 11 (+1 day) of Period 2. 
Please note that Cohort 9 is the same 6 subjects that were in Cohort 8, 
Arm 4 (IR tablet formulation) under fed conditions. In Cohort 8, Arm 4, 
subjects fasted. 
6.5.1 
Fasting/Meals 
First paragraph, change from: 
Fasted cohorts: Optional meals (lunch, snack, and dinner) may be served the 
day of check-in. All subjects will then be required to fast for at least 10 hours 
before dosing. The subjects will fast for 4 hours after dosing. Standard meals 
will be provided at appropriate times after dosing. 
To: 


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Part 1 fasted cohorts and Part 2, Cohort 8, Arm 4 only: Optional meals 
(lunch, snack, and dinner) may be served the day of check-in. All subjects 
will then be required to fast for at least 10 hours before dosing. The subjects 
will fast for 4 hours after dosing. Standard meals will be provided at 
appropriate times after dosing. 
Second paragraph, change from: 
Food-effect cohort: Optional meals (lunch, snack, and dinner) may be served 
the day of check-in.  
To: 
Part 1 food-effect cohort, Part 2, Cohort 8, Arms 1-3 and Cohort 9: 
Optional meals (lunch, snack, and dinner) may be served the day of check-in.  
Fourth paragraph, first sentence, change from:  
In the fed study period. Subjects will be required to fast for at least 10 hours 
overnight before consuming a required FDA standard high-fat, high-calorie 
breakfast. 
To: 
In the fed study period of Part 1 and Part 2 (Cohort 8, Arms 1-3 and 
Cohort 9), subjects will be required to fast for at least 10 hours overnight 
before consuming a required FDA standard high-fat, high-calorie breakfast. 
Add the following to the end of the section: 
Please note that Part 2, Cohort 9 is the same 6 subjects that were in 
Cohort 8 Arm 4 (IR tablet formulation) under fed conditions. In Cohort 
8 Arm 4, subjects fasted. 
6.6 
Drug 
administration 
Add the following subsection: 
6.6.3 Administration of TBI-223 SR and IR Tablets 
Add the following to the new section: 
For Part 2, Cohort 8 and Cohort 9, each subject will receive the oral dose 
of the assigned study treatment (TBI-223 SR tablet formulations 
[Prototypes 1, 2, or 3] or TBI-223 IR tablet formulation) with 
approximately 240 mL (8 fl. oz.) 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, 


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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. 
6.7.1 
Fasting cohort 
Change title of section from: 
Fasting cohort 
To: 
Part 1 fasting cohorts, Part 2, Cohort 8, Arm 4 only 
6.7.2 
Food-effect 
cohort 
Change title of section from: 
Food-effect cohort 
To: 
Part 1 food-effect cohort, Part 2, Cohort 8, Arms 1-3 only, and Cohort 9 
Add the following after the first paragraph: 
Please note that Part 2, Cohort 9 is the same 6 subjects that were in 
Cohort 8 Arm 4 (IR tablet formulation) under fed conditions. In Cohort 
8 Arm 4, subjects fasted. 
6.9.7 
Cardiac Holter 
Monitoring, and 
Cardiodynamic 
Assessment 
Add the following sentence to the end of the section: 
 
Part 2 of the study will not have cardiac Holter monitoring. 
8.4 
Indications for 
Subject 
Withdrawal 
Add the following paragraphs to the end of the section: 
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. 
For Part 1, replacement subjects will be numbered 17XX where XX is 10 
plus the original subject’s last 2 assigned numbers (e.g. if subject 1702 
needs to be replaced due to emesis, the replacement subject number 
would be 1712). Replacement subjects will receive the same dose 
allocation of study drug. 
9.2 
Pharmacokinetic 
Analysis 
Add the following to the definitions of CL/F and Vz/F: 
(TBI-223 only) 
Deleted the first sentence from third paragraph, from: 
Noncompartmental pharmacokinetic parameters of AUClast, AUCinf, Cmax, 
Tmax, CL/F, Vz/F, λz, and T1/2 will be calculated from plasma concentrations 
of TBI-223 and M2. Additional pharmacokinetic parameters may be 


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calculated if deemed appropriate. 
To: 
Additional pharmacokinetic parameters may be calculated if deemed 
appropriate. 
Add the following to last paragraph, from: 
Food Effect: The effect of food will be assessed comparing pharmacokinetic 
parameters under fed versus fasting conditions using an analysis of variance 
(ANOVA) approach. 
To: 
Food Effect: The effect of food will be assessed comparing pharmacokinetic 
parameters (Cmax, AUCs) under fed versus fasting conditions using an 
analysis of variance (ANOVA) approach.  
9.3 
Statistical 
Analysis 
Second and third paragraph, change from: 
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. 
Food-effect cohort: The effect of food will be assessed comparing 
pharmacokinetic parameters under fed versus fasting conditions using an 
analysis of variance (ANOVA) approach. 
To: 
Pharmacokinetic parameters will be summarized by cohort using descriptive 
statistics. Summary statistics will also be presented by gender within each 
cohort. Dose proportionality for exposure parameters (Cmax, AUCs) will be 
assessed using a power model approach. 
Food-effect cohort: The effect of food will be assessed comparing 
pharmacokinetic parameters (Cmax, AUCs) under fed versus fasting 
conditions using an analysis of variance (ANOVA) approach. 
11 
Drug Supplies 
Add the following to the end of the section: 
Global Alliance for TB Drug Development will supply sufficient quantity 
of the study drug, TBI 223 SR tablet formulations (Prototypes 1, 2, and 
3) and TBI-223 IR tablet formulation for Part 2 of the study. 
Study drug formulations will be shipped to Worldwide Clinical Trials 
Early Phase Services, LLC 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 


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21 Jan 2020 
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Section 
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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 
returned to the sponsor or destroyed by the site pursuant to written 
authorization by the sponsor and applicable federal and state 
regulations. 
Table 9 
Schedule of 
Assessments 
Change title of table from: 
Schedule of Assessments  
 
To: 
Schedule of Assessments, Part 1 
Appendix 
2 
Description and 
Composition of 
Test Product 
Add the following before the first paragraph:  
Oral Suspension  
Add the following to the end of the section after the fifth paragraph:  
Enteric Capsules 
Description of the Dosage Form 
TBI-223 Oral Enteric Capsules contain 150 mg TBI-223 in Vcaps® 
Enteric capsules. The capsules are filled at the clinical study site by 
manually filling TBI-223 into Vcaps® Enteric capsules which are 
commercially available empty capsule shells.   
Composition of the Drug Product 
The quantitative composition, function and quality of each ingredient in 
the drug product (TBI-223 Oral Enteric Capsules, 150 mg) is provided in 
Table 10. 
 
Table 10 Qualitative and Quantitative Composition of the TBI-223 Oral 
Enteric Capsules, 150 mg 
Ingredient 
Function 
Quality Standard 
Quantity per 300 
mg Dose 
TBI-223 
Drug 
Substance 
In-house 
300 mg 


Protocol TBI-223-CL-001 Final Version 3.0 
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21 Jan 2020 
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Section 
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Vcaps® Enteric 
Capsules1, Off-
white, Opaque, Size 
00 
Capsule shell 
Commercially 
available 
2 capsules 
Total Quantity 
300 mg in 2 
capsules 
1Capsule shell composition: titanium dioxide 2% in Hypromellose-Hypromellose 
AS. 
Container and Closure System 
TBI-223 Oral Enteric Capsules are stored in white HDPE bottles with 
PP CRC with a liner. These bottles are used for storage prior to 
administration.  
 
Tablets 
Description of the Dosage Form 
TBI-223 tablets are supplied as immediate release (IR) or sustained release 
(SR).  The description of the tablets and strengths are presented in Table 11. 
Table 11 Strength, Tablet Weight and Appearance of TBI-223 IR and SR 
Tablets 
Tablet Strength 
Tablet Weight 
Tablet Appearance 
TBI-223 Immediate Release (IR) Tablets 
600 mg 
750 mg 
White to off-white, 
capsule shaped tablets, 
debossed with “TBA” on 
one side and “22” on the 
other 
1000 mg 
1250 mg 
White to off-white, oval 
shaped tablets, debossed 
with “TBA” on one side 
and “23” on the other 
TBI-223 Sustained Release (SR) Tablets 
600 mg (Prototype 1) 
1000 mg 
White to off-white, 
capsule shaped tablets, 
debossed with “TBA” on 
one side and “11” on the 
other 
600 mg (Prototype 2) 
1000 mg 
White to off-white, 


Protocol TBI-223-CL-001 Final Version 3.0 
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21 Jan 2020 
Page xxii 
Section 
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capsule shaped tablets, 
debossed with “TBA” on 
one side and “SR” on 
the other 
900 mg (Prototype 3) 
1200 mg 
White to off-white, oval 
shaped tablets, debossed 
with “TBA” on one side 
and “900” on the other 
Composition of the Drug Product 
The composition of TBI-223 IR tablets, 600 mg and 1000 mg is presented 
in Table 12.  The composition of TBI-223 SR Tablets, 600 mg (Prototype 
1), 600 mg (Prototype 2) and 900 mg (prototype 3) is presented in Table 
13, Table 14 and Table 15, respectively. 
 
Table 12 Composition of TBI-223 IR Tablets, 600 mg and 1000 mg 
Component 
Function 
Percentage 
(% w/w) 
600 
1000 
Reference 
to 
Standard
mg/tablet 
 
 
Intragranular 
 
TBI-223 a 
Active 
80.00 
600.00 
1000.00 
In-House 
Microcrystalline 
cellulose 
(Avicel PH 302) 
b 
Diluent 
10.00 
75.00 
125.00 
USP-NF, 
Ph.Eur. 
Hypromellose 
(Methocel E5 
Premium LV) 
Binder 
3.00 
22.50 
37.50 
USP-NF, 
Ph.Eur. 
Crospovidone 
(Kollidon CL) 
Disintegrant 
3.00 
22.50 
37.50 
USP-NF, 
Ph.Eur. 
Purified water c 
Granulating 
solvent 
q.s 
q.s 
q.s 
USP, 
Ph.Eur. 
 
 
Extragranular 
 
Crospovidone 
(Kollidon CL) 
Disintegrant 
2.00 
15.00 
25.00 
USP-NF, 
Ph.Eur. 
Colloidal silicon 
dioxide 
(Aerosil 200 
Pharma) 
Glidant 
1.00 
7.50 
12.50 
USP-NF, 
Ph.Eur. 
Magnesium 
stearate 
(Ligamed MF-2-
V) 
Lubricant 
1.00 
7.50 
12.50 
USP-NF, 
Ph.Eur. 


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CONFIDENTIAL 
21 Jan 2020 
Page xxiii 
Section 
Number 
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Total unit dose 
 
100.00 
750.0 
1250.0 
 
a  
The molecular weight of TBI-223 is 365.4 g/mol. The actual quantity may 
be adjusted based on the assay value (anhydrous basis) and water 
content of the drug substance lot used.    
b   The quantity of microcrystalline cellulose may be adjusted to 
compensate for the actual amount of TBI-223 and to maintain a constant 
tablet weight. 
c   Removed during processing. 
Table 13 Composition of TBI-223 SR Tablets, 600 mg (Prototype 1) 
Component 
Function 
Percentage 
(% w/w) 
mg/tablet 
Reference 
to 
Standard 
 
 
Intragranular  
 
TBI-223 a 
Active 
60.00 
600.00 
In-House 
Lactose 
monohydrate b 
(Pharmatose 
200M) 
Diluent 
9.90 
99.00 
USP-NF, 
Ph.Eur. 
Microcrystalline 
cellulose 
(Avicel PH 200) 
Diluent 
6.60 
66.00 
USP-NF, 
Ph.Eur. 
Hypromellose 
(Methocel E5 
Premium LV) 
Binder 
5.00 
50.00 
USP-NF, 
Ph.Eur. 
Purified water c 
Granulating 
solvent 
q.s 
q.s 
USP, 
Ph.Eur. 
 
 
Extragranular 
 
Hypromellose 
(Methocel K100M 
Premium DC2) 
Control 
Release 
Polymer 
16.00 
160.00 
USP-NF, 
Ph.Eur. 
Colloidal silicon 
dioxide 
(Aerosil 200 
Pharma) 
Glidant 
1.50 
15.00 
USP-NF, 
Ph.Eur. 
Magnesium 
stearate 
(Ligamed MF-2-
V) 
Lubricant 
1.00 
10.00 
USP-NF, 
Ph.Eur. 
Total unit dose 
 
100.00 
1000.0 
 


Protocol TBI-223-CL-001 Final Version 3.0 
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21 Jan 2020 
Page xxiv 
Section 
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a  
The molecular weight of TBI-223 is 365.4 g/mol. The actual quantity 
may be adjusted based on the assay value (anhydrous basis) and 
water content of the drug substance lot used.    
b   The quantity of lactose monohydrate may be adjusted to compensate 
for the actual amount of TBI-223 and to maintain a constant tablet 
weight. 
c   
Removed during processing. 
Table 14 Composition of TBI-223 SR Tablets, 600 mg (Prototype 2) 
Component 
Function 
Percentage 
(% w/w) 
mg/tablet 
Reference 
to 
Standard 
 
 
Intragranular  
 
TBI-223 a 
Active 
60.00 
600.00 
In-House 
Lactose 
monohydrate b 
(Pharmatose 
200M) 
Diluent 
12.90 
129.00 
USP-NF, 
Ph.Eur. 
Microcrystalline 
cellulose 
(Avicel PH 200) 
Diluent 
8.60 
86.00 
USP-NF, 
Ph.Eur. 
Hypromellose 
(Methocel K4M 
Premium CR) 
Control 
Release 
Polymer 
5.00 
50.00 
USP-NF, 
Ph.Eur. 
Purified water c 
Granulating 
solvent 
q.s 
q.s 
USP, 
Ph.Eur. 
 
 
Extragranular 
 
Hypromellose 
(Methocel K100 
Premium LV) 
Control 
Release 
Polymer 
11.00 
110.00 
USP-NF, 
Ph.Eur. 
Colloidal silicon 
dioxide 
(Aerosil 200 
Pharma) 
Glidant 
1.50 
15.00 
USP-NF, 
Ph.Eur. 
Magnesium 
stearate 
(Ligamed MF-2-V) 
Lubricant 
1.00 
10.00 
USP-NF, 
Ph.Eur. 
Total unit dose 
 
100.00 
1000.0 
 


Protocol TBI-223-CL-001 Final Version 3.0 
Global Alliance for TB Drug Development 
CONFIDENTIAL 
21 Jan 2020 
Page xxv 
Section 
Number 
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Description of Change (s) 
a  
The molecular weight of TBI-223 is 365.4 g/mol. The actual quantity 
may be adjusted based on the assay value (anhydrous basis) and 
water content of the drug substance lot used.    
b   The quantity of lactose monohydrate may be adjusted to compensate 
for the actual amount of TBI-223 and to maintain a constant tablet 
weight. 
c   
Removed during processing. 
Table 15 Composition of TBI-223 SR Tablets, 900 mg (Prototype 3) 
Component 
Function 
Percentage 
(% w/w) 
mg/tablet 
Reference 
to 
Standard 
 
 
Intragranular  
 
TBI-223 a 
Active 
75.00 
900.00 
In-House 
Lactose 
monohydrate b 
(Pharmatose 
200M) 
Diluent 
3.90 
46.80 
USP-NF, 
Ph.Eur. 
Microcrystalline 
cellulose 
(Avicel PH 200) 
Diluent 
2.60 
31.20 
USP-NF, 
Ph.Eur. 
Hypromellose 
(Methocel E5 
Premium LV) 
Binder 
5.00 
60.00 
USP-NF, 
Ph.Eur. 
Purified water c 
Granulating 
solvent 
q.s 
q.s 
USP. 
Ph.Eur. 
 
 
Extragranular 
 
Hypromellose 
(Methocel K100M 
Premium DC2) 
Control 
Release 
Polymer 
11.00 
132.00 
USP-NF, 
Ph.Eur. 
Colloidal silicon 
dioxide 
(Aerosil 200 
Pharma) 
Glidant 
1.50 
18.00 
USP-NF, 
Ph.Eur. 
Magnesium 
stearate 
(Ligamed MF-2-V) 
Lubricant 
1.00 
12.00 
USP-NF, 
Ph.Eur. 
Total unit dose 
 
100.00 
1200.0 
 


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21 Jan 2020 
Page xxvi 
Section 
Number 
(s) 
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Description of Change (s) 
a  
The molecular weight of TBI-223 is 365.4 g/mol. The actual quantity 
may be adjusted based on the assay value (anhydrous basis) and 
water content of the drug substance lot used.    
b   The quantity of lactose monohydrate may be adjusted to compensate 
for the actual amount of TBI-223 and to maintain a constant tablet 
weight. 
c   Removed during processing. 
Container and Closure System 
TBI-223 IR and SR 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). 
Appendix 
6 
Part 2 of the 
study 
Add the following: 
Procedures and analyses as outlined in this protocol will be the same, 
with the following exceptions: 
The dose of TBI-223 will be delivered as follows in Cohort 8: 
• 
Arm 1 – TBI-223 SR Tablets (Prototype 1) - 1800 mg dose (3 x 
600 mg tablets), under fed conditions 
• 
Arm 2 – TBI-223 SR Tablets (Prototype 2) - 1800 mg dose (3 x 
600 mg tablets), under fed conditions 
• 
Arm 3 – TBI-223 SR Tablets (Prototype 3) - 1800 mg dose (2 x 
900 mg tablets), under fed conditions 
• 
Arm 4 – TBI-223 IR Tablets - 2000 mg dose (2 x 1000 mg 
tablets), under fasting conditions   
In Cohort 9, the subjects from Cohort 8, Arm 4, who received the IR 
tablet formulation will be brought back following a 7-day washout and 
administered TBI-223 IR tablets, 2000 mg dose (2 x 1000 mg tablets), 
under fed conditions. 
• 
A minimum of 6 subjects per treatment arm in Part 2 
• 
Part 2 will not be blinded (blinding is not necessary because all 
subjects will receive the same treatment). 
• 
Cardiac telemetry and Holter recording will not be performed 
during Part 2. Subjects will check-in on Day -1 instead of Day -2. 
With the exception of cardiac telemetry and Holter monitoring, 
the procedures that were previously scheduled for Day -2 will be 
performed on Day -1. The Day -1 results will be used to qualify 
repeat subjects for study participation. If additional subjects are 


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21 Jan 2020 
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Section 
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needed, they will undergo screening to qualify for the study. 
• 
Neurological examinations will be performed at Screening, Day -
1, and at 3 and 48 hours postdose. 
Add Table 16, Schedule of Assessments, Part 2  
 


Protocol TBI-223-CL-001 Final Version 3.0 
 
Global Alliance for TB Drug Development          CONFIDENTIAL                                               21 Jan 2020 
Page xxviii 
PROTOCOL SYNOPSIS 
Name of Sponsor/Company: Global Alliance for TB Drug Development 
Name of test product: TBI-223 oral suspension 
Name of active ingredient: TBI-223 
Title of study: A Phase 1, Partially-Blinded, Placebo-Controlled, Randomized, Single Ascending Dose 
(SAD) with a Food Effect Cohort Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of 
TBI-223 in Healthy Adult Participants 
Principal Investigator: Cynthia A. Zamora, MD 
Study Center  
Worldwide Clinical Trials Early Phase Services, LLC 
2455 NE Loop 410, Suite 150 
San Antonio, Texas 78217 
Study period (maximum duration, from screening to 
study exit):   
Part 1:  
Single ascending dose (SAD) cohort (fasting): 40 days 
Food-effect cohort: 50 days 
Part 2:  
Cohort 8: Single dose cohort of the 4 TBI-223 tablet 
formulations (Prototypes 1, 2, and 3 Sustained Release 
[SR] tablet formulations under fed conditions and one 
Immediate Release [IR] tablet formulation under fasting 
conditions): Duration 40 days. 
Cohort 9: The IR tablet formulation will be evaluated 
under fed conditions  
Single dose: 40 days 
The maximum duration of the study will depend upon the 
final number and timing of each cohort. 
Phase of development: 1 
 
Duration of treatment:  
Part 1: 
Fasting cohorts: One single dose of TBI-223 oral 
suspension or placebo for TBI-223 oral suspension 
Food-effect cohort: Two single doses of TBI-223 oral 
suspension or placebo for TBI-223 oral suspension 
separated by a washout period of at least 7 days 
Number of sites enrolling subjects: 1 


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Part 2: 
Cohort 8: Single dose cohort of 4 TBI-223 tablet 
formulations (Three SR tablet formulations as prototypes 
1, 2, and 3 and one IR tablet formulation). The SR tablet 
formulations will be evaluated under fed conditions and 
the IR tablet formulation will be evaluated under fasting 
conditions  
Cohort 9: The IR tablet formulation will be evaluated 
under fed conditions  
Number of subjects (planned):  
Part 1: 
Fasting Cohorts: Planned to enroll up to 48 subjects in a total of 6 single ascending dose (SAD) cohorts 
of 8 subjects each (6 to receive active drug and 2 to receive placebo). 
Food-effect Cohort:  1 cohort with 10 subjects (8 active and 2 placebo) who will receive TBI-223 or 
placebo under both fasting and fed conditions.   
Part 2: 
Cohort 8: Planned to enroll 24 subjects in a total of 4 arms with 6 subjects in each. Subjects will 
receive a single dose of 1 of the 3 prototypes of TBI-223 SR tablets under fed conditions (Arms 1-3) or 
a single dose of TBI-223 IR tablets under fasted conditions (Arm 4). 
Cohort 9: Plan to bring back the 6 subjects from Cohort 8, Arm 4, who received the IR tablet 
formulation, following a 7-day washout to receive the IR tablet formulation under fed conditions.  
If more than 2 subjects of these 6 subjects from Cohort 8 drop-out, they will be replaced by heathy 
volunteers (a minimum of 4 subjects are needed to complete Cohort 9). 
Additional cohorts may be enrolled if deemed appropriate by the Sponsor to repeat a dose level or to 
study another dose level. These decisions 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 this revised approach. 
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, who do not 
use tobacco or nicotine-containing products. Females must be of non-childbearing potential or must use 
an allowable method of birth control. 
Objectives:  
The primary objective of the study is: 
• 
To evaluate the safety and tolerability of single ascending doses of TBI-223 oral suspension, TBI-
223 oral enteric capsules, and TBI-223 tablet formulations in healthy adult subjects.  


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The secondary objectives of the study are: 
• 
To determine the pharmacokinetics of TBI-223 and its metabolite M2 after single doses of 
TBI-223 oral suspension, TBI-223 oral enteric capsules, and TBI-223 tablet formulations in 
healthy adult subjects; and 
• 
To compare the rate and extent of absorption of a single dose of TBI-223 oral suspension, 
TBI-223 oral enteric capsules, and TBI-223 tablet formulations when administered in healthy 
adult subjects either after a high-calorie, high-fat meal or in the fasting state. 
This is a partially-blinded, placebo-controlled, randomized SAD study with a food effect cohort. The 
study will be conducted at one study center in the United States. 
Safety will be assessed throughout the study for all subjects. 
Blood will be collected for pharmacokinetic analysis. Plasma samples will be analyzed for TBI-223 
and TBI-223 metabolite (M2).  
Part 1: 
There will be up to 6 planned dose levels. Based on interim pharmacokinetic data obtained during the 
dose escalation, a dose cohort will be selected to return for additional dosing after a high-calorie, high-
fat meal (food-effect cohort). 
Sentinel Cohort: The first cohort will be separated into 2 groups. A sentinel group of 3 subjects 
(2 active and 1 placebo) will be dosed at least 24 hours before the remaining 5 subjects (4 active and 
1 placebo). The remaining cohorts will be dosed in 2 groups of 4 subjects each (3 active and 
1 placebo), at least 24 hours apart. 
Food-effect Cohort: Based on exposure levels, subjects in one of the dose levels will return after a 
7-day minimum washout or 5 half-lives of the drug (whichever is longer) to receive the same dose 
under fed conditions. 
Dose escalation to the next cohort (i.e., dose level) 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 has been demonstrated to permit proceeding to the next cohort. 
Part 2: 
Cohort 8: 
There will be 4 arms each consisting of 6 subjects. Subjects will be assigned to one of the following 
arms and dose:  
• 
Arm 1 – TBI-223 SR Tablets (Prototype 1) - 1800 mg dose (3 x 600 mg tablets), under fed 
conditions 
• 
Arm 2 – TBI-223 SR Tablets (Prototype 2) - 1800 mg dose (3 x 600 mg tablets), under fed 
conditions 
• 
Arm 3 – TBI-223 SR Tablets (Prototype 3) - 1800 mg dose (2 x 900 mg tablets), under fed 


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conditions 
• 
Arm 4 – TBI-223 IR Tablets - 2000 mg dose (2 x 1000 mg tablets), under fasting conditions   
 
Cohort 9:  
The 6 subjects from Cohort 8, Arm 4, who received the IR tablet formulation will be brought back 
following a 7-day washout – TBI-223 IR Tablets – 2000 mg (2 x 1000 mg tablets), under fed 
conditions. 
If more than 2 subjects of these 6 subjects from Cohort 8 drop-out, they will be replaced by heathy 
volunteers (a minimum of 4 subjects are needed to complete Cohort 9). 
Additional cohorts may be enrolled if deemed appropriate (e.g. if bioavailability is lower than 
expected) by the Sponsor to repeat a dose level, to study other dose levels, change proposed cohorts, or 
to study a different dosage formulation. These 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 have been demonstrated to permit proceeding to the next cohort. The Institutional Review Board 
(IRB) should be immediately notified of this revised approach for review and approval. 


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Test product, dosage and mode of administration:  
Part 1: 
TBI-223 oral suspension, orally administered 
Dose level 1 = single dose of 50 mg TBI-223 
Dose level 2 = single dose of 100 mg TBI-223 
Dose level 3 = single dose of 300 mg TBI-223 
Dose level 3 includes a Cohort 3a with TBI-223 (oral suspension) and the same subjects participated 
in Cohort 3b with TBI-223 within oral enteric capsules 
Dose level 4 = single dose of 600 mg TBI-223 
Dose level 5 = single dose of 1200 mg TBI-223 
Dose level 6 = single dose of 2000 mg TBI-223 
Dose level 7= Single dose of 2600 mg TBI-223 
Additional cohorts may be enrolled if deemed appropriate by the Sponsor to repeat a dose level or to 
study another dose level or a different dosage formulation. 
Part 2: 
Cohort 8: 
Arm 1 - TBI-223 SR Tablets 600 mg (Prototype 1). Dose of 1800 mg (3 tablets of 600 mg), under fed 
conditions 
Arm 2 - TBI-223 SR Tablets 600 mg (Prototype 2). Dose of 1800 mg (3 tablets of 600 mg), under fed 
conditions 
Arm 3 - TBI-223 SR Tablets 900 mg (Prototype 3). Dose of 1800 mg (2 tablets of 900 mg), under fed 
conditions  
Arm 4 - TBI-223 IR Tablets 1000 mg. Dose of 2000 mg (2 tablets of 1000 mg), under fasting 
conditions  
Cohort 9: 
TBI-223 IR Tablets 1000 mg. Dose of 2000 mg (2 tablets of 1000 mg), under fed conditions.  
Additional cohorts may be enrolled if deemed appropriate by the Sponsor to repeat a dose level or to 
study another dose level or a different dosage formulation. 
Control product, dosage and mode of administration:  
Part 1 only: 
Placebo for TBI-223 oral suspension; orally administered 
All levels = Single dose of placebo for TBI-223 oral suspension 
 
 


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Criteria for evaluation:  
Safety: Safety assessments will include physical and neurological examinations, vital signs including 
heart rate and respiratory rate, electrocardiograms (ECGs), cardiac monitoring, adverse events (AEs), 
and clinical laboratory tests (including hematology, 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: Final pharmacokinetic calculations will be performed using appropriate software, 
e.g. Phoenix™ WinNonlin® (Version 8.1 or higher, Certara, L.P. in conjunction with the internet-
accessible implementation of Pharsight® Knowledgebase ServerTM [PKSO; Version 4.0.4 or higher, 
Certara, L.P.]) 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 
Clast 
The last quantifiable concentration determined directly from individual 
concentration-time data  
CL/F 
Apparent total clearance after single administration (TBI-223 only) 
Cmax 
Maximum concentration, determined directly from individual concentration-time 
data 
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
=
 
Vz/F 
Apparent volume of distribution in the terminal phase (TBI-223 only) 
λz 
The observed terminal rate constant; estimated by linear regression through at 
least 3 data points in the terminal phase of the log concentration-time profile 


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Pharmacokinetic parameters will be summarized by cohort using descriptive statistics. Dose 
proportionality will be assessed using the power model approach. 
Food Effect: The effect of food will be assessed comparing pharmacokinetic parameters (Cmax, AUCs) 
under fed versus fasting conditions using an analysis of variance (ANOVA) approach. 
Efficacy: No efficacy evaluations will be performed in this study. 
 


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TABLE OF CONTENTS 
PROTOCOL APPROVAL PAGE .................................................................................................. ii 
SUMMARY OF CHANGES ......................................................................................................... iii 
PROTOCOL SYNOPSIS ........................................................................................................ xxviii 
TABLE OF CONTENTS ...........................................................................................................xxxv 
LIST OF TABLES .................................................................................................................. xxxvii 
LIST OF FIGURES ............................................................................................................... xxxviii 
LIST OF ABBREVIATIONS .................................................................................................. xxxix 
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 
Adverse Effects, Warnings, and Precautions .......................................................................4 
1.5 
Overview and Dose Rationale .............................................................................................6 
2 
OBJECTIVE ........................................................................................................................9 
3 
STUDY DESIGN SUMMARY ...........................................................................................9 
3.1 
Part 1 Dose Escalation .......................................................................................................13 
3.2 
Stopping Rules for Cohorts ................................................................................................14 
4 
IDENTITY OF INVESTIGATIONAL PRODUCT ..........................................................14 
5 
SUBJECT SELECTION ....................................................................................................15 
5.1 
Inclusion Criteria ...............................................................................................................15 
5.2 
Exclusion Criteria ..............................................................................................................17 
5.3 
Medication and Activity Restrictions ................................................................................20 
5.4 
Screening............................................................................................................................21 
6 
STUDY PROCEDURES ...................................................................................................21 
6.1 
Subject Assignment ...........................................................................................................21 
6.2 
Blinding..............................................................................................................................22 
6.2.1 Clinical Research Staff ......................................................................................................23 
6.2.2 Study Subjects ....................................................................................................................23 
6.2.3 Bioanalytical Laboratory ...................................................................................................23 
6.2.4 Pharmacokinetic Analysis ..................................................................................................23 
6.2.5 Cardiac Vendor ..................................................................................................................23 
6.2.6 Unblinding Procedures.......................................................................................................23 
6.3 
Check-In Procedures ..........................................................................................................23 
6.4 
Confinement .......................................................................................................................24 
6.5 
Fasting/Meals/Beverages ...................................................................................................24 
6.5.1 Fasting/Meals3....................................................................................................................24 
6.5.2 Beverages ...........................................................................................................................25 
6.6 
Drug Administration ..........................................................................................................25 
6.6.1 Administration of oral care strips ......................................................................................25 


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6.6.2 Administration of TBI-223 Oral Suspension or Placebo for TBI-223 Oral Suspension ...26 
6.6.3 Administration of TBI-223 Sustained Release and Immediate Release Tablets ...............26 
6.7 
Blood Sampling, Processing and Shipment .......................................................................27 
6.7.1 Part 1 fasting cohorts, and Part 2, Cohort 8, Arm 4 only ...................................................27 
6.7.2 Part 1 food-effect cohort, Part 2, Cohort 8, Arms 1-3 only, and Cohort 9 ........................27 
6.7.3 Pharmacokinetic Sampling Time Windows .......................................................................28 
6.8 
End-of-Study Procedures ...................................................................................................28 
6.9 
Safety Monitoring and Procedures .....................................................................................29 
6.9.1 Adverse Events ..................................................................................................................29 
6.9.2 Clinical Laboratory Evaluations ........................................................................................29 
6.9.3 Vital Signs ..........................................................................................................................30 
6.9.4 Physical Examinations .......................................................................................................30 
6.9.5 Neurological Examinations ................................................................................................30 
6.9.6 12-Lead Electrocardiograms ..............................................................................................31 
6.9.7 Cardiac Holter Monitoring, and Cardiodynamic Assessment ...........................................31 
6.9.8 Other Safety Measures .......................................................................................................31 
7 
ADVERSE EVENTS .........................................................................................................32 
7.1 
Definitions..........................................................................................................................32 
7.1.1 Adverse Event ....................................................................................................................32 
7.1.2 Serious Adverse Event .......................................................................................................32 
7.2 
Attribution/Causality..........................................................................................................33 
7.3 
Reporting............................................................................................................................35 
7.3.1 Adverse Event ....................................................................................................................35 
7.4 
Serious Adverse Event Reporting ......................................................................................35 
7.5 
Follow up of Adverse Events .............................................................................................36 
7.6 
Post-Trial Serious Adverse Events ....................................................................................37 
7.7 
Clinical Laboratory Adverse Events ..................................................................................37 
7.8 
Drug Interaction .................................................................................................................38 
7.9 
Pregnancy ...........................................................................................................................38 
7.10 
Monitoring and Safety for Specific Toxicities...................................................................38 
8 
GENERAL CONSIDERATIONS .....................................................................................38 
8.1 
Basic Principles ..................................................................................................................38 
8.2 
Institutional Review Board ................................................................................................39 
8.3 
Informed Consent...............................................................................................................39 
8.4 
Indications for Subject Withdrawal ...................................................................................39 
8.5 
Termination of the Study ...................................................................................................39 
8.6 
Documentation ...................................................................................................................40 
8.7 
Trial Monitoring.................................................................................................................40 
8.8 
Reimbursement, Indemnity, and Insurance .......................................................................40 
9 
PHARMACOKINETIC ANALYSIS ................................................................................40 
9.1 
Analytical Methodology ....................................................................................................40 


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9.2 
Pharmacokinetic Analysis ..................................................................................................40 
9.3 
Statistical Analysis .............................................................................................................42 
10 
FACILITIES ......................................................................................................................42 
11 
DRUG SUPPLIES .............................................................................................................43 
12 
ADMINISTRATIVE ISSUES ...........................................................................................44 
13 
EVENTS SCHEDULE ......................................................................................................45 
14 
REFERENCES ..................................................................................................................48 
APPENDIX 1 PHARMACOKINETIC SAMPLE PROCESSING ...............................................49 
APPENDIX 2 DESCRIPTION AND COMPOSITION OF TEST PRODUCT ...........................51 
APPENDIX 3 DIVISION OF MICROBIOLOGY AND INFECTIOUS DISEASE TOXICITY 
TABLE ...........................................................................................................................................57 
APPENDIX 4 HOLTER RECORDING AND ANALYSIS .........................................................65 
APPENDIX 5 REPEAT COHORT USING DIFFERENT DOSAGE FORMULATION ............67 
APPENDIX 6 PART 2 OF THE STUDY .....................................................................................68 
 
 
LIST OF TABLES 
 
Table 1 
Comparison of Projected TBI-223 Efficacious Exposure and T>MIC at 1200 mg to the 
Efficacious Exposures in Mouse Efficacy Studies ......................................................... 7 
Table 2 
Actual Dose Cohorts for Part 1 .................................................................................... 12 
Table 3 
Identity of Investigational Product ............................................................................... 15 
Table 4 
Total Volume of Blood to be Collected for Testing: Fasting Cohorts ......................... 27 
Table 5 
Total Volume of Blood to be Collected for Testing: Food-effect Cohorts .................. 28 
Table 6 
Acceptable Pharmacokinetic Sampling Time Windows .............................................. 28 
Table 7 
Adverse Event Attribution/Causality Ratings .............................................................. 34 
Table 8 
Definitions for Adverse Event Severity Gradings ........................................................ 34 
Table 9 
Schedule of Assessments, Part 1 .................................................................................. 45 
Table 10 Qualitative and Quantitative Composition of the TBI-223 Oral Enteric Capsules, 150 
mg ................................................................................................................................. 52 
Table 11 Strength, Tablet Weight and Appearance of TBI-223 IR and SR Tablets ................... 53 
Table 12 Composition of TBI-223 IR Tablets, 600 mg and 1000 mg ........................................ 54 
Table 13 Composition of TBI-223 SR Tablets, 600 mg (Prototype 1) ....................................... 54 
Table 14 Composition of TBI-223 SR Tablets, 600 mg (Prototype 2) ....................................... 55 
Table 15 Composition of TBI-223 SR Tablets, 900 mg (Prototype 3) ....................................... 56 
Table 16 Schedule of Assessments, Part 2 .................................................................................. 69 
 
 
 


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LIST OF FIGURES 
 
Figure 1 Dosing Groups.............................................................................................................. 10 


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Page xxxix 
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 
g 
gram(s) 
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  


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Page xl 
IND 
Investigational New Drug 
IP 
Investigational Product 
IRB 
institutional review board 
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 
T½ or t½ 
terminal elimination half-life 
TB 
Tuberculosis  
Tlast 
time of the last measurable concentration 
Tmax 
time to reach Cmax 
Worldwide 
Worldwide Clinical Trials Early Phase Services, LLC 
Worldwide Clinical Trials Early Phase Services/Bioanalytical Sciences, LLC 
λz  
apparent elimination rate constant in terminal phase 
°C 
degrees Celsius/Centigrade 


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CONFIDENTIAL 
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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. 
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 


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Page 2 
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 
(AEs), especially neuropathic and myelosuppressive effects. These AEs 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.  
TBI-223 is a preclinical 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 comprehensive nonclinical pharmacology, pharmacokinetic, toxicology, and safety 
program have been completed to support the Investigational New Drug Application and 
clinical development of TBI-223.The first clinical trial will be a randomized, Single 
Ascending Dose Study with a Food Effect Cohort. The objectives are to evaluate the 
safety, tolerability, and pharmacokinetics, and to explore the potential maximum 
tolerable dose of TBI-223 in healthy men and women.  


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1.3 
Preclinical Studies and Toxicity Studies 
To support Investigational New Drug (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. 


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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 2 of 4 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 
daily (QD). Reversible tremors were observed after 8 to 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 electrocardiogram (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, which was associated with food-filled 
stomach in rats even though they were fasted overnight prior to necropsy.  
1.4 Adverse Effects, Warnings, and Precautions 
TBI-223 has not been tested in humans, therefore its potential adverse effects are 
unknown. 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 candidiasis, abnormal liver functions tests, fungal infection, tongue 
discoloration, and abdominal pain.1 


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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. 1  
Given the key safety findings in the 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.   
Study subjects will also be monitored with Holter monitoring. Holter monitoring will 
begin approximately 24 hours prior to and continue until 48 hours after dosing.  
 
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   
• 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)  


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• Coordination – assessment of upper and lower extremities, including assessment for 
tremor   
• Gait – assessment of tandem gait 
 
1.5 
Overview and Dose Rationale 
A two-compartment PK model with non-linear clearance was built to project TBI-223 
human PK parameters from animal PK parameters. 
The projected human efficacious doses range from 800 to1200 mg, with a predicted 
Cmax of 15.7-24.9 µg/mL and predicted (AUC0-24hr) of 101 to 202 µg.hr/mL. 
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). 
Comparing to the projected human exposure at 1200 mg based on nonlinear two-
compartment model, the human AUC0-24hr (205.2 µg.hr/mL) is 1.7-fold the mouse 
efficacious exposure (124 µg.hr/mL) for a 2 Log CFU reduction (Table 1). The 
AUC0-24hr at 202 µg.hr/mL could result in 2.8 Log CFU reduction. The predicted 
T>MIC at 1200 mg was 62.9% which is 1.8-fold the mouse efficacious T>MIC (34%) 
for 2 Log CFU reduction. At T>MIC of 62.9%, the calculated Log CFU reduction 
would be 3.4 based on the dose fraction study. 
Comparing to linezolid clinical efficacious doses at 600 mg and 1200 mg daily dose, 
the projected TBI-223 exposure AUC0-24hr at 1200 mg is 2-fold that of linezolid 
exposure at 600 mg daily dose and 0.7-fold of linezolid exposure at 1200 mg daily 
dose. 


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Table 1 
Comparison of Projected TBI-223 Efficacious Exposure and T>MIC at 1200 mg 
to the Efficacious Exposures in Mouse Efficacy Studies 
Dose or Log CFU reduction 
AUC0-24hr 
(µg.hr/mL) 
T>MIC 
(%) 
TBI-223 Projected 
human efficacy dose 
1200 mg QD 
202 
62.5 
TBI-223 Mouse efficacy 
studies 
100 mg/kg 
179 
61 
TBI-223 Dose fraction 
study 
2 Log CFU reduction 
124 
34 
AUC for 2.8 Log CFU reduction, or 
T>MIC for 3.7 Log CFU reduction 
202 
62.5 
Linezolid efficacious 
dose 
600 mg, human 
104 
91 
1200 mg, human 
300 
100  
 
 
Starting dose for the SAD 
 
A single dose of 50 mg appears to be an appropriate starting dose for the single 
ascending dose SAD study for the following reasons: 
 
• 
The proposed 33-fold safety margin to the human equivalent dose (HED) derived 
from the no-observed-adverse-effect level (NOAEL, 100 mg/kg) in the 28-day 
dog toxicology study is based on twice daily dosing (50 mg/kg BID) compared to 
once daily dosing proposed in humans. The daily dosing frequency was changed 
from QD to BID in the animal studies to increase tolerability of TBI-223 when 
orally administered to dogs.  
• 
The more relevant NOAEL at 50 mg/kg QD (HED 27 mg/kg) in the repeat-dose 
28-day dog toxicology study provides a 17-fold safety margin to a first-in-human 
(FIH) starting dose of 100 mg QD. However, in the nonclinical safety 
pharmacology cardiovascular study in dogs, a trend of increasing QTc 
prolongation was observed in dogs after a single oral administration of TBI-223 at 
50 and 100 mg/kg (max increase 11 to14 msec from baseline, 12 msec from 
control 2 hours post-dose) at 1 to 13 hours post-dose, and a statistically significant 
increase in QTc interval was detected at 200 mg/kg (mean increase 22 msec from 
baseline and control 2 to 5 hours post-dose, and 21 to 25 hours post-dose).   
• 
Significant toxicity was observed in the 28-day dog toxicology study at a dose of 
200 mg/kg/day (100 mg/kg BID) including intermittent and continuous tremors, 
ataxia, convulsions in several animals, QTc prolongation (10 to 11% baseline), 
decreased body weight, and vomitus. It should be noted that the dosing interval 
between twice daily dosing was not provided, and the clinical observations were 


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performed at 1 and 12 hours post-dose, and not 2 to 4 hours at Cmax/Tmax when 
tremors may have a greatest chance of occurring and being detected.  
• 
In the 14-day dog toxicology study with orally administered TBI-223, dose 
reduction from 200 mg/kg daily to 150 mg/kg (75 mg/kg BID) on Day 7 
continued to cause tremors on Days 8 to 10 of dosing.  This may be a result of 
drug accumulation noted with repeated dosing with TBI-223.  Cage-side 
observations more appropriately timed at 3 to 4 hours post-dose and 6 to 9 hours 
post-dose in this 14-day study may have provided a greater opportunity of 
detecting tremors in animals.  Had the clinical observations been performed at 
similar times in the 28-day dog toxicology study, perhaps tremors might have 
been observed at 100 mg/kg/day (50 mg/kg BID), reportedly the NOAEL in this 
study.  No tremors were observed at 75 mg/kg/day QD in dogs in the 14-day 
study. 
 
In the first cohort of this Phase 1 study, the proposed starting dose of 50 mg once daily 
(QD) is 66-fold lower than the HED of 3243 mg/day, derived from the lowest NOAEL, 
which was 50 mg/kg BID (100 mg/kg/day) in a 28-day dog GLP toxicity study. The 
proposed starting dose is 17-fold less than the HED of a single 50 mg/kg dose in dogs.  
The predicted Cmax and AUC0-24hr at the proposed first in human dose of 50 mg once 
daily are 0.711 µg/mL and 2.5 µg.hr/mL, which are 20.4- and 86-fold less than the 
NOAEL in the dog toxicity study, respectively. The proposed starting doses for this 
first-in-human SAD study are well below the predicted NOAEL. The following dose 
escalations for each cohort receiving a single dose are proposed: 50 mg, 100 mg, 
300 mg, 600 mg, 1200 mg, and 2000 mg. These proposed doses (cohorts) could change 
(e.g. if bioavailability is lower than expected or for potential emerging safety reasons).   
 
For all the reasons noted above, a starting dose of 50 mg in the SAD would likely 
provide a reasonable margin of safety to any adverse -cardiovascular or CNS- effects 
observed with TBI-223 during administration to dogs.  
 
Dose escalation will be guided by emerging safety and pharmacokinetic data so that 
predicted median Cmax of a cohort can exceed 20.2 µg/mL (the NOAEL plasma Cmax in 
the 28-day GLP dog toxicity study) only if, after data review, the prior dose was 
considered safe and well tolerated.  Human plasma M2 metabolite exposure will be 
measured at each dose level, and the M2 exposure for next dose level will be predicted 
for safety analysis by comparing to M2 exposures in dogs. However, the planned 
doses could change if the generated bioavailability is lower than expected. Therefore, 
additional cohorts may be enrolled if deemed appropriate by the Sponsor to repeat a 
dose level or to study other dose levels or a different dosage formulation. These 
decisions regarding planned additional cohorts will not take place until the Sponsor, in 
conjunction with the Principal Investigator and dose-escalating committee, has 


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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 this revised 
approach for review and approval. The new approved dose for Cohort 6 will be 
2000 mg. 
2 
OBJECTIVE 
The primary objective of the study is: 
• To evaluate the safety and tolerability of single doses of TBI-223 oral suspension, 
TBI-223 oral enteric capsules, and TBI-223 tablet formulations in healthy adult 
subjects.  
The secondary objectives of the study are: 
• To determine the pharmacokinetics of TBI-223 and its metabolite M2 after single 
doses of TBI-223 oral suspension, TBI-223 oral enteric capsules, and TBI-223 
tablet formulations in healthy adult subjects; and 
• To compare the rate and extent of absorption of a single dose of TBI-223 oral 
suspension, TBI-223 oral enteric capsules, and TBI-223 tablet formulations when 
administered in healthy adult subjects either after a high-calorie, high-fat meal or in 
the fasting state. 
3 
STUDY DESIGN SUMMARY 
Part 1: 
Up to 48 subjects in 6 dosing cohorts are planned to be enrolled; within each cohort, 
6 subjects will be assigned to active treatment and 2 to placebo.  
Each subject will participate in 1 dose level. Based on interim pharmacokinetic data 
obtained during the dose escalation, a dose cohort will be selected to return for 
additional dosing after a high-calorie, high-fat meal (food-effect cohort). 
Each cohort will be dosed in 2 groups in order to monitor subjects for adverse 
experiences, in particular, convulsions (in the dog toxicity studies, tremors were 
observed at Cmax or plasma concentration of ≥82µg/mL, and convulsions were observed 
at plasma concentration or Cmax of ≥ 158µg/mL). 
In the first cohort, a sentinel group of 3 subjects (2 active and 1 placebo) will be dosed 
at least 24 hours before the remaining 5 subjects (4 active and 1 placebo). 
The remaining cohorts will be dosed in 2 groups of 4 subjects each (3 active and 
1 placebo), at least 24 hours apart.  


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Safety will be assessed throughout the study for all subjects. Safety assessments will 
include physical and neurological examinations, vital signs, ECGs, cardiac monitoring, 
AEs, and clinical laboratory tests (including hematology, serum chemistry, coagulation, 
and urinalysis).  
Blood and urine will be collected for clinical laboratory evaluations. 
Female subjects will have blood collected for serum pregnancy testing. Postmenopausal 
females will have blood collected to measure follicle-stimulating hormone (FSH) 
levels.  
Blood will be collected for pharmacokinetic analysis. 
Dose escalation to the next cohort (i.e., dose level) will not take place until the Sponsor, 
in conjunction with the Principal Investigator, has determined that adequate safety, 
tolerability and pharmacokinetic data from the previous cohorts have been 
demonstrated to permit proceeding to the next cohort.  
The Principal Investigator, in conjunction with the Sponsor may collect additional 
blood if necessary, for repeat laboratory or safety evaluations including AE follow up. 
An overview of the dosing groups in Part 1 is presented in Figure 1. 
Figure 1 Dosing Groups 
 
 


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Based on the interim pharmacokinetics for the dose escalation decisions, 10 subjects 
will be selected to participate in the food-effect cohort. These subjects will receive 
TBI-223 or placebo under fasting conditions in the first study period. They will return 
after a washout of at least 7 days or 5 half-lives (whichever is longer) of their fasting 
dose to receive the same dose under fed conditions.3 
Additional cohorts (8 subjects per cohort) may be enrolled if it is deemed appropriate 
by the Sponsor to repeat a dose level or to study another dose level or dosage 
formulation. The IRB will notified of this revised approach.  
Note: In the event that a dose level is repeated to study a different dosage formulation, 
procedures and analyses will be conducted as outlined in Appendix 5. 
Interim pharmacokinetic analyses will be performed for the dose escalation decisions, 
to select the dose for the food-effect cohort, and to reconsider the timing, reducing, or 
adding of sampling time points as the study progresses.  
Blood samples will be obtained prior to study drug administration on Day 1 and at 
serial timepoints through 72 hours after study drug administration. Plasma 
pharmacokinetic samples will be analyzed for TBI-223 and M2 using validated 
analytical methods. Appropriate pharmacokinetic parameters will be calculated for each 
formulation using non-compartmental methods.  
An unblinded pharmacist will be responsible for dispensing the study treatment and to 
ensure that study personnel are blinded.  
Except for during the fed period of the food-effect cohort, TBI-223 or matching 
placebo dose will be administered orally with 200 mL of water after a minimum 
10-hour overnight fasting, and food will be given approximately 4 hours after each dose 
level. 
Table 2 presents the actual dose cohorts for Part 1 of the study. 
 
 
 


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Table 2 
Actual Dose Cohorts for Part 1 
Cohorta (Groupb) 
Dosec 
1 (sentinel group) 
Single dose of 50 mg TBI-223 (n=2) 
Placebo (n=1) 
1 (remainder of cohort) 
Single dose of 50 mg TBI-223 (n=4) 
Placebo (n=1) 
2 (Group 1) 
Single dose of 100 mg TBI-223 (n=3)  
Placebo (n=1) 
2 (Group 2) 
Single dose of 100 mg TBI-223 (n=3)  
Placebo (n=1) 
3a (Group 1) 
Single dose of 300 mg TBI-223 (n=3)  
Placebo (n=1) 
3a(Group 2) 
Single dose of 300 mg TBI-223 (n=3)  
Placebo (n=1) 
3b (Capsule cohort) 
Single dose of 300 mg (TBI-223 in oral enteric 
capsules) (n=4) 
N/A 
4 (Group 1) 
Single dose of 600 mg TBI-223 (n=3)  
Placebo (n=1) 
4 (Group 2) 
Single dose of 600 mg TBI-223 (n=3)  
Placebo (n=1) 
5 (Group 1) 
Single dose of 1200 mg TBI-223 (n=3)  
Placebo (n=1) 
5 (Group 2) 
Single dose of 1200 mg TBI-223 (n=3)  
Placebo (n=1) 
6 (Group 1) 
Single dose of 2000 mg TBI-223 (n=3)  
Placebo (n=1) 
6 (Group 2) 
Single dose of 2000 mg TBI-223 (n=3)  
Placebo (n=1) 
7 (Group 1) 
Single dose of 2600 mg TBI-223 (n=3)  
Placebo (n=1) 
7 (Group 2) 
Single dose of 2600 mg TBI-223 (n=3)  
Placebo (n=1) 
mg = milligram; n = number of subjects. 
a) Additional cohorts may be enrolled if deemed appropriate by the Sponsor to repeat a dose level or to 
study another dose level or another dosage formulation. 
b) Dosing between Groups 1 and 2 to occur at least 24 hours apart. 
c) Subjects will be dosed under fasted conditions. One of the dose cohorts will be selected to return for 
an additional dose under fed conditions.  
Part 2:  
Cohort 8: A minimum of 24 subjects in 4 dosing arms are planned to be enrolled; 
within each arm, 6 subjects will be assigned to receive a single dose treatment. Subjects 
will be assigned to one of the following arms and dose:  
• 
Arm 1 – TBI-223 SR Tablets (Prototype 1) - 1800 mg dose (3 x 600 mg tablets), under 
fed conditions 
• 
Arm 2 – TBI-223 SR Tablets (Prototype 2) -1800 mg dose (3 x 600 mg tablets), under 
fed conditions 
• 
Arm 3 – TBI-223 SR Tablets (Prototype 3) - 1800 mg dose (2 x 900 mg tablets), under 
fed conditions 
• 
Arm 4 – TBI-223 IR Tablets - 2000 mg dose (2 x 1000 mg tablets), under fasting 
conditions   


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Procedures and analyses will be conducted as outlined in Appendix 6.  
Cohort 9: The 6 subjects from Cohort 8, Arm 4, who received the IR tablet formulation 
fasted will return after a 7-day washout and receive a single dose of TBI-223 IR 
Tablets, 2000 mg dose (2 x 1000 mg tablets), under fed conditions. 
If more than 2 subjects of these 6 subjects from Cohort 8 drop-out, they will be 
replaced by heathy volunteers (a minimum of 4 subjects are needed to complete 
Cohort 9). 
Procedures and analyses will be conducted as outlined in Appendix 6. 
3.1 
Part 1 Dose Escalation 
Each of the fasting cohorts will be dosed in 2 groups. The first cohort will start with a 
sentinel group. The decisions on continuing of dosing Group 2 (at least 24 hours after 
dosing of Group 1) will not take place until the Sponsor, in conjunction with the 
Principal Investigator, has determined adequate safety and tolerability. 
Dose Escalation Review 
A review period will take place after the dosing of all subjects in each cohort in order to 
evaluate and interpret all pharmacokinetic and safety data collected. 
The review of all pertinent safety/tolerability data will include physical and 
neurological examinations, ECGs, vital signs, clinical laboratory tests, cardiac 
monitoring, and AEs or serious adverse events (SAEs) through Day 4. Also, data from 
the current dose cohort and all previous cohorts will be considered.   
The Sponsor and Investigator will determine if there are sufficient data available from 
all subjects to make a dose escalation decision. Any AEs of grade ≥2 toxicities (per 
Division of Microbiology and Infectious Disease [DMID] toxicity table; Appendix 3) 
must be considered in the decision to escalate to the next dose level. ECG 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). 
Pharmacokinetic analysis will be completed only on the active treatment subjects and 
will be blinded to subject. Blinding will also extend to others who are intimately 
involved with the study except for the designated unblinded pharmacy staff and in 
cases of medical emergencies. 
Upon review of relevant cohort data, the Sponsor, in conjunction with the Investigator 
may decide to:  
1: 
Escalate the dose as planned  
2: 
If concerns arise from pharmacokinetic and safety data that do not warrant 
ceasing escalation: 
a: evaluate an intermediate dose level prior to the next planned dose level;  


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OR 
b: repeat a given dose level in a new cohort of subjects 
c: Repeat a dose level using a different dosage formulation. 
3. 
Add a cohort or increase the dose of the next cohort if the bioavailability is lower 
than expected in the previous cohort and there were no safety concerns. 
4. 
Halt the study. 
The next dose in the escalating phase of the SAD study will be guided by emerging 
safety and PK data. After each cohort, Bayesian linear models will be fitted to the data 
from all available cohorts with log-transformed Cmax as the response variable and log-
transformed dose as the predictor variable. Different prior distributions on the 
coefficient of log-transformed dose, representing different assumptions about dose 
proportionality, will be considered. Predictive distributions will be generated for Cmax 
at doses to be considered for the next level of escalation. These predictive distributions, 
together with emerging safety data, will be assessed by the clinical team to reach a 
decision on the next dose. Key features of the predictive distributions to be evaluated 
are the median Cmax and the number of subjects out of those receiving TBI-223 in the 
next cohort expected to have Cmax exceed 20.2 μg/mL. (the NOAEL plasma Cmax in the 
28-day GLP dog toxicity study). 
3.2 
Stopping Rules for Cohorts 
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. Two or more subjects experience drug-related SAEs; 
2. Two or more subjects experience grade 2 or higher (per DMID toxicity table; 
Appendix 3) central nervous system (CNS) AEs considered related to drug.  
3. Two or more subjects develop drug-related QTcF prolongation greater than or 
equal to 500 msec or a change from baseline greater than 60 msec, after 
completing repeat testing.   
4. Two or more subjects experience drug-related Grade 3 or Grade 4 cardiac 
rhythm cardiac disturbances. 
4 
IDENTITY OF INVESTIGATIONAL PRODUCT 
The Investigational Medicinal Product (IMP) will be supplied as TBI-223 25 mg/mL 
oral suspension or matching placebo.  
Refer to Appendix 2 for details regarding the description and composition of TBI-223. 


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Table 3 Identity of Investigational Product 
 
Part 1 
Test Product:  
TBI-223 oral suspension 25 mg/mL 
Manufactured for Global Alliance for TB Drug Development 
Control Product: 
Placebo for TBI-223 oral suspension  
Manufactured for Global Alliance for TB Drug Development 
Test Product: 
Cohort 3b 
TBI-223 Oral Enteric Capsules, 150 mg 
Manufactured for Global Alliance for TB Drug Development 
Part 2 
Test Products: 
Cohort 8  
(Arms 1-4) 
TBI-223 SR Tablets 600 mg (Prototype 1) 
Manufactured for Global Alliance for TB Drug Development 
by Piramal Enterprise Limited 
TBI-223 SR Tablets 600 mg (Prototype 2) 
Manufactured for Global Alliance for TB Drug Development 
by Piramal Enterprise Limited 
TBI-223 SR Tablets 900 mg (Prototype 3) 
Manufactured for Global Alliance for TB Drug Development 
by Piramal Enterprise Limited 
TBI-223 IR Tablets 1000 mg  
Manufactured for Global Alliance for TB Drug Development 
by Piramal Enterprise Limited 
Test Products: 
Cohort 9 
TBI-223 IR Tablets 1000 mg 
Manufactured for Global Alliance for TB Drug Development 
by Piramal Enterprise Limited 
 
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, 19 to 50 years of age (inclusive) 
at the time of screening.  


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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. 
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. If female of non-childbearing potential, she has undergone one of the following 
sterilization procedures at least 6 months before dosing: 
• Hysteroscopic sterilization; 
• Bilateral tubal ligation or bilateral salpingectomy; 
• Hysterectomy; or 
• Bilateral oophorectomy; 
• Or is postmenopausal with amenorrhea for at least 1 year before the first dose 
with serum follicle-stimulating hormone (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. 


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7. If a non-vasectomized male (or male vasectomized less than 120 days prior to 
study start) he 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. 
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. 
11. If enrolled in the food-effect cohort, is willing and able to consume the entire 
high-calorie, high-fat breakfast meal in the timeframe required.  
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. Evidence on physical exam and targeted neurologic exam of specific findings 
such as resting or intention tremor, dysmetria, nystagmus or ataxia, or abnormal 
deep tendon reflexes (either zero or hyper-reflexia). 
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. 


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6. History of sensitivity or contraindication to use of linezolid, sulfa drugs, 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 
• 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 (pre-dose), or history of prolonged QT syndrome. For the 
triplicate ECGs taken at screening and on Day -1, the average QTcF interval of 
the 3 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 1 or any combination of, the following: 


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• 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 CNS or related neurological system, particularly 
one that may lower the seizure threshold.  
16. Lactose intolerant. 
17. History or presence of allergic or adverse response to Listerine breath strips or 
aspartame.  
Specific Treatments 
18. Use of any prescription medication within 14 days prior to dosing. 
19. 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 
(erythromycin, clarithromycin, astemizole, type Ia [quinidine, procainamide, 
disopyramide] and III [amiodarone, sotalol] anti-arrhythmics, carbamazepine, 
sulfonylureas, and meperidine).  
20. 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. 
21. 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. 
22. 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. 
23. Use of any drugs or substance known to lower the seizure threshold. 


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Laboratory Abnormalities 
24. 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. 
25. Positive results at screening for human immunodeficiency virus (HIV), 
hepatitis B surface antigen (HBsAg), or hepatitis C antibodies (HCV). 
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 discharge from the clinic. 
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 
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. 


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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 (ICDs) will be discussed with each potential 
participant, and each individual will sign an ICD 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, coagulation, chemistry, and urinalysis) 
• Serum pregnancy (all female subjects) 
• FSH test (female subjects claiming post-menopausal status)  
• Urine test for drugs of abuse, alcohol, and cotinine  
• 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 
For Part 1, up to 50 subjects are planned to be enrolled in the study. Additional subjects 
may be enrolled if deemed appropriate by the Sponsor to repeat a dose level or to study 
another dose level. For Part 2, Cohort 8, 24 subjects will be enrolled. For Part 2, 


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Cohort 9, the 6 subjects from Cohort 8 who received the IR tablet formulation fasted 
will return after a 7-day washout and receive the IR tablet formulation under fed 
conditions. If more than 2 subjects of these 6 subjects from Cohort 8 drop-out, they will 
be replaced by heathy volunteers (a minimum of 4 subjects are needed to complete 
Cohort 9).  
The number of subjects selected for the study was based on the adequate number 
considered to provide sufficient safety data. This study has not been formally powered. 
For Part 1, 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.  
Note: the repeat cohort using a different dosage formulation in Part 1 and subjects in 
Part 2 will be non-randomized and unblinded; see Appendix 5 and Appendix 6. 
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 
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.  


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Note: The blinding rules and procedures described in the protocol do not apply to the 
unblinded repeat cohort using a different dosage formulation; see Appendix 5. 
6.2.1 
Clinical Research Staff 
All observers who evaluate any reported AE, 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 
Cardiac Vendor 
Electrocardiogram data will be analyzed in a blinded fashion and then unblinded by the 
cardiac vendor in order to be presented by treatment group in aggregate (reviewers will 
remain blinded by subject).   
6.2.6 
Unblinding Procedures 
Unblinding of cohort data will occur after completion of the final subject study visit and 
follow-up telephone call for the cohort. 
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 
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 for Part 1 and Day -1 for Part 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).  


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Subjects will undergo the following assessments during the confinement period prior to 
dosing: 
• Physical and neurological examinations 
• Weight 
• Vital signs (temperature, respirations, blood pressure, pulse, and pulse oximetry) 
• Triplicate 12-lead ECG 
• Clinical laboratory tests 
• 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 
• Cardiac telemetry (Part 1 only) 
6.4 
Confinement 
Part 1 fasting cohorts, and Part 2, Cohort 8, Arm 4 only: Subjects will be admitted to the 
research center on Day -2 (Part 1) or Day -1 (Part 2) and remain confined until after 
completion of the 48-hour procedures on Day 3. Subjects will return for a follow-up 
visit approximately 72 hours after dosing (Day 4) and receive a follow up phone call on 
Day 11 (+1 day). 
Part 1 food-effect cohort, Part 2, Cohort 8, Arms 1-3 and Cohort 9: Subjects will be 
admitted to the research center on Day -2 of Period 1 and Period 2 (Part 1) or Day -1 
(Part 2) and remain confined until after completion of the 48-hour procedures on Day 3 
of each study period. Subjects will return for a follow-up visit approximately 72 hours 
after dosing (Day 4) in each study period. Subjects will receive a follow up phone call 
on Day 11 (+1 day) of Period 2. 
Please note that Cohort 9 is the same 6 subjects that were in Cohort 8, Arm 4 (IR tablet 
formulation) under fed conditions. In Cohort 8, Arm 4, subjects fasted. 
6.5 
Fasting/Meals/Beverages 
6.5.1 
Fasting/Meals3  
Part 1 fasted cohorts and Part 2, Cohort 8, Arm 4 only Optional meals (lunch, snack, 
and dinner) may be served the day of check-in. All subjects will then be required to fast 
for at least 10 hours before dosing. The subjects will fast for 4 hours after dosing. 
Standard meals will be provided at appropriate times after dosing. 
Part 1 food-effect cohort, Part 2, Cohort 8, Arms 1-3 and Cohort 9: Optional meals 
(lunch, snack, and dinner) may be served the day of check-in.  


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In the fasting study period, all subjects will be required to fast overnight for at least 
10 hours before dosing.  
In the fed study period of Part 1 and Part 2 (Cohort 8, Arms 1-3 and Cohort 9) subjects 
will be required to fast for at least 10 hours overnight 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 prior to scheduled 
administration of the dose and to end (last bite taken) within 5 minutes prior to dosing. 
The subjects will fast for 4 hours thereafter. The following high-fat (approximately 50% 
of total caloric content of the meal), high-calorie (approximately 1000 calories) 
breakfast will be ingested 30 minutes prior to administration of the drug: 
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 with Sponsor approval prior to administration of the meal. 
Subjects will fast for 4 hours after dosing. Standard meals will be provided at 
appropriate times after dosing. 
Please note that Part 2, Cohort 9 is the same 6 subjects that were in Cohort 8 Arm 4 (IR 
tablet formulation) under fed conditions. In Cohort 8 Arm 4, subjects fasted. 
6.5.2 
Beverages 
Each dose of TBI-223 oral suspension and placebo for TBI-223 oral suspension will be 
administered orally followed by approximately 200 mL of room temperature water. 
Except for 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 oral care strips  
Listerine® oral care strips (or similar product) will be used to blind subjects to treatment 
(TBI-223 Oral Suspension or placebo for TBI-223 oral suspension). One strip will be 
added to the subject’s tongue immediately before administration of the study treatment. 
Another strip will be placed on the subject’s tongue immediately after the subject has 
swallowed the study treatment and 200 mL of water. Research staff will place the strip 
on the midsection of the subject’s tongue. The subject should keep the strip on the 


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tongue while it dissolves but may swallow when they feel the need to. A mouth check 
will be performed, using a flashlight and tongue depressor, after each administration of 
Listerine oral care strip to ensure that all of the film has been dissolved. 
6.6.2 
Administration of TBI-223 Oral Suspension or Placebo for TBI-223 Oral Suspension  
Note: Detailed instructions for preparing and dispensing TBI-223 will be provided in 
a separate pharmacy manual. Any instructions in the pharmacy manual shall 
supersede those presented in this protocol. 
TBI-223 Oral Suspension or placebo for TBI-223 oral suspension will be transferred 
and stored in Pyrex glass reagent bottles with a polypropylene (PP) screw cap without a 
liner. These bottles will be used for mixing, sampling, and storage prior to 
administration. 
The required doses of the drug product will be dispensed using commercially available 
oral syringes of suitable capacity. The suspension will be dispensed just prior to dosing 
and not stored in the oral syringes. 
Each dose of TBI-223 will be administered orally followed by approximately 200 mL 
of room temperature water. A mouth check will be performed immediately after dose to 
ensure that the medication has been appropriately swallowed. 
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 dosing on these days, 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.  
6.6.3 
Administration of TBI-223 Sustained Release and Immediate Release Tablets 
For Part 2, Cohort 8 and Cohort 9, each subject will receive the oral dose of the 
assigned study treatment (TBI-223 SR tablet formulations [Prototypes 1, 2, or 3] or 
TBI-223 IR tablet formulation) with approximately 240 mL (8 fl. oz.) 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. 


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6.7 
Blood Sampling, Processing and Shipment 
Blood samples will be collected as detailed in Appendix 1. 
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. 
6.7.1 
Part 1 fasting cohorts, and Part 2, Cohort 8, Arm 4 only 
A total of 80 mL (20 x 4 mL samples) will be collected for pharmacokinetic analysis 
from each subject. Approximately 51.5 mL of blood will be collected for the clinical 
laboratory evaluations and coagulation testing. The total volume of blood collected 
from each subject will not exceed approximately 131.5 mL.  
Table 4 
Total Volume of Blood to be Collected for Testing: Fasting 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 (check-in, 24 and 
72 hours/end-of-study) 
3 
8.5 
25.5 
Coagulation 
5 
2.7 
13.5 
Pharmacokinetic analysis 
20 
4.0 
80.0 
Total 
131.5 
6.7.2 
Part 1 food-effect cohort, Part 2, Cohort 8, Arms 1-3 only, and Cohort 9 
A total of 160 mL (40 x 4 mL samples) will be collected for pharmacokinetic analysis 
from each subject. Approximately 90.5 mL of blood will be collected for the clinical 
laboratory evaluations and coagulation testing. The total volume of blood collected 
from each subject will not exceed approximately 250.5 mL.  
Please note that Part 2, Cohort 9 is the same 6 subjects that were in Cohort 8 Arm 4 (IR 
tablet formulation) under fed conditions. In Cohort 8 Arm 4, subjects fasted. 


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Table 5 
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 (check-in, 24 and 
72 hours/end-of-study) 
6 
8.5 
51.0 
Coagulation 
10 
2.7 
27.0 
Pharmacokinetic analysis 
40 (20 in each 
study period) 
4.0 
160.0 
Total 
250.5 
 
6.7.3 
Pharmacokinetic Sampling Time Windows 
Blood samples collected within the time windows listed below will not be considered 
deviations. Note: For the food-effect cohort, time windows are relative to dosing in 
each study period. 
Table 6 
Acceptable Pharmacokinetic Sampling Time Windows 
Investigation and 
examination 
Allowable Time Window 
Postdose* 
≤24 hours 
˃24 hours to ≤48 hours 
>48 hours 
Plasma sample collection 
for pharmacokinetic 
assessment 
± 2 minutes 
± 5 minutes 
± 10 minutes 
For the food-effect cohort, time windows are relative to dosing in each study period. 
6.8 
End-of-Study Procedures 
On the day of study discharge (Day 4), the following procedures will be conducted: 
• Physical and neurological examinations 
• Vital signs measurements (blood pressure, pulse, temperature, respirations, and 
pulse oximetry) 
• Blood collection for hematology, chemistry, coagulation 
• Urine collection for urinalysis 
• Concomitant medication review 
• AE assessment 
Subjects will receive a follow up phone call (Day 11 [+1 day].  
For the food-effect cohort, the timing of these assessments is relative to study period 2. 


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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 appropriate 
events schedule (Table 9), 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. 
• 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). 


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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 appropriate events 
schedule (Table 9). 
NOTE: Blood pressure and pulse rate will be noted and collected at the same time. 
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. 
Additional vital signs measurements may be performed as deemed medically necessary 
by research personnel.  
Blood pressure and heart rate should be measured after subjects are in a seated position 
for at least 2 minutes and then again after standing for at least 1 minute, except when 
they are supine or semi-reclined because of study procedures and/or AEs, or as deemed 
necessary by the Investigator.  
6.9.4 
Physical Examinations 
Physical examinations, including height and weight measurements, will be conducted at 
the times noted on the appropriate events schedule (Table 9). 
6.9.5 
Neurological Examinations 
Detailed neurological examinations will be conducted at the times noted on the 
appropriate events schedule (Table 9) 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 


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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 appropriate events schedule (Table 9). 
The interpretation of these ECGs will be noted, but not the ECG intervals, unless as part 
of an AE (e.g. 1st degree AV block with PR interval of 240 msec). 
All safety ECGs will be performed after the subject has been in supine position for a 
minimum of 5 minutes.  
6.9.7 
Cardiac Holter Monitoring, and Cardiodynamic Assessment 
In order to detect potential changes in ECG parameters, study subjects will undergo 
cardiac Holter monitoring. Holter monitoring will begin approximately 24 hours before 
dosing and continue for at least 48 hours after dosing. 
On Day -2 and Day -1, subjects should fast until lunch to avoid circadian fluctuations. 
In addition, replicate ECGs will be obtained after dosing, specifically around the 
estimated Tmax (which is estimated to be around 3 hours after dosing; although the 
timing may be altered based on generated phase 1 pharmacokinetic data). ECG data will 
be analyzed focusing in particular on changes of the QT segment although other ECG 
parameters will be analyzed, as specified in the Statistical Analysis Plan (SAP). 
Continuous 12-lead ECGs (Holter) will be recorded for 24 hours prior to dose and for at 
least 48 hours post dose. The ECG waveforms will be stored for analysis as appropriate 
after the completion of the study. Replicate 12-lead ECGs will be extracted prior to 
dosing and serially after dosing by the central ECG laboratory at the time points shown 
in Table 9. At each time point for ECG extraction, subjects should be resting in the 
supine position for at least 10 minutes.  
NOTE: When ECG extractions coincide with safety ECGs, vital signs assessment and 
blood draws, procedures should be carried out in said order.   
Details regarding the equipment and methods to be used for continuous Holter 
extraction and analysis are provided in Appendix 4.   
Part 2 of the study will not have cardiac Holter monitoring. 
6.9.8 
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 
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.  


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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 
definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 


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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. 
• The investigator may change his/her opinion of causality in light of follow-up 
information and send a SAE follow-up report with the updated causality 
assessment. 


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Table 7 
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 8 
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 11+1 day). 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: 
PPD PVG (pharmacovigilance service provider for TB Alliance) 
Email: rtpsafety@ppdi.com 
Safety Hotline: +1 888 483 7729 
Safety Fax Number +1 888 529 3580  
And 
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 


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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). 
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: 


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• 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 AEs. It is the 
Investigators’ responsibility to review the results of all laboratory tests as they become 
available. This review must be documented by the Investigators’ dated signature on the 
laboratory report. For each abnormal laboratory test result, the Investigator needs to 
ascertain and document if this is a clinically significant change from baseline for that 
individual participant. This determination, however, does not necessarily need to be 
made the first time an abnormal value is observed. The Investigator may repeat the 
laboratory test or request additional tests to verify the results of the original laboratory 


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tests.  If this laboratory value is determined by the Investigator to be a clinically 
significant change from baseline for that participant, it is considered to be an AE. 
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 AE.  
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 
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). 


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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 ICD 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 ICD must be used to consent prospective study subjects. One copy of the 
signed and dated ICD 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. 
For Part 1, replacement subjects will be numbered 17XX where XX is 10 plus the 
original subject’s last 2 assigned numbers (e.g. if subject 1702 needs to be replaced due 
to emesis, the replacement subject number would be 1712). Replacement subjects will 
receive the same dose allocation of study drug (active or placebo) and they will all be 
blinded aside from the pharmacist assigning the drug. 
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. 


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8.6 
Documentation 
All documents pertaining to the study, including a copy of the approved protocol, copy 
of the ICD 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 oral suspension will not be 
analyzed. 
9.2 
Pharmacokinetic Analysis 
Final pharmacokinetic calculations will be performed using appropriate software, e.g. 
Phoenix™ WinNonlin® (Version 8.1 or higher, Certara, L.P. in conjunction with the 
internet-accessible implementation of Pharsight® Knowledgebase ServerTM [PKSO; 


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Version 4.0.4 or higher, Certara, L.P.]) 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 
Clast 
The last quantifiable concentration determined directly from individual 
concentration-time data 
CL/F 
Apparent total clearance after single administration (TBI-223 only) 
Cmax 
Maximum concentration, determined directly from individual 
concentration-time data 
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
=
 
Vz/F 
Apparent volume of distribution in the terminal phase (TBI-223 only) 
λz 
The observed terminal rate constant; estimated by linear regression through at 
least 3 data points in the terminal phase of the log concentration-time profile 
Additional pharmacokinetic parameters may be calculated if deemed appropriate. 
Pharmacokinetic parameters will be summarized by cohort using descriptive statistics. 
Dose proportionality will be assessed using the power model approach. 
Food Effect: The effect of food will be assessed comparing pharmacokinetic 
parameters (Cmax, AUCs) under fed versus fasting conditions using an analysis of 
variance (ANOVA) approach. 


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9.3 
Statistical Analysis 
Final statistical analyses will be performed using appropriate software, e.g. Phoenix™ 
WinNonlin® (Version 8.1 or higher, Certara, L.P. in conjunction with the internet-
accessible implementation of Pharsight® Knowledgebase ServerTM [PKSO; Version 
4.0.4 or higher, Certara, L.P.]) and SAS® (Version 9.4 or higher, SAS Institute Inc.). 
Pharmacokinetic parameters will be summarized by cohort using descriptive statistics. 
Summary statistics will also be presented by gender within each cohort. Dose 
proportionality for exposure parameters (Cmax, AUCs) will be assessed using a power 
model approach. 
Food-effect cohort: The effect of food will be assessed comparing pharmacokinetic 
parameters (Cmax, AUCs) under fed versus fasting conditions using an analysis of 
variance (ANOVA) approach.3 
10 
FACILITIES 
CLINICAL TRIAL SITE 
Worldwide Clinical Trials Early Phase Services, LLC 
2455 N.E. Loop 410, Suite 150 
San Antonio, Texas 78217 
Telephone: 210.635.1500 
Fax: 210.635.1646 
CLINICAL LABORATORIES 
Worldwide Clinical Trials Early Phase Services, LLC 
2455 N.E. Loop 410, Suite 150 
San Antonio, Texas 78217 
Telephone: 210.635.1500 
Fax: 210.635.1646 
ANALYTICAL LABORATORY 
Alliance Pharma, Inc. 
Project Manager: Michelle Black 
Contact for Sample Shipment: Anna Cucinotta 
17 Lee Boulevard 
Malvern, PA 19355 
Phone: 610.296.3152 
Fax: 610.296.3153 
Email: samples@alliancepharmaco.com 
Web: www.alliancepharmaco.com 


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CARDIAC VENDOR 
iCardiac Technologies, Inc. 
150 Allens Creek Road 
Rochester, New York 14618 
Phone: 585.295.7610 
Fax: 585.285.4130 
11 
DRUG SUPPLIES 
Global Alliance for TB Drug Development will supply sufficient a quantity of the study 
drug, TBI-223 for preparation of TBI-223 oral suspension. Study drug will be shipped 
to Worldwide Clinical Trials Early Phase Services, LLC pursuant to site standard 
operating procedures. Upon receipt of the study drug, the study drug will be inventoried 
and stored in an environmentally controlled and secure, limited access area. The 
suspending vehicle and other supplies will be procured, inventoried, and stored 
appropriately by Worldwide Clinical Trials Early Phase Services, LLC pursuant to site 
standard operating procedures. 
The lot numbers of the study drug, vehicle, and other supplies 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. 
Samples will be collected from each batch of test product (TBI-223 Oral Suspension) 
and stored frozen until the clinical study report is issued. At the conclusion of the study, 
any unused study drug will be returned to the Sponsor or destroyed by the site pursuant 
to written authorization by the Sponsor and applicable federal and state regulations. 
Global Alliance for TB Drug Development will supply sufficient quantity of the study 
drug, TBI-223 SR tablet formulations (Prototypes 1, 2, and 3) and TBI-223 IR tablet 
formulation for Part 2 of the study. 
Study drug formulations will be shipped to Worldwide Clinical Trials Early Phase 
Services, LLC 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 returned to the sponsor or destroyed by the site pursuant to 
written authorization by the sponsor and applicable federal and state regulations. 


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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 9 
Schedule of Assessments, Part 1 
 
SCR 
CONFINEMENT 
FU 
STUDY DAY 
-28  
to 
-2 
-2 
CI 
 
-1 
DAY 1 
DAY 2 
3 
4 
11 
(+1)a 
STUDY HOUR 
EVENT  
0 
0.5 
1 
1.5 
2 
3 
4 
5 
6 
7 
8 
12 
16b 
20 
24 
30 
36 
42 
48 
72 
N/A 
Informed 
consent and 
medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical and 
neurological 
examinationsc 
X 
X 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
 
X 
X 
 
Vital signs 
(blood pressure, 
pulse, 
temperature, 
respiration rate, 
and pulse 
oximetry) d 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
12-lead safety 
ECGse 
X 
X 
Xf 
X 
 
X 
 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
HIV/hepatitis B, 
C 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical 
laboratory tests 
(hematology, 
chemistry, and 
urinalysis) 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
Coagulation 
tests 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 


Protocol TBI-223-CL-001 Final Version 3.0 
 
Global Alliance for TB Drug Development 
CONFIDENTIAL 
21 Jan 2020 
Page 46 
 
SCR 
CONFINEMENT 
FU 
STUDY DAY 
-28  
to 
-2 
-2 
CI 
 
-1 
DAY 1 
DAY 2 
3 
4 
11 
(+1)a 
STUDY HOUR 
EVENT  
0 
0.5 
1 
1.5 
2 
3 
4 
5 
6 
7 
8 
12 
16b 
20 
24 
30 
36 
42 
48 
72 
N/A 
Urine drug, 
alcohol, cotinine 
screen 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum 
pregnancy 
(females only) 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FSH (post-
menopausal 
females only) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
medication 
review 
X 
<---------------------------------------------------------------X-----------------------------------------------------------------------> 
 
Check-in 
questions 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse eventsg 
X 
X 
 
X 
 
X 
 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
High-fat, high-
calorie breakfast 
(food-effect 
cohort only)h 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Breath strip 
applicationi 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dosej 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK blood 
collectionk 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Cardiac 
telemetry 
12-lead Holter 
monitoringl 
 
 
<-----------------------------------------------------------------X-----------------------------------------------------------> 
 
 
ECG extractions 
from Holter 
recordingm 
 
 
X 
X* 
X 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 


Protocol TBI-223-CL-001 Final Version 3.0 
 
Global Alliance for TB Drug Development 
CONFIDENTIAL 
21 Jan 2020 
Page 47 
CI = check-in; ECG = electrocardiogram; FSH = follicle-stimulating hormone; FU = follow up; HIV = human 
immunodeficiency virus; N/A = not applicable; PK = pharmacokinetic; SCR = screening; T and R = temperature 
and respirations 
a. 
For the food-effect cohort, the timing of the Day 11 (+1) follow up phone call will be relative to Period 2 
dosing. 
b. 
The 16-hour time point following dosing on Day 1 will either be on Day 1 or Day 2, depending upon time of 
dosing on Day 1.   
c. 
A detailed neurological exam will be conducted by a licensed physician or suitably medically qualified designee 
at both scheduled and unscheduled time points as deemed necessary by the Investigator. The neurological 
examination is planned to be performed around the estimated Tmax (currently estimated at 3 hours post dosing; 
this time could change based on data generated during the study). Timepoints can be altered based on generated 
PK data. 
d. 
Vitals signs will be measured at screening, check-in, and while subjects are in confinement. Vitals signs will be 
measured within 90 minutes prior to dosing and within 15 minutes of the remaining defined time points in 
flowchart.  Both blood pressure and heart rate (pulse) should be captured simultaneously. Blood pressure and 
heart rate should be measured after subjects are in a seated position for at least 2 minutes and then again after 
standing for 1 minute, except when they are supine or semi-reclined because of study procedures and/or AEs, or 
as deemed necessary by the Investigator.  
e. 
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 at 48 hours only. All other time points will be single 
ECG readings within 15 minutes at time points within flowchart. The predose ECG should be performed prior 
to the pre-dose blood draw. 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.   
f. 
The first ECG may be done within 2 hours prior to dosing and must be completed 20 minutes prior to the 
pre-dose blood draw. All safety ECGs on Day 1 and Day 2 will be extracted from a continuous 12 lead Holter 
recording at discrete timepoints as noted in above flow chart and Day -1 will be extracted at the same time as 
vital sign measurements.   
g. 
Subjects will be monitored for treatment-emergent AEs from the time of dosing and throughout the study via 
safety assessments, observation, and subject reporting. A specific inquiry regarding AEs will be conducted prior 
to dosing and at time points determined by the Investigator postdose and upon return to clinic for subsequent 
visits. The inquiry to collect AEs using non-leading questions on Day 11 (±1 day) will be done via a phone call. 
h. 
In the fed treatment period of the food-effect cohort, a high-fat, high-calorie breakfast meal will be given 
30 minutes before treatment administration. 
i. 
A breath strip will be added to the subject’s tongue before and after dose administration in order to blind the 
subject to treatment. 
j. 
TBI-223 oral suspension and placebo for TBI-223 oral suspension will be administered orally followed by 
approximately 200 mL of water. 
k. 
Samples collected for plasma pharmacokinetic analysis will be processed per the instructions in Appendix 1.  
l. 
Cardiac telemetry will begin at least 24 hours before and end at least 48 hours after dosing.   
m. Replicate 12-lead ECGs will be extracted from a continuous Holter recording at discrete timepoints as noted on 
Day 1 in above flow chart for cardiodynamic assessment.  
*Three timepoints before dosing: -45, -30, and -15 minutes. 
NOTE: When ECG extractions coincide with safety ECGs, vital signs assessments, and/or blood draws, then 
procedures should be carried out in said order.


Protocol TBI-223-CL-001 Final Version 3.0 
 
Global Alliance for TB Drug Development 
CONFIDENTIAL 
21 Jan 2020 
Page 48 
14 REFERENCES 
1. Prescription Monograph for Linezolid 
2. FDA Guidance for Industry, Estimating the Maximum Safe Starting Dose in Initial 
Clinical Trials for Therapeutics in Adult Healthy Volunteers 
3. FDA Food-Effect Guidance 
[https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/
guidances/ucm070241.pdf]. 


Protocol TBI-223-CL-001 Final Version 3.0 
 
Global Alliance for TB Drug Development 
CONFIDENTIAL 
21 Jan 2020 
Page 49 
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-001 Final Version 3.0 
 
Global Alliance for TB Drug Development 
CONFIDENTIAL 
21 Jan 2020 
Page 50 
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: Anna Cucinotta 
Contact e-mail: samplesa@alliancepharmaco.com  
 
 
 
 
 


Protocol TBI-223-CL-001 Final Version 3.0 
 
Global Alliance for TB Drug Development 
CONFIDENTIAL 
21 Jan 2020 
Page 51 
APPENDIX 2 DESCRIPTION AND COMPOSITION OF TEST PRODUCT 
Oral Suspension 
Description of the Dosage Form 
TBI-223 Oral Suspension is a compounded preparation at 25 mg/mL TBI-223 in Ora-Blend®.  
The suspension is compounded at the clinical study site with TBI-223 and Ora-Blend®, a 
commercially available flavored suspending vehicle.   
Placebo for TBI-223 Oral Suspension is Ora-Blend®, a commercially available flavored 
suspending vehicle (without TBI-223).  The placebo suspension, 100% Ora-Blend®, is purchased 
commercially by the clinical study site. 
The required doses of the drug product are dispensed using commercially available oral syringes 
of suitable capacity. 
Composition of the Drug Product 
The quantitative composition, function and quality of each ingredient in the drug product (TBI-
223 Oral Suspension, 25 mg/mL) is described in the table below. 
Qualitative and Quantitative Composition of the TBI-223 Oral Suspension, 25 mg/mL 
Ingredient 
Function 
Quality 
Standard 
Quantity per 
Dose (50 mg) 
Quantity 
per Dose 
(100 mg) 
Quantity 
per Dose 
(300 mg) 
Quantity 
per Dose 
(600 mg) 
Quantity 
per Dose 
(1200 mg) 
Quantity 
per Dose 
(1400 mg) 
TBI-223 
Drug 
Substance 
In-house 
50 mg 
100 mg 
300 mg 
600 mg 
1200 mg 
1400 mg 
Ora-Blend®1 
Flavored 
Oral 
Suspending 
Vehicle 
Commercially 
available 
q.s. to 2 mL 
q.s to 
4 mL 
q.s to 
12 mL 
q.s. to 
24 mL 
q.s. to 
48 mL 
q.s to 
56 mL 
Total Volume 
2 mL 
4 mL 
12 mL 
24 mL 
48 mL 
56 mL 
1Purified water, sucrose, glycerin, sorbitol, flavoring, microcrystalline cellulose, carboxymethylcellulose sodium, 
xanthan gum, carrageenan, calcium sulfate, trisodium phosphate, citric acid and sodium phosphate as buffers, 
dimethicone antifoam emulsion. Preserved with methylparaben and potassium sorbate. 
 
Container and Closure System 
TBI-223 drug substance is shipped to the clinical study site in amber colored wide mouth glass 
bottles with a polypropylene screw cap without a liner.   


Protocol TBI-223-CL-001 Final Version 3.0 
 
Global Alliance for TB Drug Development 
CONFIDENTIAL 
21 Jan 2020 
Page 52 
TBI-223 Oral Suspension is transferred and stored in Pyrex glass reagent bottles with a 
polypropylene (PP) screw cap without a liner.  These bottles are used for mixing, sampling and 
storage prior to administration. 
Enteric Capsules 
Description of the Dosage Form 
TBI-223 Oral Enteric Capsules contain 150 mg TBI-223 in Vcaps® Enteric capsules. The 
capsules are filled at the clinical study site by manually filling TBI-223 into Vcaps® Enteric 
capsules which are commercially available empty capsule shells.   
Composition of the Drug Product 
The quantitative composition, function and quality of each ingredient in the drug product 
(TBI-223 Oral Enteric Capsules, 150 mg) is provided in Table 10. 
Table 10 Qualitative and Quantitative Composition of the TBI-223 Oral Enteric Capsules, 
150 mg 
Ingredient 
Function 
Quality Standard 
Quantity per 300 mg Dose 
TBI-223 
Drug Substance 
In-house 
300 mg 
Vcaps® Enteric Capsules1, Off-
white, Opaque, Size 00 
Capsule shell 
Commercially available 
2 capsules 
Total Quantity 
300 mg in 2 capsules 
1Capsule shell composition: titanium dioxide 2% in Hypromellose-Hypromellose AS. 
Container and Closure System 
TBI-223 Oral Enteric Capsules are stored in white HDPE bottles with PP CRC with a liner. 
These bottles are used for storage prior to administration.  
Tablets 
Description of the Dosage Form 
TBI-223 tablets are supplied as immediate release (IR) or sustained release (SR).  The 
description of the tablets and strengths are presented in Table 11. 


Protocol TBI-223-CL-001 Final Version 3.0 
 
Global Alliance for TB Drug Development 
CONFIDENTIAL 
21 Jan 2020 
Page 53 
Table 11 
Strength, Tablet Weight and Appearance of TBI-223 IR and SR Tablets 
Tablet Strength 
Tablet Weight 
Tablet Appearance 
TBI-223 Immediate Release (IR) Tablets 
600 mg 
750 mg 
White to off-white, capsule 
shaped tablets, debossed with 
“TBA” on one side and “22” on 
the other 
1000 mg 
1250 mg 
White to off-white, oval shaped 
tablets, debossed with “TBA” on 
one side and “23” on the other 
TBI-223 Sustained Release (SR) Tablets 
600 mg (Prototype 1) 
1000 mg 
White to off-white, capsule 
shaped tablets, debossed with 
“TBA” on one side and “11” on 
the other 
600 mg (Prototype 2) 
1000 mg 
White to off-white, capsule 
shaped tablets, debossed with 
“TBA” on one side and “SR” on 
the other 
900 mg (Prototype 3) 
1200 mg 
White to off-white, oval shaped 
tablets, debossed with “TBA” on 
one side and “900” on the other 
Composition of the Drug Product 
The composition of TBI-223 IR tablets, 600 mg and 1000 mg is presented in Table 12.  The 
composition of TBI-223 SR Tablets, 600 mg (Prototype 1), 600 mg (Prototype 2) and 900 mg 
(prototype 3) is presented in Table 13, Table 14 and Table 15, respectively. 
 


Protocol TBI-223-CL-001 Final Version 3.0 
 
Global Alliance for TB Drug Development 
CONFIDENTIAL 
21 Jan 2020 
Page 54 
Table 12 Composition of TBI-223 IR Tablets, 600 mg and 1000 mg 
Component 
Function 
Percentage 
(% w/w) 
600 mg 
1000 mg 
Reference to 
Standard 
mg/tablet 
 
 
Intragranular 
 
TBI-223 a 
Active 
80.00 
600.00 
1000.00 
In-House 
Microcrystalline cellulose 
(Avicel PH 302) b 
Diluent 
10.00 
75.00 
125.00 
USP-NF, 
Ph.Eur. 
Hypromellose 
(Methocel E5 Premium LV) 
Binder 
3.00 
22.50 
37.50 
USP-NF, 
Ph.Eur. 
Crospovidone 
(Kollidon CL) 
Disintegrant 
3.00 
22.50 
37.50 
USP-NF, 
Ph.Eur. 
Purified water c 
Granulating 
solvent 
q.s 
q.s 
q.s 
USP, Ph.Eur. 
 
 
Extragranular 
 
Crospovidone 
(Kollidon CL) 
Disintegrant 
2.00 
15.00 
25.00 
USP-NF, 
Ph.Eur. 
Colloidal silicon dioxide 
(Aerosil 200 Pharma) 
Glidant 
1.00 
7.50 
12.50 
USP-NF, 
Ph.Eur. 
Magnesium stearate 
(Ligamed MF-2-V) 
Lubricant 
1.00 
7.50 
12.50 
USP-NF, 
Ph.Eur. 
Total unit dose 
 
100.00 
750.0 
1250.0 
 
a  
The molecular weight of TBI-223 is 365.4 g/mol. The actual quantity may be adjusted based on the assay value 
(anhydrous basis) and water content of the drug substance lot used.    
b   The quantity of microcrystalline cellulose may be adjusted to compensate for the actual amount of TBI-223 
and to maintain a constant tablet weight. 
c   Removed during processing. 
Table 13 Composition of TBI-223 SR Tablets, 600 mg (Prototype 1) 
Component 
Function 
Percentage 
(% w/w) 
mg/tablet 
Reference to 
Standard 
 
 
Intragranular  
 
TBI-223 a 
Active 
60.00 
600.00 
In-House 
Lactose monohydrate b 
(Pharmatose 200M) 
Diluent 
9.90 
99.00 
USP-NF, Ph.Eur. 
Microcrystalline cellulose 
(Avicel PH 200) 
Diluent 
6.60 
66.00 
USP-NF, Ph.Eur. 
Hypromellose 
(Methocel E5 Premium LV) 
Binder 
5.00 
50.00 
USP-NF, Ph.Eur. 
Purified water c 
Granulating 
solvent 
q.s 
q.s 
USP, Ph.Eur. 


Protocol TBI-223-CL-001 Final Version 3.0 
 
Global Alliance for TB Drug Development 
CONFIDENTIAL 
21 Jan 2020 
Page 55 
Component 
Function 
Percentage 
(% w/w) 
mg/tablet 
Reference to 
Standard 
 
 
Intragranular  
 
 
 
Extragranular 
 
Hypromellose (Methocel 
K100M Premium DC2) 
Control Release 
Polymer 
16.00 
160.00 
USP-NF, Ph.Eur. 
Colloidal silicon dioxide 
(Aerosil 200 Pharma) 
Glidant 
1.50 
15.00 
USP-NF, Ph.Eur. 
Magnesium stearate 
(Ligamed MF-2-V) 
Lubricant 
1.00 
10.00 
USP-NF, Ph.Eur. 
Total unit dose 
 
100.00 
1000.0 
 
a  
The molecular weight of TBI-223 is 365.4 g/mol. The actual quantity may be adjusted based on the assay 
value (anhydrous basis) and water content of the drug substance lot used.    
b   The quantity of lactose monohydrate may be adjusted to compensate for the actual amount of TBI-223 
and to maintain a constant tablet weight. 
c   
Removed during processing. 
Table 14 Composition of TBI-223 SR Tablets, 600 mg (Prototype 2) 
Component 
Function 
Percentage 
(% w/w) 
mg/tablet 
Reference to 
Standard 
 
 
Intragranular  
 
TBI-223 a 
Active 
60.00 
600.00 
In-House 
Lactose monohydrate b 
(Pharmatose 200M) 
Diluent 
12.90 
129.00 
USP-NF, Ph.Eur. 
Microcrystalline cellulose 
(Avicel PH 200) 
Diluent 
8.60 
86.00 
USP-NF, Ph.Eur. 
Hypromellose 
(Methocel K4M Premium CR) 
Control Release 
Polymer 
5.00 
50.00 
USP-NF, Ph.Eur. 
Purified water c 
Granulating 
solvent 
q.s 
q.s 
USP, Ph.Eur. 
 
 
Extragranular 
 
Hypromellose (Methocel K100 
Premium LV) 
Control Release 
Polymer 
11.00 
110.00 
USP-NF, Ph.Eur. 
Colloidal silicon dioxide 
(Aerosil 200 Pharma) 
Glidant 
1.50 
15.00 
USP-NF, Ph.Eur. 
Magnesium stearate 
(Ligamed MF-2-V) 
Lubricant 
1.00 
10.00 
USP-NF, Ph.Eur. 
Total unit dose 
 
100.00 
1000.0 
 


Protocol TBI-223-CL-001 Final Version 3.0 
 
Global Alliance for TB Drug Development 
CONFIDENTIAL 
21 Jan 2020 
Page 56 
Component 
Function 
Percentage 
(% w/w) 
mg/tablet 
Reference to 
Standard 
 
 
Intragranular  
 
a  
The molecular weight of TBI-223 is 365.4 g/mol. The actual quantity may be adjusted based on the assay 
value (anhydrous basis) and water content of the drug substance lot used.    
b   The quantity of lactose monohydrate may be adjusted to compensate for the actual amount of TBI-223 
and to maintain a constant tablet weight. 
c   
Removed during processing. 
Table 15 Composition of TBI-223 SR Tablets, 900 mg (Prototype 3) 
Component 
Function 
Percentage 
(% w/w) 
mg/tablet 
Reference to 
Standard 
 
 
Intragranular  
 
TBI-223 a 
Active 
75.00 
900.00 
In-House 
Lactose monohydrate b 
(Pharmatose 200M) 
Diluent 
3.90 
46.80 
USP-NF, Ph.Eur. 
Microcrystalline cellulose 
(Avicel PH 200) 
Diluent 
2.60 
31.20 
USP-NF, Ph.Eur. 
Hypromellose 
(Methocel E5 Premium LV) 
Binder 
5.00 
60.00 
USP-NF, Ph.Eur. 
Purified water c 
Granulating 
solvent 
q.s 
q.s 
USP. Ph.Eur. 
 
 
Extragranular 
 
Hypromellose (Methocel 
K100M Premium DC2) 
Control Release 
Polymer 
11.00 
132.00 
USP-NF, Ph.Eur. 
Colloidal silicon dioxide 
(Aerosil 200 Pharma) 
Glidant 
1.50 
18.00 
USP-NF, Ph.Eur. 
Magnesium stearate 
(Ligamed MF-2-V) 
Lubricant 
1.00 
12.00 
USP-NF, Ph.Eur. 
Total unit dose 
 
100.00 
1200.0 
 
a  
The molecular weight of TBI-223 is 365.4 g/mol. The actual quantity may be adjusted based on the assay 
value (anhydrous basis) and water content of the drug substance lot used.    
b   The quantity of lactose monohydrate may be adjusted to compensate for the actual amount of TBI-223 
and to maintain a constant tablet weight. 
c   Removed during processing. 
Container and Closure System 
TBI-223 IR and SR 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-001 Final Version 3.0 
 
Global Alliance for TB Drug Development 
CONFIDENTIAL 
21 Jan 2020 
Page 57 
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-001 Final Version 3.0 
 
Global Alliance for TB Drug Development 
CONFIDENTIAL 
21 Jan 2020 
Page 58 
• 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-001 Final Version 3.0 
 
Global Alliance for TB Drug Development 
CONFIDENTIAL 
21 Jan 2020 
Page 59 
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-001 Final Version 3.0 
 
Global Alliance for TB Drug Development 
CONFIDENTIAL 
21 Jan 2020 
Page 60 
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-001 Final Version 3.0 
 
Global Alliance for TB Drug Development 
CONFIDENTIAL 
21 Jan 2020 
Page 61 
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 
1) For protocol TBI-223-CL-001, defined as increase from baseline in predose vital signs. 
 
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-001 Final Version 3.0 
 
Global Alliance for TB Drug Development 
CONFIDENTIAL 
21 Jan 2020 
Page 62 
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-001 Final Version 3.0 
 
Global Alliance for TB Drug Development 
CONFIDENTIAL 
21 Jan 2020 
Page 63 
MUSCULOSKELETAL 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Arthralgia (joint pain) 
mild pain not 
interfering with 
function 
moderate pain, 
analgesics and/or 
pain interfering with 
function but not with 
activities of daily 
living 
severe pain; pain 
and/or analgesics 
interfering with 
activities of daily 
living 
disabling pain 
Arthritis 
mild pain with 
inflammation, 
erythema or joint 
swelling – but not 
interfering with 
function 
moderate pain with 
inflammation, 
erythema or joint 
swelling – interfering 
with function, but not 
with activities of 
daily living 
severe pain with 
inflammation, 
erythema or joint 
swelling –and 
interfering with 
activities of daily 
living 
permanent and/or 
disabling joint 
destruction 
Myalgia 
myalgia with no 
limitation of activity 
muscle tenderness 
(at other than 
injection site) or with 
moderate 
impairment of 
activity 
severe muscle 
tenderness with 
marked impairment 
of activity 
frank 
myonecrosis 
 
SKIN 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Mucocutaneous 
erythema; pruritus 
diffuse, maculo 
papular rash, dry 
desquamation 
vesiculation or moist 
desquamation or 
ulceration 
exfoliative dermatitis, 
mucous membrane 
involvement or 
erythema, 
multiforme or 
suspected Stevens-
Johnson or  necrosis 
requiring surgery 
Induration 
< 15mm  
15-30 mm 
>30mm 
 
Erythema 
< 15mm  
15-30 mm 
>30mm 
 
Edema 
< 15mm  
15-30 mm 
>30mm 
 
Rash at Injection 
Site 
< 15mm  
15-30 mm 
>30mm 
 
Pruritus 
slight itching at 
injection site 
moderate itching at 
injection extremity 
itching over entire 
body 
 
 
 


Protocol TBI-223-CL-001 Final Version 3.0 
 
Global Alliance for TB Drug Development 
CONFIDENTIAL 
21 Jan 2020 
Page 64 
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 
 
 


Protocol TBI-223-CL-001 Final Version 3.0 
 
Global Alliance for TB Drug Development 
CONFIDENTIAL 
21 Jan 2020 
Page 65 
APPENDIX 4 HOLTER RECORDING AND ANALYSIS 
Continuous 12-lead ECGs (Holters) will be recorded using the Mortara Surveyor system.  
The continuous 12-lead digital ECG data will be stored and transmitted to iCardiac using the 
appropriate medium (e.g., file transfer protocol [FTP], disc, or flash drive). ECGs to be used in 
the analyses will be selected by pre-determined time points as defined in the Schedule of 
Assessments and Procedures, and will be read centrally by iCardiac Technologies, Inc. 
The following principals will be followed in iCardiac’s core laboratory: 
• ECG analysts are blinded to the subject, visit and treatment allocation 
• Baseline and on-treatment ECGs for a particular subject will be over-read on the same 
lead and will be analyzed by the same reader. 
• The primary analysis lead is lead II. If lead II is not analyzable, then primary lead of 
analysis will be changed to another lead for the entire subject data set. 
 
The following is a brief description of ECG analysis methods utilized by iCardiac’ core 
laboratory. 
TQT Plus ECG Extraction Technique 
Ten 14-second digital 12-lead ECG tracings will be extracted from the continuous Holter 
recordings using the “TQT Plus method”, a computer-assisted and statistical process utilized by 
iCardiac Technologies. The method enables extraction of ECGs with the lowest HR variability 
and noise within the protocol-specified extraction time window (e.g., the HR and QT changes 
from beat-to-beat in the range of <10%). At each protocol-specified timepoint, 10 ECG 
replicates will be extracted from a 5-minute “ECG window” (typically, the last 5 minutes of the 
15-minute period when the subject is maintained in a supine or semi-recumbent quiet position). 
High-Precision QT Analysis 
High-precision QT analysis will be performed on all analyzable (non-artifact) beats in the 
10 ECG replicates. Statistical quality control procedures are used to review and assess all beats 
and identify “high” and “low” confidence beats using several criteria, including: 
• QT or QTc values exceeding or below certain thresholds (biologically unlikely). 
• RR values exceeding or below certain thresholds (biologically unlikely). 
• Rapid changes in QT, QTc or RR from beat to beat. 
Measurements of all primary ECG parameters (QT, QTc, RR) in all recorded beats of all 
replicates that are deemed “high confidence” is performed using COMPAS software. All low 
confidence beats are reviewed manually and adjudicated using pass-fail criteria. The final QC 
assessment is performed by a cardiologist. The beats found acceptable by manual review are 
included in the analysis. The median QT, QTc, and RR value from each extracted replicate is 


Protocol TBI-223-CL-001 Final Version 3.0 
 
Global Alliance for TB Drug Development 
CONFIDENTIAL 
21 Jan 2020 
Page 66 
calculated, and then the mean of all available medians from a nominal timepoint is used as the 
subject’s reportable value at that timepoint. 
Categorical T-wave morphology analysis and the measurement of PR and QRS intervals will be 
performed manually in 3 of the 10 ECG replicates at each timepoint.  Each fiducial point (onset 
of P-wave, onset of Q-wave, offset of S-wave, and offset of T-wave) is electronically marked. 
T-wave morphology categories (assessed manually) 
Category 
Description 
Normal T-wave 
Any T-wave not meeting any criterion below 
Flat T-waves 
T amplitude < 1 mm (either positive or negative) including flat isoelectric 
line 
Notched T-wave (+) 
Presence of notch(es) of at least 0.05 mV amplitude on ascending or 
descending arm of the positive T-wave 
Biphasic 
T-wave that contains a second component with an opposite phase that is 
at least 0.1 mV deep (both positive and negative/positive and polyphasic 
T-waves included) 
Normal T-wave (-) 
T amplitude that is negative, without biphasic T-wave or notches 
Notched T-wave (-) 
Presence of notch(es) of at least 0.05 mV amplitude on descending or 
ascending arm of the negative T-wave 
 
In addition to the T-wave categorical analysis, the presence of abnormal U-waves is noted. 
 
 


Protocol TBI-223-CL-001 Final Version 3.0 
 
Global Alliance for TB Drug Development 
CONFIDENTIAL 
21 Jan 2020 
Page 67 
APPENDIX 5 REPEAT COHORT USING DIFFERENT DOSAGE FORMULATION 
Procedures and analyses as outlined in this protocol will be the same, with the following 
exceptions: 
• The dose of TBI-223 will be delivered in enteric capsules. 
• All subjects will receive active treatment. 
• A minimum of 6 subjects is needed. Ideally, all 8 subjects who participated in the 
original cohort will participate in the re-dose cohort. If less than 6 subjects from the 
original cohort agree to participate, additional subjects will be screened as needed in 
order to dose a minimum of 6 subjects.  
• Repeat subjects will be assigned a new subject number so as not to break the blinding of 
the original cohort. 
• The repeat cohort will not be blinded (blinding is not necessary because all subjects will 
receive the same treatment). 
• Cardiac telemetry and Holter recording will not be performed during the re-dose cohort. 
• Subjects will check-in on Day -1 instead of Day -2. With the exception of cardiac 
telemetry and Holter monitoring, the procedures that were previously scheduled for Day 
-2 will be performed on Day -1. The Day -1 results will be used to qualify repeat subjects 
for study participation. If additional subjects are needed, they will undergo screening to 
qualify for the study. 
• Neurological examinations will be performed at Screening, Day -1, and at 3 and 48 hours 
postdose. 


Protocol TBI-223-CL-001 Final Version 3.0 
 
Global Alliance for TB Drug Development 
CONFIDENTIAL 
21 Jan 2020 
Page 68 
APPENDIX 6 PART 2 OF THE STUDY  
Procedures and analyses as outlined in this protocol will be the same, with the following 
exceptions: 
The dose of TBI-223 will be delivered as follows in Cohort 8: 
• Arm 1 – TBI-223 SR Tablets (Prototype 1) - 1800 mg dose (3 x 600 mg tablets), under fed 
conditions 
• Arm 2 – TBI-223 SR Tablets (Prototype 2) - 1800 mg dose (3 x 600 mg tablets), under fed 
conditions 
• Arm 3 – TBI-223 SR Tablets (Prototype 3) - 1800 mg dose (2 x 900 mg tablets), under fed 
conditions 
• Arm 4 – TBI-223 IR Tablets - 2000 mg dose (2 x 1000 mg tablets), under fasting conditions   
 
In Cohort 9, the subjects from Cohort 8, Arm 4, who received the IR tablet formulation will be 
brought back following a 7-day washout and administered TBI-223 IR tablets, 2000 mg dose 
(2 x 1000 mg tablets), under fed conditions. 
• A minimum of 6 subjects per treatment arm in Part 2.  
• Part 2 will not be blinded (blinding is not necessary because all subjects will receive the 
same treatment). 
• Cardiac telemetry and Holter recording will not be performed during Part 2. Subjects will 
check-in on Day -1 instead of Day -2. With the exception of cardiac telemetry and Holter 
monitoring, the procedures that were previously scheduled for Day -2 will be performed 
on Day -1. The Day -1 results will be used to qualify repeat subjects for study 
participation. If additional subjects are needed, they will undergo screening to qualify for 
the study. 
• Neurological examinations will be performed at Screening, Day -1, and at 3 and 48 hours 
postdose.


Protocol TBI-223-CL-001 Final Version 3.0 
 
Global Alliance for TB Drug Development 
CONFIDENTIAL 
21 Jan 2020 
Page 69 
Table 16 Schedule of Assessments, Part 2  
 
SCR 
CONFINEMENT 
FU 
STUDY DAY 
-28  
to 
-2 
-1 
CI 
DAY 1 
DAY 2 
3 
4 
11 
(+1) 
STUDY HOUR 
EVENT  
0 
0.5 
1 
1.5 
2 
3 
4 
5 
6 
7 
8 
12 
16a 
20 
24 
30 
36 
42 
48 
72 
N/A 
Informed 
consent and 
medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical and 
neurological 
examinationsb 
X 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
X 
 
Vital signs 
(blood pressure, 
pulse, 
temperature, 
respiration rate, 
and pulse 
oximetry) c 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
12-lead safety 
ECGsd 
X 
X 
 
Xe 
 
X 
 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
HIV/hepatitis B, 
C 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical 
laboratory tests 
(hematology, 
chemistry, and 
urinalysis) 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
Coagulation 
tests 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
Urine drug, 
alcohol, cotinine 
screen 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol TBI-223-CL-001 Final Version 3.0 
 
Global Alliance for TB Drug Development 
CONFIDENTIAL 
21 Jan 2020 
Page 70 
 
SCR 
CONFINEMENT 
FU 
STUDY DAY 
-28  
to 
-2 
-1 
CI 
DAY 1 
DAY 2 
3 
4 
11 
(+1) 
STUDY HOUR 
EVENT  
0 
0.5 
1 
1.5 
2 
3 
4 
5 
6 
7 
8 
12 
16a 
20 
24 
30 
36 
42 
48 
72 
N/A 
Serum 
pregnancy 
(females only) 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FSH (post-
menopausal 
females only) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
medication 
review 
X 
<---------------------------------------------------------------X-----------------------------------------------------------------------> 
 
Check-in 
questions 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse eventsf 
X 
X 
 
X 
 
X 
 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
High-fat, high-
calorie 
breakfastg 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dose 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK blood 
collectionh 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 


Protocol TBI-223-CL-001 Final Version 3.0 
 
Global Alliance for TB Drug Development 
CONFIDENTIAL 
21 Jan 2020 
Page 71 
CI = check-in; ECG = electrocardiogram; FSH = follicle-stimulating hormone; FU = follow up; HIV = human 
immunodeficiency virus; N/A = not applicable; PK = pharmacokinetic; SCR = screening; T and R = temperature 
and respirations 
a. 
The 16-hour time point following dosing on Day 1 will either be on Day 1 or Day 2, depending upon time of 
dosing on Day 1.   
b. 
A detailed neurological exam will be conducted by a licensed physician or suitably medically qualified designee 
at both scheduled and unscheduled time points as deemed necessary by the Investigator. The neurological 
examination is planned to be performed around the estimated Tmax (currently estimated at 3 hours post dosing; 
this time could change based on data generated during the study). Timepoints can be altered based on generated 
PK data. 
c. 
Vitals signs will be measured at screening, check-in, and while subjects are in confinement. Vitals signs will be 
measured within 90 minutes prior to dosing and within 15 minutes of the remaining defined time points in 
flowchart.  Both blood pressure and heart rate (pulse) should be captured simultaneously. Blood pressure and 
heart rate should be measured after subjects are in a seated position for at least 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.  
d. 
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 at 48 hours only. All other time points will be single 
ECG readings within 15 minutes at time points within flowchart. The predose ECG should be performed prior 
to the pre-dose blood draw. 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.   
e. 
The first ECG may be done within 2 hours prior to dosing and must be completed 20 minutes prior to the 
pre-dose blood draw. All safety ECGs on Day 1 and Day 2 will be extracted from a continuous 12 lead Holter 
recording at discrete timepoints as noted in above flow chart and Day -1 will be extracted at the same time as 
vital sign measurements.   
f. 
Subjects will be monitored for treatment-emergent adverse events from the time of dosing and throughout the 
study via safety assessments, observation, and subject reporting. A specific inquiry regarding adverse events 
will be conducted prior to dosing and at time points determined by the Investigator postdose and upon return to 
clinic for subsequent visits. The inquiry to collect adverse events using non-leading questions on 
Day 11 (±1 day) will be done via a phone call. 
g. 
In Part 2, Cohort 8, Arms 1-3 and Cohort 9, a high-fat, high-calorie breakfast meal will be given 30 minutes 
before treatment administration. 
h. 
Samples collected for plasma pharmacokinetic analysis will be processed per the instructions in Appendix 1.  
*Three timepoints before dosing: -45, -30, and -15 minutes. 
NOTE: When ECG extractions coincide with safety ECGs, vital signs assessments, and/or blood draws, then 
procedures should be carried out in said order.    
 
 

SAP_001.pdf: 
Worldwide Clinical Trials Controlled Quality Management Document 
 
Sponsor: 
TB Alliance 
Protocol Number: 
TBI-223-CL-001 
STATISTICAL ANALYSIS PLAN – PHASE 1 
 
QMD Ref: Worldwide-TMP-ST-006-4.0 Effective: 12Aug2019 
 
Governing QMD: Worldwide-SOP-ST-001 
Confidentiality Statement 
This document is the property of Worldwide Clinical Trials Inc. and may not be duplicated, copied, altered or removed from company without 
prior approval from Worldwide Quality Assurance or in compliance with Worldwide Standard Operating Procedures. 
REF: Worldwide-TMP-QA-001f-1.3 
 
Page 1 of 31 
 
 
 
Statistical Analysis Plan 
A Phase 1, Partially-Blinded, Placebo-Controlled, Randomized Single Ascending 
Dose (SAD) with a Food Effect Cohort Study to Evaluate the Safety, Tolerability, 
and Pharmacokinetics of TBI-223 in Healthy Adult Participants 
Protocol Number: TBI-223-CL-001 
Protocol Version: 3.0, dated 21-Jan-2020 
 
SAP Version 2.0 
SAP Issue Date: 28-April-2020 
SAP Authors: Aimie Nunn, MSc,  
Kathryn Roupe, PhD 
 
Previous SAP Versions 
Version 1.0, dated 05-March-2019 
 
 


Worldwide Clinical Trials Controlled Quality Management Document 
 
Sponsor: 
TB Alliance 
Protocol Number: 
TBI-223-CL-001 
STATISTICAL ANALYSIS PLAN – PHASE 1 
 
QMD Ref: Worldwide-TMP-ST-006-4.0 Effective: 12Aug2019 
 
Governing QMD: Worldwide-SOP-ST-001 
Confidentiality Statement 
This document is the property of Worldwide Clinical Trials Inc. and may not be duplicated, copied, altered or removed from company without 
prior approval from Worldwide Quality Assurance or in compliance with Worldwide Standard Operating Procedures. 
REF: Worldwide-TMP-QA-001f-1.3 
 
Page 2 of 31 
SAP Amendments Before Database Lock 
Version Issue Date 
Revision/Addition 
2.0 
28-Apr-20 
SAP v2.0 has been updated in line with Protocol v3.0, dated 
21-Jan-2020.  The following changes affecting the analyses 
described in SAP v1.0, dated 05-March-2019 are as follows:  
Changes to dose cohorts 
TBI-223 (1400 mg) suspension was replaced with TBI-223 
(2000 mg) suspension.  
TBI-223 (2600 mg) suspension cohort was added 
TBI-223 300 mg oral capsule repeat cohort was added.  
Study Part 2 was added, including, 
- Arm 1 - TBI-223 SR Tablets 600 mg (Prototype 1). 
Dose of 1800 mg (3 tablets of 600 mg), under fed 
conditions 
- Arm 2 - TBI-223 SR Tablets 600 mg (Prototype 2). 
Dose of 1800 mg (3 tablets of 600 mg), under fed 
conditions 
- Arm 3 - TBI-223 SR Tablets 900 mg (Prototype 3). 
Dose of 1800 mg (2 tablets of 900 mg), under fed 
conditions 
- Arm 4 - TBI-223 IR Tablets 1000 mg. Dose of 2000 mg 
(2 tablets of 1000 mg), under fasting conditions 
 
- TBI-223 IR Tablets 1000 mg. Dose of 2000 mg (2 
tablets of 1000 mg), under fed conditions. 
Changes to safety analyses 
All Enrolled Subjects analysis set was added.  
Subject Disposition will be summarized for All Enrolled 
Subjects rather than the Randomized Set.   


Worldwide Clinical Trials Controlled Quality Management Document 
 
Sponsor: 
TB Alliance 
Protocol Number: 
TBI-223-CL-001 
STATISTICAL ANALYSIS PLAN – PHASE 1 
 
QMD Ref: Worldwide-TMP-ST-006-4.0 Effective: 12Aug2019 
 
Governing QMD: Worldwide-SOP-ST-001 
Confidentiality Statement 
This document is the property of Worldwide Clinical Trials Inc. and may not be duplicated, copied, altered or removed from company without 
prior approval from Worldwide Quality Assurance or in compliance with Worldwide Standard Operating Procedures. 
REF: Worldwide-TMP-QA-001f-1.3 
 
Page 3 of 31 
Version Issue Date 
Revision/Addition 
Safety data will be tabulated by study part, period (where 
applicable) and treatment group.  
SAP sections 4 Sample Size and 5 Randomization were 
updated to reflect study Parts 1 and 2.   
Changes to PK analyses 
As of SAP v2.0, PK concentration and parameter data will also 
be stratified by gender. 
Description of PK analyses and outputs were updated to reflect 
protocol and dose group changes.   
 
 
 


Worldwide Clinical Trials Controlled Quality Management Document 
 
Sponsor: 
TB Alliance 
Protocol Number: 
TBI-223-CL-001 
STATISTICAL ANALYSIS PLAN – PHASE 1 
 
QMD Ref: Worldwide-TMP-ST-006-4.0 Effective: 12Aug2019 
 
Governing QMD: Worldwide-SOP-ST-001 
Confidentiality Statement 
This document is the property of Worldwide Clinical Trials Inc. and may not be duplicated, copied, altered or removed from company without 
prior approval from Worldwide Quality Assurance or in compliance with Worldwide Standard Operating Procedures. 
REF: Worldwide-TMP-QA-001f-1.3 
 
Page 4 of 31 
Table of Contents 
1 
INTRODUCTION ............................................................................................... 6 
2 
STUDY OBJECTIVES ....................................................................................... 7 
2.1 
Primary Objective ........................................................................................................... 7 
2.2 
Secondary Objectives...................................................................................................... 7 
3 
ENDPOINTS ....................................................................................................... 7 
3.1 
Safety Endpoints ............................................................................................................. 7 
3.2 
Pharmacokinetic Endpoints ............................................................................................ 7 
4 
SAMPLE SIZE .................................................................................................... 8 
5 
RANDOMIZATION ........................................................................................... 8 
6 
PLANNED ANALYSES ..................................................................................... 9 
6.1 
Analysis Sets ................................................................................................................... 9 
6.1.1 
All Enrolled Subjects ................................................................................................ 9 
6.1.2 
Randomized Set ........................................................................................................ 9 
6.1.3 
Safety Analysis Set ................................................................................................... 9 
6.1.4 
PK Analysis Set ........................................................................................................ 9 
6.2 
Derived Data ................................................................................................................... 9 
6.2.1 
Race......................................................................................................................... 10 
6.2.2 
Baseline ................................................................................................................... 10 
6.2.3 
Early Withdrawal Assessments............................................................................... 10 
6.2.4 
Duration/Study Day ................................................................................................ 10 
6.2.5 
Conventions for Missing and Partial Dates ............................................................ 10 
6.2.6 
Inexact Values ......................................................................................................... 10 
6.2.7 
Electrocardiogram Data .......................................................................................... 10 
6.2.8 
Unscheduled Visits ................................................................................................. 11 
6.2.9 
PK Parameters ......................................................................................................... 11 
6.3 
Conventions .................................................................................................................. 13 
6.3.1 
Decimal Places ........................................................................................................ 16 
6.4 
Subject Disposition ....................................................................................................... 16 
6.5 
Protocol Deviations ....................................................................................................... 16 
6.6 
Baseline Comparability ................................................................................................. 16 
6.7 
Demographic Data ........................................................................................................ 16 
6.8 
Medical History ............................................................................................................ 17 


Worldwide Clinical Trials Controlled Quality Management Document 
 
Sponsor: 
TB Alliance 
Protocol Number: 
TBI-223-CL-001 
STATISTICAL ANALYSIS PLAN – PHASE 1 
 
QMD Ref: Worldwide-TMP-ST-006-4.0 Effective: 12Aug2019 
 
Governing QMD: Worldwide-SOP-ST-001 
Confidentiality Statement 
This document is the property of Worldwide Clinical Trials Inc. and may not be duplicated, copied, altered or removed from company without 
prior approval from Worldwide Quality Assurance or in compliance with Worldwide Standard Operating Procedures. 
REF: Worldwide-TMP-QA-001f-1.3 
 
Page 5 of 31 
6.9 
Prior and Concomitant Medications ............................................................................. 17 
6.10 
Exposure to Study Drug ................................................................................................ 17 
6.11 
Pharmacokinetic Analyses ............................................................................................ 17 
6.12 
Safety Analyses ............................................................................................................. 19 
6.12.1 
Adverse Events ....................................................................................................... 20 
6.12.2 
Laboratory Data ...................................................................................................... 21 
6.12.3 
Vital Signs ............................................................................................................... 21 
6.12.4 
Electrocardiogram Data .......................................................................................... 21 
6.12.5 
Cardiac Telemetry (Holter) Data ............................................................................ 22 
6.12.6 
Physical Examination.............................................................................................. 22 
6.12.7 
Neurological Examination ...................................................................................... 22 
7 
CHANGES TO PLANNED PROTOCOL ANALYSIS ...................................22 
8 
REFERENCES ..................................................................................................23 
9 
LIST OF TABLES, FIGURES AND LISTINGS .............................................24 
 


Worldwide Clinical Trials Controlled Quality Management Document 
 
Sponsor: 
TB Alliance 
Protocol Number: 
TBI-223-CL-001 
STATISTICAL ANALYSIS PLAN – PHASE 1 
 
QMD Ref: Worldwide-TMP-ST-006-4.0 Effective: 12Aug2019 
 
Governing QMD: Worldwide-SOP-ST-001 
Confidentiality Statement 
This document is the property of Worldwide Clinical Trials Inc. and may not be duplicated, copied, altered or removed from company without 
prior approval from Worldwide Quality Assurance or in compliance with Worldwide Standard Operating Procedures. 
REF: Worldwide-TMP-QA-001f-1.3 
 
Page 6 of 31 
1 INTRODUCTION 
This document details the planned statistical analyses for the Global Alliance for TB Drug 
Development, protocol “TBI-223-CL-001” study titled “A Phase 1, Partially-Blinded, Placebo-
Controlled, Randomized Single Ascending Dose (SAD) with a Food Effect Cohort Study to 
Evaluate the Safety, Tolerability, and Pharmacokinetics of TBI-223 in Healthy Adult 
Participants”.  The proposed analyses are based on the contents of protocol version 3.0, dated 
21-Jan-2020 and Protocol Clarification Letter No. 4, dated 24-Feb-2020.  
This is a partially blinded, placebo-controlled, randomized, SAD study with a food effect cohort. 
The study will be conducted at one study center in the United States.   
Part 1 
Part 1 of the study will have up to 6 planned dose levels. Based on interim pharmacokinetic data 
obtained during the dose escalation, a dose cohort will be selected to return for additional dosing 
after a high-calorie, high-fat meal (food-effect cohort).   
Part 2 
Part 2 of the study will comprise 4 arms each consisting of 6 subjects. Subjects will be assigned to 
one of the following dosing arms:  
Arm 1 
TBI-223 SR Tablets (Prototype 1) - 1800 mg dose (3 x 600 mg tablets) under fed 
conditions 
Arm 2 
TBI-223 SR Tablets (Prototype 2) - 1800 mg dose (3 x 600 mg tablets) under fed 
conditions  
Arm 3 
TBI-223 SR Tablets (Prototype 3) - 1800 mg dose (2 x 900 mg tablets) under fed 
conditions 
Arm 4 
TBI-223 IR Tablets - 2000 mg dose (2 x 1000 mg tablets) under fasting 
conditions 
*IR = Immediate Release; SR = Sustained Release 
The 6 subjects from Arm 4, who received the IR tablet formulation will be brought back following 
a 7-day washout period to receive TBI-223 IR Tablets 2000 mg (2 x 1000 mg tablets), under fed 
conditions.  If more than 2 of the 6 subjects drop-out, they will be replaced by heathy volunteers 
(a minimum of 4 subjects is required to complete the Fed cohort).   
Additional cohorts may be enrolled if deemed appropriate (e.g. if bioavailability is lower than 
expected) by the Sponsor to repeat a dose level, to study other dose levels, change proposed 


Worldwide Clinical Trials Controlled Quality Management Document 
 
Sponsor: 
TB Alliance 
Protocol Number: 
TBI-223-CL-001 
STATISTICAL ANALYSIS PLAN – PHASE 1 
 
QMD Ref: Worldwide-TMP-ST-006-4.0 Effective: 12Aug2019 
 
Governing QMD: Worldwide-SOP-ST-001 
Confidentiality Statement 
This document is the property of Worldwide Clinical Trials Inc. and may not be duplicated, copied, altered or removed from company without 
prior approval from Worldwide Quality Assurance or in compliance with Worldwide Standard Operating Procedures. 
REF: Worldwide-TMP-QA-001f-1.3 
 
Page 7 of 31 
cohorts, or to study a different dosage formulation. These 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 have been demonstrated to permit proceeding to the 
next cohort. The Institutional Review Board (IRB) should be immediately notified of this revised 
approach for review and approval.   
2 STUDY OBJECTIVES 
2.1 Primary Objective 
The primary objective of the study is to evaluate the safety and tolerability of single doses of TBI-
223 oral suspension, TBI-223 oral enteric capsules, and TBI-223 tablet formulations in healthy 
adult subjects.   
2.2 Secondary Objectives 
The secondary objectives of the study are:  
• To determine the pharmacokinetics of TBI-223 and its metabolite M2 after single doses of 
TBI-223 oral suspension, TBI-223 oral enteric capsules, and TBI-223 tablet formulations 
in healthy adult subjects.  
• To compare the rate and extent of absorption of a single dose of TBI-223 oral suspension, 
TBI-223 oral enteric capsules, and TBI-223 tablet formulations when administered in 
healthy adult subjects either after a high-calorie, high-fat meal or in the fasting state.   
3 ENDPOINTS 
3.1 Safety Endpoints 
Safety assessments will include physical and neurological examinations, vital signs including heart 
rate and respiratory rate, electrocardiograms (ECGs), cardiac monitoring, adverse events (AEs), 
and clinical laboratory tests (including hematology, serum chemistry, coagulation, and urinalysis).   
3.2 Pharmacokinetic Endpoints 
Serial blood samples will be collected pre-dose and post-dose through 72 hours to determine 
concentrations of TBI-223 and its metabolite (M2) in plasma.  


Worldwide Clinical Trials Controlled Quality Management Document 
 
Sponsor: 
TB Alliance 
Protocol Number: 
TBI-223-CL-001 
STATISTICAL ANALYSIS PLAN – PHASE 1 
 
QMD Ref: Worldwide-TMP-ST-006-4.0 Effective: 12Aug2019 
 
Governing QMD: Worldwide-SOP-ST-001 
Confidentiality Statement 
This document is the property of Worldwide Clinical Trials Inc. and may not be duplicated, copied, altered or removed from company without 
prior approval from Worldwide Quality Assurance or in compliance with Worldwide Standard Operating Procedures. 
REF: Worldwide-TMP-QA-001f-1.3 
 
Page 8 of 31 
Noncompartmental pharmacokinetic parameters of AUClast, AUCinf, Cmax, Tmax, Clast, Tlast, 
AUCExtrap%, λz, and T½ will be calculated from plasma concentrations of TBI-223 (parent) and 
TBI-223 M2 (metabolite); CL/F and Vz/F will be calculated for TBI-223 only.  
For Part 1, pharmacokinetic parameters will be summarized by cohort using descriptive statistics. 
Dose proportionality will be assessed using the power model approach (Cohorts 1-7, under fasted 
conditions). The 90% confidence intervals for geometric mean ratios, fed-to-fasted, of AUClast, 
AUCinf, and Cmax will be determined as appropriate for Cohort 5.  
For Part 2, pharmacokinetic parameters will be summarized by cohort and treatment/arm using 
descriptive statistics. The 90% confidence intervals for geometric mean ratios, test-to-reference, 
of AUClast, AUCinf, and Cmax will be determined as appropriate for Cohorts 8 and 9. 
Additional pharmacokinetic parameters may be calculated if deemed appropriate.  
4 SAMPLE SIZE 
For Part 1, up to 50 subjects are planned to be enrolled in the study. 
Fasting Cohorts: It was planned to enroll up to 48 subjects in a total of 6 cohorts of 8 subjects each 
(6 to receive active drug and 2 to receive placebo).   
Food-effect Cohort: One of the 6 planned dose cohorts will be selected to enroll 10 subjects (8 
active and 2 placebo) who will receive TBI-223 or placebo under both fasting and fed conditions.   
Additional subjects may be enrolled if deemed appropriate by the Sponsor to repeat a dose level 
or to study another dose level.  
For Part 2, 24 subjects will be enrolled. The 6 subjects who received the IR tablet formulation 
under fasted conditions will return after a 7-day washout and receive the IR tablet formulation 
under fed conditions. If more than 2 subjects of these 6 subjects drop-out, they will be replaced by 
heathy volunteers (a minimum of 4 subjects are needed to complete the cohort).   
The number of subjects selected for the study was based on the adequate number considered to 
provide sufficient safety data. This study has not been formally powered.  
5 RANDOMIZATION 
Each subject in Part 1 will receive an assigned treatment (active or placebo) based on the 
randomization schedule prepared by the unblinded statistician.  The first cohort will be separated 
into two groups. A sentinel group of 3 subjects (2 active and 1 placebo) will be dosed at least 24 


Worldwide Clinical Trials Controlled Quality Management Document 
 
Sponsor: 
TB Alliance 
Protocol Number: 
TBI-223-CL-001 
STATISTICAL ANALYSIS PLAN – PHASE 1 
 
QMD Ref: Worldwide-TMP-ST-006-4.0 Effective: 12Aug2019 
 
Governing QMD: Worldwide-SOP-ST-001 
Confidentiality Statement 
This document is the property of Worldwide Clinical Trials Inc. and may not be duplicated, copied, altered or removed from company without 
prior approval from Worldwide Quality Assurance or in compliance with Worldwide Standard Operating Procedures. 
REF: Worldwide-TMP-QA-001f-1.3 
 
Page 9 of 31 
hours before the remaining 5 subjects (4 active and 1 placebo). The remaining cohorts will be 
dosed in 2 groups of 4 subjects each (3 active and 1 placebo), 24 hours apart.  Based on exposure 
levels, subjects in one of the dose levels will return after a 7-day minimum washout or 5 half-lives 
of the drug (whichever is longer) to receive the same dose under fed conditions.  All subjects and 
clinical staff (except for the unblinded pharmacy staff) will be blinded to treatment.   
Subjects in Part 1 who participate in the repeat cohort will receive a different treatment 
formulation.  In Part 2, subjects will be non-randomized and unblinded.   
6 PLANNED ANALYSES 
No statistical analysis plan (SAP) prepared in advance of the data can be definitive and the final 
clinical study report (CSR) may contain additional tables or statistical tests if warranted by the 
data obtained.  The justification for any such additional analyses will be fully documented in the 
final CSR. 
6.1 Analysis Sets 
Subjects excluded from the analysis sets and the reason for their exclusion will be listed in 
Appendix 16.2. 
6.1.1 
All Enrolled Subjects 
Enrolled subjects include all subjects who have given informed consent to participate in the study.   
6.1.2 
Randomized Set 
The Randomized Set includes all subjects to whom a treatment was randomly assigned.   
6.1.3 
Safety Analysis Set 
The Safety Analysis Set includes all subjects who received any dose of study drug.   
6.1.4 
PK Analysis Set 
The PK Analysis Set includes all subjects with sufficient data to derive PK parameters.  
6.2 Derived Data 
This section describes the derivations required for statistical analysis. Unless otherwise stated, 
variables derived in the source data will not be re-calculated. 


Worldwide Clinical Trials Controlled Quality Management Document 
 
Sponsor: 
TB Alliance 
Protocol Number: 
TBI-223-CL-001 
STATISTICAL ANALYSIS PLAN – PHASE 1 
 
QMD Ref: Worldwide-TMP-ST-006-4.0 Effective: 12Aug2019 
 
Governing QMD: Worldwide-SOP-ST-001 
Confidentiality Statement 
This document is the property of Worldwide Clinical Trials Inc. and may not be duplicated, copied, altered or removed from company without 
prior approval from Worldwide Quality Assurance or in compliance with Worldwide Standard Operating Procedures. 
REF: Worldwide-TMP-QA-001f-1.3 
 
Page 10 of 31 
6.2.1 
Race 
Where more than one race category has been selected for a subject, these race categories will be 
combined into a single category labeled “Multiple Race” in the summary tables. The listings will 
reflect the original selected categories.  
6.2.2 
Baseline 
Baseline is defined as the last non-missing value (either scheduled, unscheduled or repeat) before 
the subject receives the single dose of study drug in the relevant study part and dosing period.   
6.2.3 
Early Withdrawal Assessments 
Early withdrawal assessments will be tabulated with End of Study (EOS).   
6.2.4 
Duration/Study Day  
Study day will be calculated as the number of days from single dose of study drug in the relevant 
dosing period (fasted or fed).  
• date of the event – date of the first dose of study drug + 1, for events on or after first dose  
• date of the event – date of the first dose of study drug, for events before first dose.   
6.2.5 
Conventions for Missing and Partial Dates 
It is not expected that there will be any missing dates, however in the rare case that an AE start 
date or time is missing, and it is unclear whether the AE is treatment emergent or not then a 
conservative approach will be taken and it will be assumed that the AE occurred after first dosing.  
All dates presented in the individual subject listings will be as recorded on the eCRF.  
6.2.6 
Inexact Values 
In the case where a safety laboratory variable is recorded as “> x”, “≥ x”, “< x” or “≤ x”, a value 
of x will be taken for analysis purposes.   
6.2.7 
Electrocardiogram Data 
For ECG data recorded on continuous scales, if more than one value is recorded at a time point, 
the mean value rounded to the integer will be presented.  For overall interpretation if more than 
one value is recorded, the most severe (worst case) of the respective readings will be taken. 


Worldwide Clinical Trials Controlled Quality Management Document 
 
Sponsor: 
TB Alliance 
Protocol Number: 
TBI-223-CL-001 
STATISTICAL ANALYSIS PLAN – PHASE 1 
 
QMD Ref: Worldwide-TMP-ST-006-4.0 Effective: 12Aug2019 
 
Governing QMD: Worldwide-SOP-ST-001 
Confidentiality Statement 
This document is the property of Worldwide Clinical Trials Inc. and may not be duplicated, copied, altered or removed from company without 
prior approval from Worldwide Quality Assurance or in compliance with Worldwide Standard Operating Procedures. 
REF: Worldwide-TMP-QA-001f-1.3 
 
Page 11 of 31 
6.2.8 
Unscheduled Visits 
Only scheduled post-baseline assessments will be tabulated. Post-baseline repeat/unscheduled 
assessments will not be summarized but will be listed in the relevant appendices to the CSR.   
6.2.9 
PK Parameters 
Blood Samples for PK analysis in plasma will be collected at pre-dose (0), and at 0.5, 1, 1.5, 2, 3, 
4, 5, 6, 7, 8, 12, 16, 20, 24, 30, 36, 42, 48, and 72 hours post-dose. 
Concentration-time data for TBI-223 (parent) and TBI-223 M2 (metabolite) will be analyzed using 
noncompartmental methods in Phoenix™ WinNonlin® (Version 8.1, Certara, L.P)1. 
During the pharmacokinetic analysis, concentrations below the limit of quantitation (BLQ) up to 
the time of the first quantifiable concentration will be treated as zero. Embedded (values between 
2 quantifiable concentrations) and terminal BLQ concentrations will be treated as “missing”. 
The following PK parameters will be calculated for TBI-223 and TBI-223 M2 for Parts 1 and 2: 
Parameter 
Definition 
Cmax 
Maximum plasma concentration, determined directly from individual 
concentration-time- data 
Tmax 
Time of the maximum plasma concentrations 
Clast 
Last quantifiable plasma concentration determined directly from individual 
concentration-time data 
Tlast 
Time of the last quantifiable plasma concentration 
AUClast 
Area under the plasma concentration-time curve from time-zero to the time of 
the last quantifiable concentration (Clast), as calculated by the linear trapezoidal 
rule 
AUCinf 
Area under the plasma concentration-time- curve from the time of dosing 
extrapolated to infinity, calculated as:  


Worldwide Clinical Trials Controlled Quality Management Document 
 
Sponsor: 
TB Alliance 
Protocol Number: 
TBI-223-CL-001 
STATISTICAL ANALYSIS PLAN – PHASE 1 
 
QMD Ref: Worldwide-TMP-ST-006-4.0 Effective: 12Aug2019 
 
Governing QMD: Worldwide-SOP-ST-001 
Confidentiality Statement 
This document is the property of Worldwide Clinical Trials Inc. and may not be duplicated, copied, altered or removed from company without 
prior approval from Worldwide Quality Assurance or in compliance with Worldwide Standard Operating Procedures. 
REF: Worldwide-TMP-QA-001f-1.3 
 
Page 12 of 31 
Parameter 
Definition 
AUCinf = AUClast + Clast/λz, where λz is the apparent terminal elimination rate 
constant calculated by linear regression of the terminal linear portion of the log 
concentration versus time curve 
AUCExtrap 
The percentage of AUCinf based on extrapolation, calculated as: 
 [1 - (AUClast/AUCinf)]* 100 
λz (Kel , 
Lambda z) 
The apparent elimination rate constant λz will be calculated as the negative of 
the slope of the linear regression through the terminal log-linear segment of 
the plasma concentration-time curve; the range of data to be used will be 
determined by visual inspection of a semi-logarithmic plot of concentration vs. 
time.  
T½ 
The observed terminal elimination half-life, calculated as:  
T½ = ln(2)/λz 
CL/F 
The apparent total plasma clearance after an oral dose, calculated as: 
CL/F=Dose/AUCinf, where F is the bioavailability, 
 (calculated for parent only) 
Vz/F 
The apparent volume of distribution after an oral dose, calculated as:  
Vz/F=Dose/(AUCinf x z), where F is the bioavailability, 
(calculated for parent only) 
DN_Cmax 
For Cohort 8: maximum plasma concentration for TB-223 SR prototype 
tablets, 1800 mg, dose-normalized to 2000 mg  
DN_AUClast 
For Cohort 8, area under the plasma concentration-time curve from time-zero 
to the time of the last quantifiable concentration (Clast), as calculated by the 
linear trapezoidal rule, for TB-223 SR prototype tablets, 1800 mg, dose-
normalized to 2000 mg 


Worldwide Clinical Trials Controlled Quality Management Document 
 
Sponsor: 
TB Alliance 
Protocol Number: 
TBI-223-CL-001 
STATISTICAL ANALYSIS PLAN – PHASE 1 
 
QMD Ref: Worldwide-TMP-ST-006-4.0 Effective: 12Aug2019 
 
Governing QMD: Worldwide-SOP-ST-001 
Confidentiality Statement 
This document is the property of Worldwide Clinical Trials Inc. and may not be duplicated, copied, altered or removed from company without 
prior approval from Worldwide Quality Assurance or in compliance with Worldwide Standard Operating Procedures. 
REF: Worldwide-TMP-QA-001f-1.3 
 
Page 13 of 31 
Parameter 
Definition 
DN_AUCinf 
For Cohort 8, area under the plasma concentration-time- curve from the time 
of dosing extrapolated to infinity, calculated as:  
AUCinf = AUClast + Clast/λz, where λz is the apparent terminal elimination rate 
constant calculated by linear regression of the terminal linear portion of the 
log concentration versus time curve, for TB-223 SR prototype tablets, 
1800 mg, dose-normalized to 2000 mg 
Lambda-z (λz) Acceptance Criteria 
The following criteria will be used to report lambda-z and related parameters: 
• At least 3 quantifiable concentration-time points should be used in the regression 
• Cmax or data prior to Cmax should not be included in the regression 
• Adjusted R2 should be ≥ 0.8000 
If these acceptance criteria are not met, lambda-z and descriptive parameters such as the time range 
for the regression, adjusted R2, etc. will be retained in a parameter listing for informational 
purposes. Lambda-z will be excluded from summary statistics and from subsequent PK 
calculations; parameters calculated using lambda-z (e.g. t1/2, AUCinf, CL/F, and Vz/F) will be 
reported as ND (not determinable). 
If lambda-z acceptance criteria are met and AUCinf is estimable, the following criteria are used to 
report AUCinf: 
• The percentage of AUCinf based on extrapolation should be <30.0%. 
If the percentage of AUCinf based on extrapolation is 30.0% or greater, AUCinf and AUCExtrap will 
be retained in a PK parameter listing for informational purposes; these parameters will be excluded 
from summary statistics, subsequent PK calculations (e.g. CL/F, Vz/F), and statistical analysis (e.g. 
ANOVA). 
6.3 Conventions 
All clinical data listings, summaries and statistical analyses will be generated using SAS (Version 
9.4 or higher)2.  Summaries of clinical data will be presented by treatment period and treatment 
group or overall.  


Worldwide Clinical Trials Controlled Quality Management Document 
 
Sponsor: 
TB Alliance 
Protocol Number: 
TBI-223-CL-001 
STATISTICAL ANALYSIS PLAN – PHASE 1 
 
QMD Ref: Worldwide-TMP-ST-006-4.0 Effective: 12Aug2019 
 
Governing QMD: Worldwide-SOP-ST-001 
Confidentiality Statement 
This document is the property of Worldwide Clinical Trials Inc. and may not be duplicated, copied, altered or removed from company without 
prior approval from Worldwide Quality Assurance or in compliance with Worldwide Standard Operating Procedures. 
REF: Worldwide-TMP-QA-001f-1.3 
 
Page 14 of 31 
PK data listings, summaries, figures, and statistical analyses will be generated using Phoenix™ 
WinNonlin® (Version 8.1) or SAS (Version 9.4 or higher).  PK concentration data will be 
summarized by study part, analyte, and treatment at each nominal sample time. PK parameter data 
will be summarized by study part, analyte, and treatment.  PK concentration and parameter data 
will also be stratified by gender.  
Treatment group labels will be displayed as follows:  
Part 1 / Oral Suspension / Period 1 (Fasted) 
Placebo 
TBI-223 
50 mg 
TBI-223 
100 mg 
TBI-223 
300 mg 
TBI-223 
600 mg 
TBI-223 
1200 mg 
TBI-223 
2000 mg 
TBI-223 
2600 mg 
Part 1 / Oral Suspension / Period 2 (Fed) 
Placebo 
TBI-223 
1200 mg 
Part 1 / Capsule Formulation / Repeat Cohort 
TBI-223 
300 mg 
Capsule 
Part 2 / Tablet Formulation / Period 1 
TBI-223 1800 mg 
SR-1 tablet 
(Fed) 
TBI-223 1800 mg 
SR-2 tablet 
(Fed) 
TBI-223 1800 mg 
SR-3 tablet 
(Fed) 
TBI-223 2000 mg 
IR tablet 
(Fasted) 
Part 2 / Tablet Formulation / Period 2 
TBI-223 2000 mg 
IR tablet 
(Fed) 


Worldwide Clinical Trials Controlled Quality Management Document 
 
Sponsor: 
TB Alliance 
Protocol Number: 
TBI-223-CL-001 
STATISTICAL ANALYSIS PLAN – PHASE 1 
 
QMD Ref: Worldwide-TMP-ST-006-4.0 Effective: 12Aug2019 
 
Governing QMD: Worldwide-SOP-ST-001 
Confidentiality Statement 
This document is the property of Worldwide Clinical Trials Inc. and may not be duplicated, copied, altered or removed from company without 
prior approval from Worldwide Quality Assurance or in compliance with Worldwide Standard Operating Procedures. 
REF: Worldwide-TMP-QA-001f-1.3 
 
Page 15 of 31 
Adverse Event summaries will be displayed as follows: 
Part 1 / Oral Suspension and Capsule Formulation 
Placebo 
TBI-223 
50 mg 
TBI-223 
100 mg 
TBI-223 
300 mg 
TBI-223 
300 mg 
Capsule 
TBI-223 
600 mg 
TBI-223 
1200 mg 
(Fasted) 
TBI-223 
1200 mg 
(Fed) 
TBI-223 
2000 mg 
TBI-223 
2600 mg 
Overall 
The Placebo column will include Period 1 (Fasted) and Period 2 (Fed) events.  
Placebo is not administered to subjects in the repeat cohort who will receive capsule formulation.   
Overall column will include all reported events during Part 1.  
Part 2 / Tablet Formulation 
TBI-223 
1800 mg 
SR-1 tablet 
(Fed) 
TBI-223 
1800 mg 
SR-2 tablet 
(Fed) 
TBI-223 
1800 mg 
SR-3 tablet 
(Fed) 
TBI-223 
2000 mg 
IR tablet 
(Fasted) 
TBI-223 
2000 mg 
IR tablet 
(Fed) 
Overall 
Overall column will include all reported events during Part 2.  
Listings will be sorted in the following order: Study part, period (where applicable), treatment 
group (Placebo followed by TBI-223 in ascending dose order), subject number, parameter, and 
visit unless otherwise stated. All data will be listed.   
For clinical data, continuous variables will be summarized by the number of non-missing 
observations, mean, median, standard deviation, and minimum and maximum.   
PK data (concentration-time data and PK parameters) will be summarized by the number of non-
missing observations (n), mean, standard deviation (SD), median, minimum (min), maximum 
(max), and coefficient of variation (CV%), calculated as (SD/Mean)*100.  In addition, the 
geometric mean and geometric CV%, calculated as SQRT[exp(SD2 of log transformed data)-
1]*100, will be reported for Cmax and AUCs.  
Categorical variables will be summarized by presenting the frequency and percent. Percentages 
will be based on the number of non-missing observations or the subject population unless 


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Page 16 of 31 
otherwise specified. For each variable, all categories will be shown. Zero frequencies (but not the 
percent) within a category will be presented.  
6.3.1 
Decimal Places 
Means, medians and percentiles will be displayed to one more decimal place than the data, 
dispersion statistics (e.g. standard deviation) will have two more decimal places, and the minimum 
and maximum will be displayed to the same number of decimal places as reported in the raw data. 
Percentages will be displayed with one decimal place.  
For PK data, individual concentrations will be reported to 3 significant figures and individual PK 
parameters will be reported to the precision as stated in Section 6.2.9.  For summary statistics, n 
will be reported as a whole number; mean, standard deviation, median, minimum, maximum, and 
geometric mean will be reported to the same precision as for individual data.  CV% and geometric 
CV% will be reported to 2 decimal places; p-values will be reported to 4 decimal places.  Percent 
ratios of the geometric least squares means and associated 90% confidence intervals will be 
reported to 2 decimal places.  
6.4 Subject Disposition 
Subject disposition will be summarized as follows:  
• The number of subjects in each analysis set will be summarized by study part, period 
(where applicable), treatment group and overall for all enrolled subjects.  
• The number of early withdrawals and the reasons for withdrawals will be tabulated by 
study part, period (where applicable), treatment group and overall for all enrolled subjects.  
6.5 Protocol Deviations 
A listing of protocol deviations will be provided within Appendix 16.2.  
6.6 Baseline Comparability 
The comparability of treatment groups with respect to subject demographics and baseline 
characteristics will be assessed in a descriptive manner, but no formal statistical testing will be 
performed.  The Safety Analysis Set will be used to summarize all baseline and demographic data. 
6.7 Demographic Data 
Standard continuous or categorical variable summaries will be presented by treatment group for 
the following variables based on the Safety Analysis Set. 


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• Age at Informed Consent (years) 
• Sex 
• Ethnicity 
• Race, where more than one race is selected the subject will be presented under the ‘Multiple 
races’ category in the summary but each selected race will be identified in the listing. 
• Weight at Screening (kg) 
• Height at Screening (cm) 
• BMI at Screening (kg/m2) 
6.8 Medical History 
Separate listings of previous and ongoing conditions at Screening will be presented for the Safety 
Set. Conditions will be coded using the Medical Dictionary of Regulated Activities (MedDRA 
version 21.0 or higher) primary system organ class (SOC) and preferred term (PT). Any medical 
condition will be classed as resolved if a stop date is recorded, otherwise, the condition will be 
classed as ongoing.   
6.9 Prior and Concomitant Medications 
Prior and concomitant medications will be listed for the Safety Analysis Set. Prior medications are 
defined as all medications starting and stopping before the date of first dose of study drug. 
Concomitant medications are defined as medications taken on or after the date of first dose of 
study drug. Each concomitant medication will be assigned to the last study drug taken prior to 
starting the concomitant medication.  Prior and concomitant medications will be coded using the 
World Health Organization (WHO) Drug Dictionary B3 – September 2018 version.   
6.10 Exposure to Study Drug 
All dosing information will be listed.  
6.11 Pharmacokinetic Analyses 
Concentration-time data will be tabulated by nominal time, analyte, and cohort using descriptive 
statistics. For presentation of the individual data and summary statistics, concentrations below the 
limit of quantitation (BLQ) will be set to zero. 
Mean and individual subject concentration-time data will be presented graphically on linear and 
semi-logarithmic scales. Mean concentration-time data will be presented for all doses and for fed 
vs. fasted cohorts. Mean data will be plotted using nominal sample times, and individual data will 


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Page 18 of 31 
be plotted using actual times. For all subject plots (spaghetti plots, all subjects per treatment in one 
plot), subjects will be identified by subject number in the legend. 
PK parameters will be calculated as described in Section 6.2.9. 
PK parameters will be summarized by analyte and cohort using descriptive statistics. 
Part 1; Dose Proportionality (Cohorts 1-7, fasted conditions): 
The pharmacokinetic parameters Cmax, AUClast, and AUCinf for TBI-223 for fasted cohorts will be 
compared across doses to assess dose proportionality (i.e., proportionality of a change in systemic 
exposure with a change in dose).  Statistical analyses will be done using a power model (Smith, 
2000) of the following general form,  
ln(PK) = ln(β0) + β1·ln(Dose) + ε, 
where 
PK is the pharmacokinetic parameter tested (e.g. Cmax or AUC) 
ln(β0) is the y-intercept, 
β1 is the slope (a value of β1  1 indicates linearity), and 
ε is an error term  
The estimate of β1 with the 90% CIs will be reported along with the dose range for proportionality.  
Part 1; Food Effect (Cohort 5): 
Statistical comparison of the PK parameters of exposure (Cmax, AUClast, and AUCinf) will be 
performed using an Analysis of Variance (ANOVA) model for a 2-way crossover design on the 
ln-transformed data with treatment as the fixed effects and subject as a random effect. Conclusions 
regarding the results of the statistical analysis of PK parameters across treatments will be based on 
the ratio of the geometric means expressed as a percent (100Fed/Fasted) and the 90% confidence 
interval about the ratio.  A lack of food effect will be demonstrated if the 90% confidence intervals 
are fully contained within the limits of 80.00% to 125.00%.  


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Part 1; Cohort 3 Repeat: 
Statistical comparison of the PK parameters of exposure (Cmax, AUClast, and AUCinf) will be 
performed using an Analysis of Variance (ANOVA) model for a two-way crossover design on the 
ln-transformed data with treatment as a fixed effect and subject as a random effect. Conclusions 
regarding the results of the statistical analysis of PK parameters across treatments will be based on 
the ratio of the geometric means expressed as a percent (100Test/Reference; TBI-223 oral enteric 
capsules, Cohort 3 repeat vs. TBI-223 oral suspension, Cohort 3) and the 90% confidence interval 
about the ratio.  Similar bioavailability will be demonstrated if the 90% confidence intervals are 
fully contained within the limits of 80.00% to 125.00%. 
Part 2; Cohorts 8 and 9: 
Statistical comparison of the PK parameters of exposure (Cmax, AUClast, and AUCinf) will be 
performed using an Analysis of Variance (ANOVA) model for a parallel design on the ln-
transformed data with treatment as a fixed effect. Conclusions regarding the results of the statistical 
analysis of PK parameters across treatments will be based on the ratio of the geometric means 
expressed as a percent (100Test/Reference) and the 90% confidence interval about the ratio.  The 
following comparisons will be made: 
• IR, 2000 mg (2 x 1000 mg tablets) / FED (Cohort 9) vs. IR, 2000 mg (2 x 1000 mg tablets) / 
FASTED (Cohort 8) 
• SR (Prototype 1, 2 or 3), 1800 mg (2 x 900 mg tablets) / FED (Cohort 8) vs. , 2000 mg (2 x 
1000 mg tablets) / FASTED (Cohort 8) 
• SR (Prototype 1, 2 or 3), 1800 mg (2 x 900 mg tablets) / FED (Cohort 8) vs. IR, 2000 mg (2 
x 1000 mg tablets) / FED 
Note: 1800 mg TBI-223 SR Tablets will be dose-normalized to 2000 mg for the purpose of 
statistical comparisons. 
6.12 Safety Analyses 
The safety analyses will be presented by the treatment received for the Safety Analysis Set. 


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6.12.1 
Adverse Events 
A treatment emergent adverse event (TEAE) is defined as: 
• Any AE that has an onset on or after the first dose of study drug through the end-of-study 
follow-up call (Day 11).  
• Any pre-existing AE that has worsened in severity on or after the first dose through the 
end-of-study follow-up call (Day 11). 
Relatedness of an AE to treatment is defined as Not Related, Unlikely, Possible, Probable or 
Certain.  A treatment-related AE is defined as any AE classified as possibly, probably or certainly 
related to the study drug.  If an AE has missing relationship it is assumed to be related to the study 
drug for analysis purposes.  
Severity of AEs will be graded using the Division of Microbiology and Infectious Disease (DMID) 
Toxicity Grade November 2007 version: Grade 1 (Mild), Grade 2 (Moderate), Grade 3 (Severe), 
Grade 4 (Potentially Life-Threatening).  Maximum grade will be assumed for an AE with missing 
grade. 
The following tables will be presented for AEs: 
• Overall incidence and number of AEs, SAEs, TEAEs leading to withdrawal. 
• TEAEs by system organ class and preferred term, incidence and number of events 
• Treatment-related TEAEs by system organ class and preferred term, incidence and number 
of events 
• TEAEs by system organ class, preferred term and maximum grade, incidence 
• TEAEs by system organ class, preferred term and relationship, incidence  
• Listing of TEAEs Leading to Early Withdrawal (presented in the Table section of the 
appendices) 
• Listing of Serious TEAEs (presented in the Table section of the appendices) 
• Listing of Deaths (presented in the Table section of the appendices) 
System organ class will be presented in descending order of overall frequency and then 
alphabetically.  Preferred terms will be displayed in descending order of overall frequency and 
then alphabetically.  
Where a subject reports more than one AE per system organ class and preferred term they will 
only be counted once for the most severe event or the most related event.  


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Page 21 of 31 
All AEs will be listed.   
6.12.2 
Laboratory Data 
Descriptive statistics of the observed values and change from baseline (continuous data) will be 
presented by study part, period (where applicable), treatment group and visit for each hematology, 
serum chemistry, coagulation and urinalysis parameter. Each measurement (continuous data) will 
be classed as below, within, or above normal range, based on ranges supplied by the laboratory 
used. Shift tables in relation to the normal range from baseline to each follow-up visit will be 
presented.   
A listing of any clinically significant laboratory measurements recorded throughout the study will 
be presented. 
6.12.3 
Vital Signs 
Descriptive statistics for observed values and changes from baseline in the following vital signs 
will be presented by study part, period (where applicable) and treatment group at each visit: 
• Systolic blood pressure (mmHg) 
• Diastolic blood pressure (mmHg) 
• Pulse rate (bpm)  
• Respiration rate (breath/min) 
• Body temperature (degrees Celsius) 
• Pulse oximetry (%) 
 
All vital sign data will be listed. 
6.12.4 
Electrocardiogram Data 
Descriptive statistics for observed values and changes from baseline in the following ECG 
variables will be tabulated by study part, period (where applicable) and treatment group at each 
post-baseline assessment:  
• Heart rate (bpm) 
• PR interval (ms) 
• RR interval (ms)  
• QRS complex (ms)   
• QT interval (ms)  


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Page 22 of 31 
• QTc interval (ms)  
• QTc interval (ms) [Bazett’s formula - QTcB]  
• QTc interval (ms) [Fridericia’s formula - QTcF]  
Shift tables in relation to the overall interpretation (Normal, Abnormal NCS, and Abnormal CS) 
from baseline to each post-baseline assessment will be presented.  All ECG data, including details 
of any abnormalities, will be listed. 
6.12.5 
Cardiac Telemetry (Holter) Data 
Data relating to the collection of cardiac telemetry (Holter) data will be listed.  Timings of 12-lead 
ECGs extracted from the continuous Holter recording will be collected on the eCRF but will not 
be listed for this study.   
6.12.6 
Physical Examination 
Shift tables for the observed status of each of the body systems (Normal, Abnormal NCS, and 
Abnormal CS) will be tabulated by study part, period (where applicable) and treatment group at 
each post-baseline assessment.  All data, including details of clinically significant findings will be 
listed.  
6.12.7 
Neurological Examination 
Shift tables for the observed status of each neurological aspect (Normal, Abnormal NCS, and 
Abnormal CS) will be tabulated by study part, period (where applicable) and treatment group at 
each post-baseline assessment.  All data, including details of clinically significant findings will be 
listed.  
7 CHANGES TO PLANNED PROTOCOL ANALYSIS 
No changes to the planned analyses have been identified.  
 


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Page 23 of 31 
8 REFERENCES 
1. Phoenix™ WinNonlin® (Version 8.1, Certara L.P) 
2. SAS Institute Inc., Cary, NC, 27513, USA 
 
 
 


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Page 24 of 31 
9 LIST OF TABLES, FIGURES AND LISTINGS 
The following table includes details of the tables, figures and listings to be included within each 
section of the eCTD. The eCTD section is shown in bold. The following validation methods maybe 
used:  
• Independent programming of numbers and manual review of format (IP) 
• Independent programming by statistician of numbers and manual review of format (Stat IP) 
• Manual review (MR) 
• Code review (CR) 
Please note, PK Table, Figure and Listing numbers and titles are subject to change and may be 
consolidated upon final analysis. 
Table 
Number 
Table Title 
Validation 
Method 
Shell 
Number 
(if 
repeat) 
Items in bold are not table titles but references to the section headings within eCTD. 
 
14.1  
Demographics Data 
 
 
14.1.1  
Disposition 
 
 
14.1.1.1 
Subject Disposition, Early Withdrawals - All Enrolled 
Subjects 
IP 
 
14.1.2  
Demographics 
 
 
14.1.2.1 
Demographics - Safety Analysis Set 
IP 
 
14.1.3 
Baseline Characteristics 
 
 
 
Not Applicable 
 
 
14.2  
Efficacy Data 
 
 
 
Not Applicable 
 
 
14.3  
Safety Data 
 
 
14.3.1  
Displays of Adverse Events 
 
 
14.3.1.1 
Adverse Events, Overall Summary of Treatment-Emergent 
Adverse Events (TEAEs) – Safety Analysis Set 
IP 
 
14.3.1.2 
Adverse Events, TEAEs by Primary System Organ Class and 
Preferred Term – Safety Analysis Set 
IP 
 
14.3.1.3 
Adverse Events, Treatment-Related TEAEs by Primary 
System Organ Class and Preferred Term – Safety Analysis Set 
IP 
 
14.3.1.4 
Adverse Events, TEAEs by Primary System Organ Class, 
Preferred Term and Maximum Grade – Safety Analysis Set 
IP 
 


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Page 25 of 31 
Table 
Number 
Table Title 
Validation 
Method 
Shell 
Number 
(if 
repeat) 
14.3.1.5 
Adverse Events, TEAEs by Primary System Organ Class, 
Preferred Term and Nearest Relationship – Safety Analysis Set 
IP 
 
14.3.2  
Listings of Deaths, Other Serious and Significant Adverse 
Events 
 
 
14.3.2.1 
TEAEs Leading to Early Withdrawal, Listing – Safety 
Analysis Set 
IP 
 
14.3.2.2 
Serious TEAEs, Listing – Safety Analysis Set 
IP 
 
14.3.2.3 
Deaths, Listing – Safety Analysis Set 
IP 
 
14.3.3  
Narratives of Deaths, Other Serious and Certain Other 
Significant Adverse Events 
 
 
14.3.4  
Abnormal Laboratory Values 
 
 
14.3.4.1 
Listing of Clinically Significant Laboratory Values – Safety 
Analysis Set 
IP 
 
14.3.5  
Extent of Exposure, Dosage Information, and Compliance 
 
 
 
Not Applicable 
 
 
14.3.6  
Vital Signs and Physical Examination 
 
 
14.3.6.1 
Vital Signs, Descriptive Statistics – Safety Analysis Set 
IP 
 
14.3.6.2 
Physical Examination, Change from Baseline – Safety 
Analysis Set 
IP 
 
14.3.6.3 
Neurological Examination, Change from Baseline – Safety 
Analysis Set 
IP 
 
14.3.7  
Other Safety 
 
 
14.3.7.1 
Hematology Data, Descriptive Statistics – Safety Analysis Set 
IP 
 
14.3.7.2 
Hematology Data, Normal Range Shifts – Safety Analysis Set 
IP 
 
14.3.7.3 
Serum Chemistry Data, Descriptive Statistics – Safety 
Analysis Set 
IP 
 
14.3.7.4 
Serum Chemistry Data, Normal Range Shifts – Safety 
Analysis Set 
IP 
 
14.3.7.5 
Coagulation Data, Descriptive Statistics – Safety Analysis Set 
IP 
 
14.3.7.6 
Coagulation Data, Normal Range Shifts – Safety Analysis Set 
IP 
 
14.3.7.7 
Urinalysis Data, Descriptive Statistics – Safety Analysis Set 
IP 
 
14.3.7.8 
Urinalysis Data, Normal Range Shifts – Safety Analysis Set 
IP 
 
14.3.7.9 
12-Lead ECG Data, Descriptive Statistics – Safety Analysis 
Set 
IP 
 


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Table 
Number 
Table Title 
Validation 
Method 
Shell 
Number 
(if 
repeat) 
14.3.7.10 12-Lead ECG Data, Overall Interpretation – Safety Analysis 
Set 
IP 
 
14.3.8  
Concomitant Medication 
 
 
 
Not Applicable 
 
 
14.4  
PK Tables 
 
 
14.4.1 
Descriptive Statistics for Concentration-Time Data of 
TBI-223 and TBI-223 M2 after Single Doses of TBI-223 
(Part 1; Cohorts 1-7) 
MR 
 
14.4.2 
Descriptive Statistics for Concentration-Time Data of 
TBI-223 and TBI-223 M2 after Single Doses of TBI-223 
Oral Suspension (Part 1; Cohorts 1-7) by Gender 
 
 
14.4.3 
Descriptive Statistics for Concentration-Time Data of 
TBI-223 and TBI-223 M2 after Single Doses of TBI-223 
(Part 2; Cohorts 8 and 9)  
MR 
 
14.4.4 
Descriptive Statistics for Concentration-Time Data of 
TBI-223 and TBI-223 M2 after Single Doses of TBI-223 
(Part 2; Cohorts 8 and 9) by Gender  
MR 
 
14.4.5 
Plasma Pharmacokinetic Parameters of TBI-223 after Single 
Doses of TBI-223 (Part 1; Cohorts 1-7) 
MR 
 
14.4.6 
Plasma Pharmacokinetic Parameters of TBI-223 after Single 
Doses of TBI-223 (Part 1; Cohorts 1-7) by Gender  
 
 
14.4.7 
Plasma Pharmacokinetic Parameters of TBI-223 M2 after 
Single Doses of TBI-223 (Part 1; Cohorts 1-7) 
 
 
14.4.8 
Plasma Pharmacokinetic Parameters of TBI-223 M2 after 
Single Doses of TBI-223 (Part 1; Cohorts 1-7) by Gender  
 
 
14.4.9 
Plasma Pharmacokinetic Parameters of TBI-223 after Single 
Doses of TBI-223 (Part 2; Cohorts 8 and 9) 
 
 
14.4.10 
Plasma Pharmacokinetic Parameters of TBI-223 after Single 
Doses of TBI-223 (Part 2; Cohorts 8 and 9) by Gender  
 
 
14.4.11 
Plasma Pharmacokinetic Parameters of TBI-223 M2 after 
Single Doses of TBI-223 (Part 2; Cohorts 8 and 9) 
 
 
14.4.12 
Plasma Pharmacokinetic Parameters of TBI-223 M2 after 
Single Doses of TBI-223 (Part 2; Cohorts 8 and 9) by Gender  
 
 


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Table 
Number 
Table Title 
Validation 
Method 
Shell 
Number 
(if 
repeat) 
14.4.13 
Assessment of Dose Proportionality Following Single-Dose 
Administrations of TBI-223 under Fasted Conditions (Part 1; 
Cohorts 1-7) 
MR 
 
14.4.14 
Statistical Analysis of the Natural Log-
Transformed- Systemic Exposure of TBI-223 after a Single 
1200 mg Dose of TBI-223 Oral Suspension under Fed (Test) 
and Fasted (Reference) Conditions (Part 1; Cohort 5) 
MR 
 
14.4.15 
Statistical Analysis of the Natural Log-
Transformed- Systemic Exposure of TBI-223 after a Single 
300 mg Dose of TBI-223 Capsule Formulation (Cohort 3 
Repeat; Part 1) and a Single 300 mg Dose of TBI-223 Oral 
Suspension (Cohort 3; Part 1) 
 
 
14.4.16 
Statistical Analysis of the Natural Log-
Transformed- Systemic Exposure of IR, 2000 mg (2 x 
1000 mg TBI-223 tablets) under Fed Conditions  (Cohort 9) 
and IR, 2000 mg (2 x 1000 mg TBI-223 tablets) under Fasted 
Conditions (Cohort 8) 
MR 
 
14.4.17 
Statistical Analysis of the Natural Log-
Transformed- Systemic Exposure of SR (Prototypes 1, 2, 
and 3), 1800 mg (2 x 900 mg TBI-223 tablets) under Fed 
Conditions (Cohort 8) and IR, 2000 mg (2 x 1000 mg TBI-
223 tablets) under Fasted Conditions (Cohort 8) 
MR 
 
14.4.18 
Statistical Analysis of the Natural Log-
Transformed- Systemic Exposure of SR (Prototypes 1, 2, 
and 3), 1800 mg (2 x 900 mg TBI-223 tablets) under Fed 
Conditions (Cohort 8) and IR, 2000 mg (2 x 1000 mg 
TBI-223 tablets) under Fed Conditions (Cohort 9 ) 
MR 
 
 
 
 


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This document is the property of Worldwide Clinical Trials Inc. and may not be duplicated, copied, altered or removed from company without 
prior approval from Worldwide Quality Assurance or in compliance with Worldwide Standard Operating Procedures. 
REF: Worldwide-TMP-QA-001f-1.3 
 
Page 28 of 31 
Figure 
Number 
Figure Title 
 
 
14.4.1 
Mean Plasma Concentration-Time Profiles of TBI-223 and 
TBI-223 M2 after Single Doses of TBI-223 Administered 
under Fasted Conditions (Part 1; Cohorts 1-7) on Linear 
and Semi Logarithmic Scales 
MR 
 
14.4.2 
Mean Plasma Concentration-Time Profiles of TBI-223 and 
TBI-223 M2 after a Single 1200 mg Dose of TBI-223 Oral 
Suspension under Fed and Fasted Conditions (Part 1; 
Cohort 5) on Linear and Semi Logarithmic Scales 
MR 
 
14.4.3 
Mean Plasma Concentration-Time Profiles of TBI-223 and 
TBI-233 M2 after a Single 300 mg Dose of TBI-223 Oral 
Suspension (Cohort 3; Part 1) and a Single 300 mg Dose of 
TBI-223 Capsule Formulation (Cohort 3 Repeat; Part 1) on 
Linear and Semi Logarithmic Scales 
MR 
 
14.4.4 
Mean Plasma Concentration-Time Profiles of TBI-223 and 
TBI-223 M2 after Single Doses of TBI-223 (Cohorts 8, 
and 9; Part 2) on Linear and Semi Logarithmic Scales 
MR 
 
14.4.5 
Mean Plasma Concentration-Time Profiles of TBI-223 and 
TBI-223 M2 for Males and Females by Cohort (Part 1) on 
Linear and Semi Logarithmic Scales 
 
 
14.4.6 
Mean Plasma Concentration-Time Profiles of TBI-223 and 
TBI-223 M2 for Males and Females by Cohort (Part 2) on 
Linear and Semi Logarithmic Scales 
 
 
14.4.7 
All Subject Plasma Concentration-Time Profiles of TBI-
223 and TBI-223 M2 after Single Doses of TBI-223 
(Cohorts 1-7; Part 1) on Linear and Semi Logarithmic 
Scales 
MR 
 
14.4.8 
All Subject Plasma Concentration-Time Profiles of TBI-
223 and TBI-223 M2 after Single Doses of TBI-223 
(Cohorts 8 and 9; Part 2) on Linear and Semi Logarithmic 
Scales 
MR 
 
14.4.9 
Individual Plasma Concentration-Time Profiles of TBI-223 
and TBI-223 M1 after a Single 1200 mg Dose of TBI-223 
Oral Suspension under Fed and Fasted Conditions (Part 1, 
Cohort 5) on Linear and Semi Logarithmic Scales 
MR 
 
14.4.10 
Individual Plasma Concentration-Time Profiles of TBI-223 
and TBI-223 M2 after a Single Dose of TBI-223 Oral 
Suspension (Cohort 3; Part 1) and a Single Dose of 
MR 
 


Worldwide Clinical Trials Controlled Quality Management Document 
 
Sponsor: 
TB Alliance 
Protocol Number: 
TBI-223-CL-001 
STATISTICAL ANALYSIS PLAN – PHASE 1 
 
QMD Ref: Worldwide-TMP-ST-006-4.0 Effective: 12Aug2019 
 
Governing QMD: Worldwide-SOP-ST-001 
Confidentiality Statement 
This document is the property of Worldwide Clinical Trials Inc. and may not be duplicated, copied, altered or removed from company without 
prior approval from Worldwide Quality Assurance or in compliance with Worldwide Standard Operating Procedures. 
REF: Worldwide-TMP-QA-001f-1.3 
 
Page 29 of 31 
Figure 
Number 
Figure Title 
 
 
TBI-223 Capsule Formulation (Cohort 3 Repeat; Part 1) on 
Linear and Semi Logarithmic Scales 
14.4.11 
Concentration-Time Profiles for TBI-223 and TBI-223 M2 
with Linear Regression for Estimating the Terminal 
Elimination Rate 
MR 
 
 
 


Worldwide Clinical Trials Controlled Quality Management Document 
 
Sponsor: 
TB Alliance 
Protocol Number: 
TBI-223-CL-001 
STATISTICAL ANALYSIS PLAN – PHASE 1 
 
QMD Ref: Worldwide-TMP-ST-006-4.0 Effective: 12Aug2019 
 
Governing QMD: Worldwide-SOP-ST-001 
Confidentiality Statement 
This document is the property of Worldwide Clinical Trials Inc. and may not be duplicated, copied, altered or removed from company without 
prior approval from Worldwide Quality Assurance or in compliance with Worldwide Standard Operating Procedures. 
REF: Worldwide-TMP-QA-001f-1.3 
 
Page 30 of 31 
Listing 
Number 
Listing Title 
Validation 
Method 
Shell 
Number 
(if repeat) 
16.2  
Subject Data Listings 
 
 
16.2.1  
Discontinued Subjects 
 
 
16.2.1.1 
Subject Disposition - All Enrolled Subjects 
IP 
 
16.2.2 
Protocol Deviations 
 
 
16.2.2.1 
Protocol Deviations – Safety Analysis Set 
IP 
 
16.2.3 
Subjects Excluded from The Efficacy Analyses 
 
 
16.2.3.1 
Analysis Sets - All Enrolled Subjects 
IP 
 
16.2.4  
Demographic Data 
 
 
16.2.4.1  
Demographic Data – Safety Analysis Set 
IP 
 
16.2.4.2 
Previous and Ongoing Medical History – Safety 
Analysis Set 
IP 
 
16.2.5  
Compliance and/or Drug Concentration Data 
 
 
16.2.5.1 
PK Sampling Data – Safety Analysis Set 
IP 
 
16.2.5.2 
Dosing Information – Safety Analysis Set 
IP 
 
16.2.5.3  
Prior and Concomitant Medication – Safety Analysis Set 
IP 
 
16.2.6  
Individual Efficacy Response Data   
 
 
16.2.6.1 
Plasma TBI-223 and TBI-223 M2 Concentration Listing 
by Subject (Part 1) 
MR 
 
16.2.6.2 
Plasma TBI-223 and TBI-223 M2 Concentration Listing 
by Subject (Part 2) 
 
 
16.2.6.3 
Terminal Elimination Rate of TBI-223 and TBI-223 M2 
in Plasma for Individual Subjects (Part 1) 
MR 
 
16.2.6.4 
Terminal Elimination Rate of TBI-223 and TBI-223 M2 
in Plasma for Individual Subjects (Part 2) 
 
 
16.2.6.5 
PK Output for TBI-223 and TBI-223 M2 
MR 
 
16.2.6.6 
Statistical 
Analysis 
SAS 
Output 
for 
Dose 
Proportionality (Part 1) 
MR 
 
16.2.6.7 
Statistical Analysis SAS Output for Food Effect 
Assessment (Part 1, Cohort 5) 
MR 
 
16.2.6.8 
Statistical Analysis SAS Output for Formulation Effect 
Assessment (Part 1, Cohort 3 and Cohort 3 Repeat) 
MR 
 
16.2.6.9 
Statistical Analysis SAS Output for Food Effect 
Assessment (IR tablets; Part 2) 
MR 
 
16.2.6.10 
Statistical Analysis SAS Output (SR Fed vs. IR Fasted; 
Part 2)  
MR 
 


Worldwide Clinical Trials Controlled Quality Management Document 
 
Sponsor: 
TB Alliance 
Protocol Number: 
TBI-223-CL-001 
STATISTICAL ANALYSIS PLAN – PHASE 1 
 
QMD Ref: Worldwide-TMP-ST-006-4.0 Effective: 12Aug2019 
 
Governing QMD: Worldwide-SOP-ST-001 
Confidentiality Statement 
This document is the property of Worldwide Clinical Trials Inc. and may not be duplicated, copied, altered or removed from company without 
prior approval from Worldwide Quality Assurance or in compliance with Worldwide Standard Operating Procedures. 
REF: Worldwide-TMP-QA-001f-1.3 
 
Page 31 of 31 
Listing 
Number 
Listing Title 
Validation 
Method 
Shell 
Number 
(if repeat) 
16.2.6.11 
Statistical Analysis SAS Output (SR Fed vs IR Fed; Part 
2)  
MR 
 
16.2.7  
Adverse Event Listings 
 
 
16.2.7.1 
Adverse Event Data – Safety Analysis Set 
IP 
 
16.2.8  
Individual Laboratory Measurement and Other 
Safety 
 
 
16.2.8.1 
Hematology Data – Safety Analysis Set 
IP 
 
16.2.8.2 
Serum Chemistry Data – Safety Analysis Set 
IP 
 
16.2.8.3 
Coagulation Data – Safety Analysis Set 
IP 
 
16.2.8.4 
Urinalysis Data – Safety Analysis Set 
IP 
 
16.2.8.5 
Drug and Alcohol Screening Data – Safety Analysis Set 
IP 
 
16.2.8.6 
Serology Data – Safety Analysis Set 
IP 
 
16.2.8.7 
Pregnancy Test Data – Safety Analysis Set 
IP 
 
16.2.8.8 
Vital Signs Data – Safety Analysis Set 
IP 
 
16.2.8.9 
Physical Examination Data – Safety Analysis Set 
IP 
 
16.2.8.10 
Neurological Examination Data – Safety Analysis Set 
IP 
 
16.2.8.11 
12-Lead ECG Data – Safety Analysis Set 
IP 
 
16.2.8.12 
Cardiac Telemetry (Holter) Collection Data – Safety 
Analysis Set 
IP 
 
16.2.8.13 
Breath Strip Application Data – Safety Analysis Set 
IP