A Phase 1, Partially Blind, Placebo Controlled, Randomized, Combined Single Ascending Dose With a Food Effect Cohort, Multiple Ascending Dose, and Relative Bioavailability Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of TBAJ-876 in Healthy Adult Subjects
Phase: PHASE1
Conditions: Pulmonary Disease, Tuberculosis, Pulmonary, Tuberculosis, Multi Drug Resistant Tuberculosis, Drug Sensitive Tuberculosis, Drug-resistant Tuberculosis, Mycobacterium Tuberculosis Infection
Sponsor: Global Alliance for TB Drug Development

Protocol TBAJ-876-CL-001 version 8.0 
Global Alliance for TB Drug Development 
CONFIDENTIAL 
03 Dec 2021 
Page i 
 
CLINICAL STUDY PROTOCOL 
A Phase 1, Partially Blind, Placebo Controlled, Randomized, Combined 
Single Ascending Dose with a Food Effect Cohort (Part 1), Multiple 
Ascending Dose (Part 2), and Relative Bioavailability (Part 3) Study to 
Evaluate the Safety, Tolerability, and Pharmacokinetics of TBAJ-876 in 
Healthy Adult Subjects  
PROTOCOL NUMBER 
TBAJ-876-CL001 
VERSION 8.0 DATE 
03 Dec 2021 
 
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. 
1

Protocol TBAJ-876-CL-001 version 8.0 
Global Alliance for TB Drug Development 
CONFIDENTIAL 
03 Dec 2021 
Page ii 
PROTOCOL APPROVAL PAGE 
A Phase 1, Partially Blind, Placebo Controlled, Randomized, Combined Single Ascending Dose 
with a Food Effect Cohort (Part 1), Multiple Ascending Dose (Part 2), and Relative 
Bioavailability (Part 3) Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of 
TBAJ-876 in Healthy Adult Subjects 
Protocol Number: 
TBAJ-876-CL001 
Sponsor: 
Global Alliance for TB Drug Development 
Sponsor Contact: 
Antonio (Tony) Lombardi, MD 
 
Global Alliance for TB Drug Development 
 
40 Wall Street, 24th Floor 
 
New York, NY  10005, United States of America 
 
Telephone/Mobile: +1 917.601.0024 
Email: antonio.lombardi-consultant@tballiance.org 
 
Facsimile: +1 212.227.7541 
 
 
 
 
 
 
 
 
(Signature) 
(Date) 
 
 
 
 
Principal Investigator: Ingela Danielsson, 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) 
 
 
2

Protocol TBAJ-876-CL-001 version 8.0 
Global Alliance for TB Drug Development 
CONFIDENTIAL 
03 Dec 2021 
Page iii 
SUMMARY OF CHANGES 
The main purpose for this amendment is to add an additional study part (Part 3) to evaluate the 
relative bioavailability of two strengths of TBAJ-876 tablets. The formulation of the two 
strengths of tablets is identical and dose proportional.  
Part 3: TBAJ-876 Tablets 
Part 3 is a single dose, open-label, parallel design study to investigate the safety, tolerability, and 
relative bioavailability of two strengths of TBAJ-876 tablets: 25 mg and 100 mg. Three groups 
of ten subjects per group are planned. 
• 
Group 1: Single dose 100 mg TBAJ-876 as 1 x 100 mg Tablet fasting 
• 
Group 2: Single dose 100 mg TBAJ-876 as 1 x 100 mg Tablet fed 
• 
Group 3 Single dose 100 mg TBAJ-876 as 4 x 25 mg Tablets fasting 
Subjects will check-in on Day -1 following a 21-day screening period, remain in the clinic for 7 
days and be discharged on Day 8. They will then return to the clinic for a follow-up visit on Day 
10 and Day 14 for PK and safety. A follow-up phone call will occur on Day 21 to check for AEs. 
The amendment also includes the updates from two previous protocol clarification letters: 
• The first dated 02 Sep 2021 for the multiple ascending dose (MAD) (Part 2) of the study 
which added an additional electrocardiogram (ECG) extraction on Day 1 and Day 14 at 
the 16 hour time point for Cohort 2 and 3, and updated the number of subjects from a 
total of 36 subjects to 39.  
• The second letter dated 06 Oct 2021 added an additional cohort (Cohort 7) to the single 
ascending dose (SAD) (Part 1) of the study and clarified the ECGs timings and 
procedures for Cohort 3 in Part 2 of the study.  
In addition, based on the review of the Cohort 1 (MAD) PK and safety, the dose for Cohort 2 
(MAD) was changed (as allowed by the protocol) to 75 mg versus the original planned dose of 
50 mg.  
The sections of protocol version 7.0 dated 17 May 2021 affected by these changes are indicated 
below.  
Section 
Number 
(s) 
Section Title(s) 
Description of Change (s) 
Title 
page, 
protocol 
approval 
page,  
Study Title  
Update the title of the study, from:  
A Phase 1, Partially Blind, Placebo Controlled, Randomized, 
Combined Single Ascending Dose with a Food Effect Cohort (Part 
1), Multiple Ascending Dose Study (Part 2) Study to Evaluate the 
3

Protocol TBAJ-876-CL-001 version 8.0 
Global Alliance for TB Drug Development 
CONFIDENTIAL 
03 Dec 2021 
Page iv 
Section 
Number 
(s) 
Section Title(s) 
Description of Change (s) 
Safety, Tolerability, Pharmacokinetics of TBAJ-876 in Healthy 
Adult Subjects 
To: 
A Phase 1, Partially Blind, Placebo Controlled, Randomized, 
Combined Single Ascending Dose with a Food Effect Cohort (Part 
1), Multiple Ascending Dose (Part 2), and Relative 
Bioavailability (Part 3) Study to Evaluate the Safety, Tolerability, 
Pharmacokinetics of TBAJ-876 in Healthy Adult Subjects 
Synopsis 
Title of study 
Update the title of the study, from:  
A Phase 1, Partially Blind, Placebo Controlled, Randomized, 
Combined Single Ascending Dose with a Food Effect Cohort (Part 
1), Multiple Ascending Dose Study (Part 2) to Evaluate the Safety, 
Tolerability, Pharmacokinetics of TBAJ-876 in Healthy Adult 
Subjects 
To: 
A Phase 1, Partially Blind, Placebo Controlled, Randomized, 
Combined Single Ascending Dose with a Food Effect Cohort (Part 
1), Multiple Ascending Dose (Part 2), and Relative 
Bioavailability (Part 3) Study to Evaluate the Safety, Tolerability, 
Pharmacokinetics of TBAJ-876 in Healthy Adult Subjects 
Synopsis 
Study Period 
Add the following after Part 2: 
Part 3: Single dose, open-label parallel relative bioavailability 
(BA) design: approximately 45 days, from Screening to study 
exit. 
Synopsis 
Duration of 
treatment  
Add the following after Part 2: 
Part 3: One single dose of 100 mg TBAJ-876 as 1 x 100 mg 
tablet (either fasted or fed) or 4 x 25 mg tablets (fasted). 
Synopsis 
Number of subjects 
Add the following after Part 1 Paragraph 2: 
Additional cohort, Cohort 7: Eight (8) subjects will be enrolled, 
6 to receive active drug and 2 to receive placebo. Subjects will 
receive a single dose under fasted conditions. Subjects will 
receive 800 mg TBAJ-876 or matching dose of placebo for 
TBAJ-876 oral suspension. 
 
 
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Protocol TBAJ-876-CL-001 version 8.0 
Global Alliance for TB Drug Development 
CONFIDENTIAL 
03 Dec 2021 
Page v 
Section 
Number 
(s) 
Section Title(s) 
Description of Change (s) 
Part 2 paragraph 1, from: 
Planned to enroll 36 subjects in 3 MAD cohorts of 12 subjects each 
(9 to receive active drug and 3 to receive placebo). All cohorts will 
receive the assigned dose under fed conditions.  
To:  
Planned to enroll 39 subjects in 3 MAD cohorts. Cohort 1 with 12 
subjects per cohort (9 to receive active drug and 3 to receive 
placebo), Cohort 2 with 13 subjects per cohort (9 to receive 
active drug and 4 to receive placebo), and Cohort 3 with 14 
subjects per cohort (9 to receive active drug and 5 to receive 
placebo). All cohorts will receive the assigned dose under fed 
conditions.  
Add the following after Part 2: 
Part 3:  
Planned to enroll 30 subjects in 3 groups of 10 subjects each. 
All groups to receive active drug under fasted or fed 
conditions. 
• 
Group 1: Single dose 1 x 100 mg tablet fasted 
• 
Group 2: Single dose 1 x 100 mg tablet fed 
• 
Group 3: Single dose 4 x 25 mg tablets fasted 
Synopsis 
Objectives 
From:  
The primary objective of the study is: 
• 
To evaluate the safety and tolerability of single and 
multiple ascending doses of TBAJ-876 oral suspension 
in healthy subjects. 
The secondary objectives of the study are: 
• 
To determine the pharmacokinetics (PK) of TBAJ-876 
and its metabolites (M2 and M3) after single and 
multiple doses of TBAJ-876 oral suspension in healthy 
adult subjects. 
• 
To compare the rate and extent of absorption of a single 
oral dose of TBAJ-876 when administered after a high-
calorie, high fat meal versus when its administered 
fasting in health adult subjects. 
To: 
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Protocol TBAJ-876-CL-001 version 8.0 
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CONFIDENTIAL 
03 Dec 2021 
Page vi 
Section 
Number 
(s) 
Section Title(s) 
Description of Change (s) 
The primary objective of the study is: 
• 
To evaluate the safety and tolerability of single and multiple 
ascending doses of TBAJ-876 oral suspension, and single 
doses of two strengths of TBAJ-876 tablets in healthy 
subjects. 
The secondary objectives of the study are: 
• 
To determine the pharmacokinetics (PK) of TBAJ-876 and 
its metabolites (M2 and M3) after single and multiple doses 
of TBAJ-876 oral suspension, and single doses of two 
strengths of TBAJ-876 tablets in healthy adult subjects. 
• 
To compare the rate and extent of absorption of a single oral 
dose of TBAJ-876 oral suspension and two strengths of 
TBAJ-876 tablets when administered after a high-calorie, 
high-fat meal versus when it is administered fasting in 
healthy adult subjects. 
• 
To compare the rate and extent of absorption of the 4 x 
25 mg tablets and the 1 x 100 mg tablet under fasted 
conditions.  
• 
To compare the rate and extent of absorption of a single 
oral dose of 100 mg of the TBAJ-876 oral suspension and 
two strengths of TBAJ-876 tablets under fed and/or 
fasted conditions. 
Synopsis 
Study design 
overview 
Paragraph 1, from: 
This study is a two-part, partially blinded, placebo 
controlled, combined single ascending dose with food-
effect and multiple ascending dose study conducted in one 
study center in the United States. 
To: 
This study is a three-part, partially blinded, placebo 
controlled, combined single ascending dose with food-
effect, a multiple ascending dose study, and a single dose 
relative bioavailability study conducted at one study 
center in the United States. 
Add the following after Part 1 Paragraph 4: 
6

Protocol TBAJ-876-CL-001 version 8.0 
Global Alliance for TB Drug Development 
CONFIDENTIAL 
03 Dec 2021 
Page vii 
Section 
Number 
(s) 
Section Title(s) 
Description of Change (s) 
Additional cohort, Cohort 7: Eight (8) subjects will be enrolled, 
6 to receive active drug and 2 to receive placebo. Subjects will 
receive a single dose under fasted conditions. 
Dose = 800 mg TBAJ-876 or matching dose of placebo for 
TBAJ-876 Oral Suspension 
Subjects will follow the procedures in Table 15, Schedule of 
Assessments and Procedures, Part 1 SAD with the following 
clarifications: 
Subjects will check-in to the clinic on Day -1 and be 
confined through Day 8. Subjects will be discharged from 
the clinic on Day 8. Subjects will return for one follow-up 
visit on Day 14 for PK and safety. Subjects will receive a 
follow-up phone call on Day 21. Subjects will complete the 
procedures specified for those study days only. All ECGs 
performed in Cohort 7 will be triplicate ECGs at each time 
point. 
In addition, subjects will have triplicate ECGs at 16 hours 
postdose. 
Part 2 Paragraph 1, from: 
Three cohorts of 12 subjects per cohort are planned to receive 
TBAJ-876 or matching placebo for 14 days, under fed conditions.  
To: 
Three cohorts are planned. Cohort 1 with 12 subjects per cohort 
(9 to receive active drug and 3 to receive placebo), Cohort 2 
with 13 subjects per cohort (9 to receive active drug and 4 to 
receive placebo), and Cohort 3 with 14 subjects per cohort (9 to 
receive active drug and 5 to receive placebo) to receive TBAJ-
876 or matching placebo for 14 days, all under fed conditions.  
For Cohorts 2 and 3, an additional ECG extraction will occur 
at 16 hours postdose on Day 1 and Day 14. For Cohort 3, all 
ECGs performed will be triplicate ECGs at each time point 
listed in the Schedule of Assessments. 
Add the following after Part 2: 
Part 3: 
Three groups each consisting of 10 subjects are planned.  
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CONFIDENTIAL 
03 Dec 2021 
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Section 
Number 
(s) 
Section Title(s) 
Description of Change (s) 
Synopsis 
Test product, 
dosage, and mode of 
administration  
Add the following dose level for Part 1:  
Dose Level 7: 800 mg TBAJ-876 
Update Dose levels 2 and 3 for Part 2, from: 
Dose Level 2: 50 mg TBAJ-876 
Dose Level 3: 100 mg TBAJ-876 
To: 
Dose Level 2: 75 mg TBAJ-876 
Dose Level 3: TBD mg TBAJ-876 
Add the following after Part 2: 
Part 3: 
TBAJ-876 Tablets, orally administered 
Group 1: 100 mg TBAJ-876 (1 x 100 mg tablet) under fasted 
conditions 
Group 2: 100 mg TBAJ-876 (1 x 100 mg tablet) under fed 
conditions 
Group 3:  100 mg TBAJ-876 (4 x 25 mg tablets) under fasted 
conditions 
Synopsis 
 
Criteria for 
evaluation 
Pharmacokinetics, add the following Part clarifications to the PK 
parameters table: 
AUCExtrap 
(%) 
The percentage of extrapolated AUC (area under the 
[plasma concentration vs. time] curve) to AUCinf 
based on extrapolation (Parts 1 and 3) 
AUCinf 
Area under the concentration-time curve from time-zero 
extrapolated to infinity; calculated for Parts 1 and 3 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 (Parts 1 and 3) 
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Protocol TBAJ-876-CL-001 version 8.0 
Global Alliance for TB Drug Development 
CONFIDENTIAL 
03 Dec 2021 
Page ix 
AUCtau 
Area under the concentration-time curve during the 
dosing interval; calculated using the linear trapezoidal 
rule (Part 2) 
Cavg 
Average concentration during the dosing interval 
(Part 2) 
Clast 
The last quantifiable concentration determined 
directly from individual concentration-time data 
(Parts 1, 2, and 3) 
CL/F 
Apparent total clearance after single administration 
(Parts 1 and 3) 
CLss/F 
Apparent total clearance after multiple administration 
(Part 2) 
Cmax 
Maximum concentration, determined directly from 
individual concentration-time data (Parts 1, 2, and 3) 
RAUC 
Accumulation factor during multiple dosing, based on 
AUCtau (Part 2) 
RCmax 
Accumulation factor during multiple dosing, based on 
Cmax (Part 2) 
Tlast 
Time of the last quantifiable concentration (Parts 1, 
2, and 3) 
Tmax 
Time of the maximum concentration (Parts 1, 2, and 
3) 
T1/2 
The observed terminal half-life, calculated for Parts 1 
and 3 as: 
z
T
λ
)
2
ln(
2
/
1
=
 
Vz/F 
Apparent volume of distribution in the terminal phase 
(Parts 1, 2, and 3) 
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 
(Parts 1, 2, and 3) 
 Update Day 1 and Day 14 parameters for Part 2, from: 
• 
Day 1: AUCtau, Cmax, Tmax, Clast, Tmax, and Cavg. 
• 
Day 14: AUCtau, Cmax, Cmin, Tmax, Ctrough, Cavg, RAUC, and RCmax. 
Parameters such as λz, and t1/2 may be calculated as reasonable. 
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CONFIDENTIAL 
03 Dec 2021 
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Section 
Number 
(s) 
Section Title(s) 
Description of Change (s) 
To: 
• 
Day 1: AUCtau, Cmax, Tmax, Clast, Tmax, and Cavg (λz, t1/2, CLss/F, 
and Vz/F may be calculated as reasonable). 
• 
Day 14: AUCtau, Cmax, Cmin, Tmax, Ctrough, Cavg, CLss/F, Vz,/F, 
RAUC, and RCmax. Parameters such as λz, and t1/2 may be 
calculated as reasonable. 
Add the following at the end of section: 
For Part 3, the following PK parameters will be calculated for 
Group 1 (1 x 100 mg tablet, fasted), Group 2 (1 x 100 mg tablet, 
fed), and Group 3 (4 x 25 mg tablets, fasted): 
Cmax, Tmax, AUClast, AUCinf, AUCExtrap, Clast, Tlast, λz, t1/2, CL/F, 
and Vz/F. 
PK parameters will be summarized by group using descriptive 
statistics. Food effect (Group 2, fed, 1 x 100 mg tablet vs. 
Group 1, fasted, 1 x 100 mg tablet) and relative bioavailability 
of the two fasted groups (Group 3, 4 x 25 mg tablets vs. Group 
1, 1 x 100 mg tablet) will be assessed using an analysis of 
variance (ANOVA) approach. 
1.2 
Tuberculosis and 
Rationale for New 
Medications 
Add the following at end of section: 
In addition, a Part 3 will be included that is an open-label study 
to determine the relative bioavailability (BA) of two strengths 
of TBAJ-876 tablets. 
1.6 
Potential Adverse 
Effects in Human 
Subjects 
Paragraph 9, Number 4, from: 
4) Treatment with TBAJ-876 at single doses between 10 mg and 
400 mg was not associated with evidence of QT prolongation or 
myocardial damage. One subject in the 400 mg had an episode of 
non-sustained ventricular tachycardia observed in the Holter 
extraction on Study Day 1, approximately 5 hours after dosing. 
Upon questioning, the subject reported a few seconds of “more 
prominent heartbeat” at the same time. There were no symptoms of 
chest pain, syncope, or palpitations, and her physical examination 
and vital signs were normal. No QT prolongation was observed on 
the Holter or in subsequent ECGs. This event was reported as 
“possibly related”. One subject in Cohort 6 had a mildly elevated 
troponin I on Day 21, with a value of 0.038 ng/mL, confirmed at 
0.034 ng/mL (ULN 0.028 ng/mL). The subject was completely 
asymptomatic, and her physical examination, vital signs, and ECG 
were normal. On the same day of the troponin I elevation, her CPK 
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Protocol TBAJ-876-CL-001 version 8.0 
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CONFIDENTIAL 
03 Dec 2021 
Page xi 
Section 
Number 
(s) 
Section Title(s) 
Description of Change (s) 
and CPK-Mb were also normal. The subject returned to the clinic 
on Study Day 23, and her troponin I levels were within the normal 
range. The finding of elevated troponin I on Study Day 21 was 
deemed to be “spurious”. 
To: 
4) Treatment with TBAJ-876 at single doses between 10 mg and 
400 mg was not associated with evidence of QT prolongation or 
myocardial damage. One subject in Cohort 6 (400 mg) had an 
episode of non-sustained ventricular tachycardia observed in the 
Holter extraction on Study Day 1, approximately 5 hours after 
dosing. Upon questioning, the subject reported a few seconds of 
“more prominent heartbeat” at the same time. There were no 
symptoms of chest pain, syncope, or palpitations, and her physical 
examination and vital signs were normal. No QT prolongation was 
observed on the Holter or in subsequent ECGs. This event was 
reported as “possibly related”. Another subject in Cohort 6 had a 
mildly elevated troponin I on Day 21, with a value of 0.038 ng/mL, 
confirmed at 0.034 ng/mL (ULN 0.028 ng/mL). The subject was 
completely asymptomatic, and her physical examination, vital 
signs, and ECG were normal. On the same day of the troponin I 
elevation, her CPK and CPK-Mb were also normal. The subject 
returned to the clinic on Study Day 23, and her troponin I levels 
were within the normal range. The finding of elevated troponin I on 
Study Day 21 was deemed by the primary investigator to be 
“spurious”. 
1.7 
Rationale for Dose 
selection (MAD) 
Delete the last sentence from the paragraph:  
The choice of the doses for subsequent cohorts will be reconsidered 
after observing the exposures and safety in the first cohort.  
Add the following paragraph to end of section: 
Upon review of the MAD Cohort 1 (25 mg) PK and safety, the 
50 mg dose planned for Cohort 2 was changed to 75 mg. This 
decision was made based on the safety of the 25 mg dose which 
was shown to be safe and well tolerated without evidence of 
cardiac, muscle skeletal, gastrointestinal, hepatic, or 
hematological toxicity, and because the total exposure of 
TBAJ-876 plus M3 at the dose of 75 mg was predicted to still 
remain below thresholds determined by the corresponding sum 
in the three-month toxicity study in dogs. 
11

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CONFIDENTIAL 
03 Dec 2021 
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Section 
Number 
(s) 
Section Title(s) 
Description of Change (s) 
2 
Objective 
From:  
The primary objective of the study is: 
• 
To evaluate the safety and tolerability of single and 
multiple ascending doses of TBAJ-876 oral 
suspension in healthy subjects. 
  The secondary objectives of the study are: 
• 
To determine the pharmacokinetics (PK) of TBAJ-
876 and its metabolites (M2 and M3) after single 
and multiple doses of TBAJ-876 oral suspension in 
healthy adult subjects. 
• 
To compare the rate and extent of absorption of a 
single oral dose of TBAJ-876 when administered 
after a high-calorie, high fat meal versus when its 
administered fasting in health adult subjects. 
To: 
The primary objective of the study is: 
• 
To evaluate the safety and tolerability of single and multiple 
ascending doses of TBAJ-876 oral suspension, and single 
doses of two strengths of TBAJ-876 tablets in healthy 
subjects. 
The secondary objectives of the study are: 
• 
To determine the pharmacokinetics (PK) of TBAJ-876 and 
its metabolites (M2 and M3) after single and multiple doses 
of TBAJ-876 oral suspension, and single doses of two 
strengths of TBAJ-876 tablets in healthy adult subjects. 
• 
To compare the rate and extent of absorption of a single oral 
dose of TBAJ-876 oral suspension and two strengths of 
TBAJ-876 tablets when administered after a high-calorie, 
high-fat meal versus when it is administered fasting in 
healthy adult subjects. 
• 
To compare the rate and extent of absorption of the 4 x 
25 mg tablets and the 1 x 100 mg tablet under fasted 
conditions.  
• 
To compare the rate and extent of absorption of a single 
oral dose of 100 mg of the TBAJ-876 oral suspension and 
two strengths of TBAJ-876 tablets under fed and/or 
fasted conditions. 
12

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CONFIDENTIAL 
03 Dec 2021 
Page xiii 
Section 
Number 
(s) 
Section Title(s) 
Description of Change (s) 
3 
Study design 
summary 
Paragraph 1, from: 
This study is a two-part, partially blinded, placebo 
controlled, combined single ascending dose (SAD) with 
food-effect and multiple ascending dose (MAD) study 
conducted in one study center in the United States.  
To: 
This study is a three-part, partially blinded, placebo 
controlled, combined single ascending dose with food-
effect, a multiple ascending dose study, and a single dose 
relative bioavailability study conducted in one study 
center in the United States. 
Add the following after Part 1 Paragraph 9: 
Additional cohort, Cohort 7: Eight (8) subjects will be enrolled, 
6 to receive active drug and 2 to receive placebo. Subjects will 
receive a single dose under fasted conditions. Subjects will 
receive 800 mg TBAJ-876 or matching dose of placebo for 
TBAJ-876 Oral Suspension. 
Subjects will follow the procedures in the Schedule of 
Assessments (Table 15) with the following clarifications: 
Subjects will check-in to the clinic on Day -1 and be confined 
through Day 8. Subjects will be discharged from the clinic on 
Day 8. Subjects will return for one follow-up visit on Day 14 for 
PK and safety. Subjects will receive a follow-up phone call on 
Day 21. Subjects will complete the procedures specified for 
those study days only. All ECGs performed in Cohort 7 will be 
triplicate ECGs at each time point. 
In addition, subjects will have triplicate ECGs at 16 hours 
postdose. 
Update sentence before Table 6, from:  
Table 6 presents the planned dose cohorts for Part 1 of the study. 
To: 
Table 6 presents the planned 6 dose cohorts and the additional 
Cohort 7 for Part 1 of the study. 
Add the following to Table 6, Single Ascending Dose Cohorts, Part 
1: 
13

Protocol TBAJ-876-CL-001 version 8.0 
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CONFIDENTIAL 
03 Dec 2021 
Page xiv 
7 
Single dose of 800 mg TBAJ-
876 (n=6) 
Placebo (n=2) 
Update Part 2, Paragraph 2 and 3, from: 
For Part 2, MAD design, dose level will be determined based on 
model predictions of multiple-dose PK behavior, and safety from 
Part 1.  
In this multiple ascending dose part, each subject is expected to 
receive TBAJ-876 or matching placebo for 14 days with 
corresponding PK and safety measurements. 
To: 
For Part 2, MAD design, the dose level of the first cohorts will be 
determined based on model predictions of multiple-dose PK 
behavior, and safety from Part 1. The dose for the second cohort 
will then be informed by safety and PK results from the first 
cohort (see Section 1.7). At the time of this writing, it is 
expected that the dose of the third cohort will be informed by 
the results from the first two. 
In this multiple ascending dose part, each subject is expected to 
receive TBAJ-876 or matching placebo for 14 days in the fed state 
with corresponding PK and safety measurements. 
Add the following after Part 2 Paragraph 7: 
For Cohorts 2 and 3, an additional ECG extraction will occur 
at 16 hours postdose on Day 1 and Day 14. For Cohort 3, all 
ECGs performed will be triplicate ECGs at each time point 
listed in Table 16, including the additional 16 hour postdose 
time point. 
Add the following after Part 2: 
Part 3: 
Part 3 is a single-dose design study with 3 planned dose groups 
each consisting of 10 subjects.  
Subjects will be assigned to one of 3 groups and dose: 
• 
Group 1: TBAJ-876 - 100 mg (1 x 100 mg tablet) under 
fasted conditions. 
• 
Group 2: TBAJ-876 -100 mg (1 x 100 mg tablet) under fed 
conditions. 
• 
Group 3: TBAJ-876 - 100 mg (4 x 25 mg tablets) under 
fasted conditions. 
14

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Section 
Number 
(s) 
Section Title(s) 
Description of Change (s) 
Subjects will be confined in the clinic prior to dosing (Day -1) 
until 7 days after dosing (Day 8). Subjects will return to the 
clinic to have subsequent follow up safety and PK 
measurements on Days 10 and 14.  A follow-up phone call to 
collect any AEs will be conducted on Day 21. Refer to the 
schedule of assessments in Table 17. 
Blood samples will be obtained before each dose of study drug, 
and at serial time points postdose on Days 1-8 and Days 10 and 
14.  Plasma PK samples will be analyzed for TBAJ-876, M2 
and M3 using validated analytical methods. 
In addition, blood and urine will be collected for clinical 
laboratory evaluations. 
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. 
4 
Identity of 
Investigational 
Product 
Update, from: 
The Investigational Medicinal Product (IMP) will be supplied as 
TBAJ-876 Oral Suspension, 5 mg/mL formulation or matching 
placebo.  
Refer to Appendix 2 for details regarding the description and 
composition of TBAJ 876 oral suspension. 
To:  
The Investigational Medicinal Product (IMP) will be supplied as 
TBAJ-876 Oral Suspension, 5 mg/mL formulation or matching 
placebo, TBAJ-876 tablets 25 mg, and TBAJ-876 tablets 100 
mg.  
Refer to Appendix 2 for details regarding the description and 
composition of TBAJ 876 oral suspension, TBAJ-876 tablets 25 
mg, and TBAJ-876 tablets 100 mg. 
Update Table 7, Identity of Investigational Products, from: 
Test Product:  
TBAJ-876 Oral Suspension 5 mg/mL 
Manufactured for Global Alliance for TB 
Drug Development 
To: 
Test Products:  
TBAJ-876 Oral Suspension 5 mg/mL 
15

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Section 
Number 
(s) 
Section Title(s) 
Description of Change (s) 
Manufactured for Global Alliance for TB 
Drug Development 
 
TBAJ-876 Tablets 25 mg 
Manufactured by Piramal Pharma Limited 
for Global Alliance for TB Drug 
Development 
 
TBAJ-876 Tablets 100 mg 
Manufactured by Piramal Pharma Limited 
for Global Alliance for TB Drug 
Development 
5.2 
Exclusion Criteria 
Update exclusion # 25, from: 
25. If assigned to the fasted/fed cohort, is lactose intolerant. 
To: 
25. Is lactose intolerant. 
6.1 
Subject assignment  
Add the following after Paragraph 4: 
Additional cohort, Cohort 7: Eight (8) subjects will be enrolled, 
6 to receive active drug and 2 to receive placebo. Subjects will 
receive a single dose under fasted conditions. Subjects will 
receive 800 mg TBAJ-876 or matching dose of placebo for 
TBAJ-876 Oral Suspension. 
Update Paragraph 6, from: 
For Part 2, 36 subjects are planned to be enrolled. There are 3 
cohorts planned with 12 subjects per cohort (9 to receive active 
drug and 3 to receive placebo). All doses in Part 2 will be under fed 
conditions.  
To: 
For Part 2, 39 subjects are planned to be enrolled. There are 3 
cohorts planned. Cohort 1 with 12 subjects per cohort (9 to receive 
active drug and 3 to receive placebo), Cohort 2 with 13 subjects 
per cohort (9 to receive active drug and 4 to receive placebo), 
and Cohort 3 with 14 subjects per cohort (9 to receive active 
drug and 5 to receive placebo). All doses in Part 2 will be under 
fed conditions. 
Add the following to end of section: 
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Section 
Number 
(s) 
Section Title(s) 
Description of Change (s) 
For Part 3, 30 subjects are planned to be enrolled. There are 3 
groups planned with 10 subjects per group. All subjects will 
receive active drug under fasted or fed conditions.   
6.2 
Blinding 
Update the section title, from: 
Blinding 
To: 
Blinding (Parts 1 and 2) 
Add the following to end of section: 
Part 3 is open-label. 
6.4 
Confinement  
Add the following after Paragraph 1: 
Additional cohort, Cohort 7: Subjects will check-in to the clinic 
on Day -1 and be confined through Day 8. Subjects will be 
discharged from the clinic on Day 8. Subjects will return for 
one follow-up visit on Day 14 for PK and safety. Subjects will 
receive a follow-up phone call on Day 21. 
Add the following to end of section: 
For Part 3, subjects will be admitted to the research center on 
the evening of Day -1 and remain in the research center until 
completion of the procedures on Day 8.  Subjects will return 
for subsequent follow-up visits on Days 10 and 14 and will 
receive a follow-up phone call on Day 21. 
6.5.1 
Fasting/Meals 
Add the following after Part 2: 
Part 3, BA 
An optional meal or snack will be served the evening of check-
in.  
Subjects in Group 1 and Group 3 will be required to fast for at 
least 10 hours before dosing. The subjects will fast for 4 hours 
after dosing.  
Subjects in Group 2 will fast for at least 10 hours before 
consuming the required FDA standard high-fat, high calorie 
breakfast as described above in the food effect cohort in Part 1.   
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Section 
Number 
(s) 
Section Title(s) 
Description of Change (s) 
Standard meals will be provided at appropriate times after 
dosing for all groups. 
6.5.2 
Beverages  
Add the following at end of section: 
Part 3, BA 
Each dose of TBAJ-876 Tablet(s) will be administered orally 
with approximately 240 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  Update the section title of 6.6.1, from: 
Administration of Oral Care Strips 
To: 
Administration of Oral Care Strips (Parts 1 and 2) 
Add the following section: 
6.6.3 Administration of TBAJ-876 Tablet 
Each dose of TBAJ-876 Tablet will be administered orally with 
approximately 240 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, 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 
Part 1  
Paragraph 1, Sentence 1 from: 
A total of 140 mL (35 x 4 mL samples) will be collected from each 
subject for PK analysis. 
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Section 
Number 
(s) 
Section Title(s) 
Description of Change (s) 
To:  
For Cohorts 1-6, a total of 140 mL (35 x 4 mL samples) will be 
collected from each subject for PK analysis. 
Add the following footnote to Table 8, Total Volume of Blood to be 
Collected for Testing: Part 1: 
a. Subjects in Cohort 7 will not have collections after Day 14. 
Update Paragraph 2, Last sentence from: 
The total volume of blood collected from each subject in Part 1 will 
not exceed approximately 320.5 mL.  
To: 
The total volume of blood collected from each subject in Part 1 
Cohorts 1-6 will not exceed approximately 320.5 mL. 
Add the following after Paragraph 2:  
For Cohort 7, a total of 124 mL (31 x 4 mL samples) will be 
collected from each subject for PK analysis. Approximately 
78.5 mL of blood will be collected for the clinical laboratory 
evaluations and coagulation testing.  The total volume of blood 
collected from each subject in Part 1 Cohort 7 will not exceed 
approximately 203 mL. 
6.7 
Blood sampling, 
Processing and 
Shipment 
Add the following section and table: 
6.7.3 
Part 3 
A total of 128 mL (32 x 4ml samples) will be collected for PK 
Analysis.  Approximately 91 mL of blood will be collected for 
the clinical laboratory evaluations and coagulation testing. 
Table 10 Total Volume of Blood to be Collected for Testing: Part 3 
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, 6 and 48 hours 
and Days 5, 7, 10, and 14 
(end-of-study). 
7 
8.5 
59.5 
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Section 
Number 
(s) 
Section Title(s) 
Description of Change (s) 
Coagulation 
7 
2.7 
18.9 
Pharmacokinetic analysis 
32 
4.0 
128.0 
Total 
218.9 
The Principal Investigator, in conjunction with the Sponsor, 
may collect additional blood if necessary, for repeat laboratory 
or safety evaluations including AE follow-up. 
6.7.3 
Pharmacokinetic 
Sampling Time 
Windows 
Change section numbering, from,  
6.7.3 
To:  
6.7.4 
Update Table 10, from: 
Table 10 Acceptable Pharmacokinetic Sampling Time Windows, 
Part 1 
To: 
Table 11 Acceptable Pharmacokinetic Sampling Time Windows, 
Part 1, and Part 3 
6.8 
End of Study 
Procedures 
Update ECG bullet, from: 
ECG 
To: 
Triplicate ECG 
6.9.4 
Vital Signs 
Add the following: 
For Part 3, vital signs (blood pressure, pulse rate, temperature, 
respiration rate, and pulse oximetry) will be measured at the 
times noted on the appropriate events schedule (Table 17). 
6.9.5 
Electrocardiograms 
Add the following after Paragraph 2: 
For Cohort 7, all ECGs will be triplicate at each time point. In 
addition, subjects in will have triplicate ECGs at 16 hours 
postdose. 
Add the following after Paragraph 4: 
For Cohorts 2 and 3, an additional ECG extraction will occur 
at 16 hours postdose on Day 1 and Day 14. For Cohort 3, all 
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Section 
Number 
(s) 
Section Title(s) 
Description of Change (s) 
ECGs performed will be triplicate ECGs at each time point 
listed in Table 16. 
Add the following: 
For Part 3, triplicate ECGs will be completed with 15 minutes 
at all timepoints on Table 17. 
6.9.6 
Cardiac Holter 
Monitoring and 
Cardiodynamic 
Assessment 
Add the following: 
For Part 3, continuous 12-lead ECGs (Holter) will be recorded 
for 1 hour prior to dose and continue for at least 24 hours post 
dose. 
7.2 
Attribution/Causality  Bullet point 6, Sentence 2, from: 
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. 
To: 
However, it is very important that the investigator always assess 
causality for every event before the initial transmission of the SAE 
data to the Sponsor/designee. 
7.7 
Clinical Laboratory 
Adverse Events 
Update the last sentence, from: 
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.  
To: 
All laboratory changes greater than or equal to Grade 2 must 
be reported as an AE regardless of clinical significance. 
9.2 
Pharmacokinetic 
Analysis 
Pharmacokinetics, add the following Part clarifications to the PK 
parameters table: 
AUCExtrap 
(%) 
The percentage of extrapolated AUC (area under the 
[plasma concentration vs. time] curve) to AUCinf 
based on extrapolation (Parts 1 and 3) 
AUCinf 
Area under the concentration-time curve from time-zero 
extrapolated to infinity; calculated for Parts 1 and 3 as: 
z
last
last
C
AUC
AUC
λ
+
=
inf
 
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Page xxii 
AUClast 
Area under the concentration-time curve from 
time-zero to the time of the last quantifiable 
concentration; calculated using the linear trapezoidal 
rule (Parts 1 and 3) 
AUCtau 
Area under the concentration-time curve during the 
dosing interval; calculated using the linear trapezoidal 
rule (Part 2) 
Cavg 
Average concentration during the dosing interval 
(Part 2) 
Clast 
The last quantifiable concentration determined 
directly from individual concentration-time data 
(Parts 1, 2, and 3) 
CL/F 
Apparent total clearance after single administration 
(Parts 1 and 3) 
CLss/F 
Apparent total clearance after multiple administration 
(Part 2) 
Cmax 
Maximum concentration, determined directly from 
individual concentration-time data (Parts 1, 2, and 3) 
RAUC 
Accumulation factor during multiple dosing, based on 
AUCtau (Part 2) 
RCmax 
Accumulation factor during multiple dosing, based on 
Cmax (Part 2) 
Tlast 
Time of the last quantifiable concentration (Parts 1, 
2, and 3) 
Tmax 
Time of the maximum concentration (Parts 1, 2, and 
3) 
T1/2 
The observed terminal half-life, calculated for Parts 1 
and 3 as: 
z
T
λ
)
2
ln(
2
/
1
=
 
Vz/F 
Apparent volume of distribution in the terminal phase 
(Parts 1, 2, and 3) 
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 
(Parts 1, 2, and 3) 
 Update Day 1 and Day 14 parameters for Part 2, from: 
22

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Section 
Number 
(s) 
Section Title(s) 
Description of Change (s) 
• 
Day 1: AUCtau, Cmax, Tmax, Clast, Tmax, and Cavg. 
• 
Day 14: AUCtau, Cmax, Cmin, Tmax, Ctrough, Cavg, RAUC, and RCmax. 
Parameters such as λz, and t1/2 may be calculated as reasonable. 
To: 
• 
Day 1: AUCtau, Cmax, Tmax, Clast, Tmax, and Cavg (λz, t1/2, CLss/F, 
and Vz/F may be calculated as reasonable). 
• 
Day 14: AUCtau, Cmax, Cmin, Tmax, Ctrough, Cavg, CLss/F, Vz,/F, 
RAUC, and RCmax. Parameters such as λz, and t1/2 may be 
calculated as reasonable. 
Add the following at the end of section: 
For Part 3, the following PK parameters will be calculated for 
Group 1 (1 x 100 mg tablet, fasted), Group 2 (1 x 100 mg tablet, 
fed), and Group 3 (4 x 25 mg tablets, fasted): 
Cmax, Tmax, AUClast, AUCinf, AUCExtrap, Clast, Tlast, λz, t1/2, CL/F, 
and Vz/F. 
PK parameters will be summarized by group using descriptive 
statistics. Food effect (Group 2, fed, 1 x 100 mg tablet vs. 
Group 1, fasted, 1 x 100 mg tablet) and relative bioavailability 
of the two fasted groups (Group 3, 4 x 25 mg tablets vs. Group 
1, 1 x 100 mg tablet) will be assessed using an analysis of 
variance (ANOVA) approach. 
9.3 
Statistical  Analysis 
Update the section, from: 
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.). 
PK 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: The effect of food will be assessed comparing PK 
parameters (Cmax, AUCs) under fed versus fasting conditions using 
an analysis of variance (ANOVA) approach.5 
To: 
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Section 
Number 
(s) 
Section Title(s) 
Description of Change (s) 
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.). 
For Parts 1, 2, and 3, PK parameters will be summarized by 
cohort using descriptive statistics. Summary statistics will also 
be presented by gender within each cohort.  
For Part 1, dose proportionality for exposure parameters (Cmax, 
AUCs) will be assessed using a power model approach. Food 
effect will be assessed using an analysis of variance (ANOVA) 
with food condition as the fixed effect. 
For Part 2, dose proportionality for exposure parameters (Cmax, 
AUCs) will be assessed using a power model approach. Steady 
state for each dose level will be assessed using an appropriate 
statistical methodology. 
For Part 3, Food effect will be assessed using an ANOVA model 
with food condition as the fixed effect.  The relative 
bioavailability analysis for the two strengths of TBAJ-876 
tablets will be assessed using an ANOVA model with the 
strength of tablet administered under fasting conditions as the 
fixed effect. 
Additional details will be provided in the SAP. 
10 
Facilities 
Update the email for analytical lab, from: 
nauman@alliancepharmaco.com 
To: 
rguan@alliancepharmaco.com 
11 
Drug Supplies 
Update Paragraph 1, from: 
Global Alliance for TB Drug Development will supply sufficient a 
quantity of the study drug, TBAJ-876 for preparation of TBAJ-876 
Oral Suspension. Study drug will be shipped to Worldwide Clinical 
Trials Early Phase Services, LLC pursuant to site SOPs. 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 (also used as Placebo) and other 
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Section 
Number 
(s) 
Section Title(s) 
Description of Change (s) 
supplies will be procured, inventoried, and stored appropriately by 
Worldwide Clinical Trials Early Phase Services, LLC pursuant to 
site SOPs. 
To: 
Global Alliance for TB Drug Development will supply sufficient a 
quantity of the study drug, TBAJ-876 for preparation of TBAJ-876 
Oral Suspension, TBAJ-876 tablets 25 mg, and TBAJ-876 
tablets 100 mg. Study drug will be shipped to Worldwide Clinical 
Trials Early Phase Services, LLC pursuant to site SOPs. Upon 
receipt of the study drug, the study drug will be inventoried and 
stored in an environmentally controlled and secure, limited access 
area. For oral suspension, the suspending vehicle (also used as 
Placebo) and other supplies will be procured, inventoried, and 
stored appropriately by Worldwide Clinical Trials Early Phase 
Services, LLC pursuant to site SOPs. 
13 
Events schedule 
Update numbering for Table 14 Schedule of Assessments and 
Procedures, Part 1 SAD to Table 15 
Table 15 Schedule of Assessments and Procedures, Part 1 SAD: 
Add “**” to “Study Day” and “Event” rows.  
Add “Xd” to “12-lead safety ECG” row on “16a” column.  
Add the following footnote:  
** Subjects in Cohort 7 will be discharged from the clinic on 
Day 8. Subjects will return for one follow-up visit on Day 14 for 
PK and safety. Subjects will receive a follow-up phone call on 
Day 21. Subjects will complete the procedures specified for 
those study days only. 
Add the following to the end of footnote d:  
All ECGs in Cohort 7 will be triplicate at each time point. In 
addition, subjects in Cohort 7 will have triplicate ECGs at 16 
hours postdose. 
Update numbering for Table 15 Schedule of Assessments and 
Procedures, Part 2 MAD to Table 16 
Table 16 Schedule of Assessments and Procedures, Part 2 MAD: 
Add the following to the end of footnote j:  
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Section 
Number 
(s) 
Section Title(s) 
Description of Change (s) 
All ECGs in Cohort 3 will be triplicate at each time point. In 
addition, subjects in Cohort 3 will have triplicate ECGs at 16 
hours postdose on Day 1 and Day 14. 
Add the following to the end of footnote n: 
For Cohorts 2 and 3, an additional extraction will be done at 
the 16 hour time point on Days 1 and 14. 
Add the following Table: 
Table 17 Schedule of Assessments and Procedures, Part 3 BA 
Appendix 
1 
Shipment 
Update the contact Email, from: 
Contact e-mail: samples@alliancepharmaco.com 
To: 
Contact E-mail: rguan@alliancepharmaco.com 
samples@alliancepharmaco.com 
Appendix 
2 
Description and 
composition of test 
product 
Update and add the following to the description of the dosage 
form, last paragraph, from: 
The required doses of the drug product are dispensed using 
commercially available oral syringes of suitable capacity. 
To: 
The required doses of the suspension drug product are dispensed 
using commercially available oral syringes of suitable capacity. 
TBAJ-876 Tablets 25 mg are white to off white, round 
uncoated tablets, plain on both sides. 
TBAJ-876 Tablets 100 mg are white to off white, capsule-
shaped uncoated tablets, plain on both sides. 
Add the following to beginning of Composition of the Drug 
Product: 
TBAJ-876 Oral Suspension 
Add the following to the end of Composition of the Drug Product: 
TBAJ-876 Tablets 
Each 25 mg tablet contains 25 mg of TBAJ-876 equivalent to 
30.7 mg of TBAJ-876 tartrate.  Each 100 mg tablet contains 
100 mg of TBAJ-876 equivalent to 122.8 mg of TBAJ-876 
26

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Section 
Number 
(s) 
Section Title(s) 
Description of Change (s) 
tartrate.  The composition of the tablets is as follows: lactose 
monohydrate, microcrystalline cellulose, povidone, 
crospovidone, colloidal silicon dioxide, and magnesium 
stearate. The formulation of the two strengths of tablets is 
identical and dose proportional. 
Add the following to the end of Container and Closure System: 
TBAJ-876 Tablets 25 mg are packaged as 30-count in 30 cc 
round high-density polyethylene (HDPE) bottles induction 
sealed and with 28 mm polypropylene (PP) child resistant 
closures (CRC). TBAJ-876 Tablets 100 mg are packaged as 30-
count in 40 cc round HDPE bottles induction sealed and with 
33 mm PP CRC.  The tables are stored at 15-30 °C (59-86 °F). 
 
27

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PROTOCOL SYNOPSIS 
Name of Sponsor/Company: Global Alliance for TB Drug Development 
Name of test product: TBAJ-876 
Name of active ingredient: TBAJ-876 Tartrate 
Title of study: A Phase 1, Partially Blind, Placebo Controlled, Randomized, Combined Single 
Ascending Dose with a Food Effect Cohort (Part 1), Multiple Ascending Dose (Part 2), and Relative 
Bioavailability (Part 3) Study to Evaluate the Safety, Tolerability, Pharmacokinetics of TBAJ-876 in 
Healthy Adult Subjects 
Principal Investigator: Ingela Danielsson, MD 
Study Center 
Worldwide Clinical Trials Early Phase Services, LLC 
2455 NE Loop 410, Suite 150 
San Antonio, Texas 78217 
Study period:   
Part 1: Single ascending dose (SAD) cohorts which 
includes a Food-effect Cohort: approximately 56 days, 
from Day -1 to study exit.  
Part 2: Multiple ascending dose (MAD) cohorts: 
approximately 133 days, from Day -1 through completion 
of clinical procedures on Day 126 followed by a phone 
call on Day 133. 
Part 3: Single dose, open-label parallel relative 
bioavailability (BA) design: approximately 45 days, from 
Screening to study exit. 
The maximum duration of the study will depend upon the 
final number and timing of each cohort and the observed 
terminal half-life (T1/2). 
Phase of development: 1 
 
Duration of treatment: 
Part 1: One single dose of TBAJ-876 Oral Suspension or 
placebo for TBAJ-876 Oral Suspension 
Food-effect Cohort: One single dose of TBAJ-876 Oral 
Suspension. Subjects will receive TBAJ-876 Oral 
Suspension in fasted or fed conditions.  
Part 2:  Multiple doses (14 doses per cohort) of 
TBAJ-876 Oral Suspension or placebo for TBAJ-876 
Oral Suspension  
Number of sites enrolling subjects: 1 
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Part 3: One single dose of 100 mg TBAJ-876 as 1 x 100 
mg tablet (either fasted or fed) or 4 x 25 mg tablets 
(fasted). 
Number of subjects (planned):  
Part 1: 
Plan to enroll 50 to 60 subjects in 6 SAD cohorts. Each cohort will consist of 8 subjects, 6 to receive 
active drug and 2 to receive placebo, all under fasting conditions.  
In addition, the effect of food on bioavailability of TBAJ-876 will be studied in a food-effect cohort 
comprised of two parallel groups, one fasting and the other fed. The fed group will enroll at least 10 
new subjects, which will yield complete data for at least 8 subjects if at most 2 fail to complete. Six 
subjects previously administered 100 mg TBAJ-876 in Cohort 4 (who have already completed the 
cohort) will be considered part of the fasted group. At least three additional subjects will be enrolled 
to be dosed in the fasted group. This will yield a complete data set for at least 8 subjects if 1 fails to 
complete. Based on exposure levels from the first 4 completed cohorts, the 100 mg dose was chosen 
for the food-effect cohort. Therefore, all subjects in the food-effect cohort will receive active drug of 
TBAJ-876, 100 mg.    
Additional cohort, Cohort 7: Eight (8) subjects will be enrolled, 6 to receive active drug and 2 to 
receive placebo. Subjects will receive a single dose under fasted conditions. Subjects will receive 
800 mg TBAJ-876 or matching dose of placebo for TBAJ-876 oral suspension. 
Part 2: 
Planned to enroll 39 subjects in 3 MAD cohorts. Cohort 1 with 12 subjects per cohort (9 to receive 
active drug and 3 to receive placebo), Cohort 2 with 13 subjects per cohort (9 to receive active drug 
and 4 to receive placebo), and Cohort 3 with 14 subjects per cohort (9 to receive active drug and 5 to 
receive placebo. All cohorts will receive the assigned dose 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 to increase number of subjects based on PK and safety information 
learned from initial cohorts. 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 cohorts have been demonstrated. The 
Institutional Review Board (IRB) should be immediately notified of this revised approach. 
Part 3:  
Planned to enroll 30 subjects in 3 groups of 10 subjects each. All groups to receive active drug under 
fasted or fed conditions. 
• 
Group 1: Single dose 1 x 100 mg tablet - fasted 
• 
Group 2: Single dose 1 x 100 mg tablet - fed 
• 
Group 3: Single dose 4 x 25 mg tablets - fasted 
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Diagnosis and main criteria for inclusion:  
Volunteers will be healthy adults, 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 and multiple ascending doses of TBAJ-876 oral 
suspension, and single doses of two strengths of TBAJ-876 tablets in healthy subjects. 
The secondary objectives of the study are: 
• 
To determine the pharmacokinetics (PK) of TBAJ-876 and its metabolites (M2 and M3) after 
single and multiple doses of TBAJ-876 oral suspension, and single doses of two strengths of 
TBAJ-876 tablets in healthy adult subjects. 
• 
To compare the rate and extent of absorption of a single oral dose of TBAJ-876 oral suspension 
and two strengths of TBAJ-876 tablets when administered after a high-calorie, high-fat meal 
versus when it is administered fasting in healthy adult subjects. 
• 
To compare the rate and extent of absorption of the 4 x 25 mg tablets and the 1 x 100 mg tablet 
under fasted conditions.  
• 
To compare the rate and extent of absorption of a single oral dose of 100 mg of the TBAJ-876 
oral suspension and two strengths of TBAJ-876 tablets under fed and/or fasted conditions. 
Study design overview:  
This study is a three-part, partially blinded, placebo controlled, combined single ascending dose with 
food-effect, multiple ascending dose study, and a single dose relative bioavailability study conducted 
at one study center in the United States.  
Safety will be assessed throughout the study for all subjects. 
Blood will be collected for PK analysis. Plasma samples will be analyzed for TBAJ-876 and its 
metabolites (M2 and M3).  
Part 1: 
Six dose levels are planned. Based on interim PK data obtained during the dose escalation, a dose 
level will be selected at which to study the effect on PK of a high-calorie, high-fat meal.  
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 not be so separated.  
Food-effect: Based on exposure levels from the first 4 completed cohorts, the 100 mg dose was 
chosen for the food-effect cohort. In this food-effect cohort, there will be two parallel groups, one 
30

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Page xxxi 
fasting and the other fed. The fed group will enroll at least 10 new subjects and the fasted group will 
include data from 6 subjects who completed Cohort 4 and at least 3 additional subjects who will be 
enrolled in the fasted group. All subjects in the food-effect cohort will receive active drug of TBAJ-
876, 100 mg.  
Additional cohorts may be enrolled if deemed appropriate by the Sponsor to repeat a dose level or to 
study another dose level or increase cohort size (subject numbers). 
Additional cohort, Cohort 7: Eight (8) subjects will be enrolled, 6 to receive active drug and 2 to 
receive placebo. Subjects will receive a single dose under fasted conditions. 
Dose = 800 mg TBAJ-876 or matching dose of placebo for TBAJ-876 Oral Suspension 
Subjects will follow the procedures in Table 15, Schedule of Assessments and Procedures, Part 1 
SAD with the following clarifications: 
Subjects will check-in to the clinic on Day -1 and be confined through Day 8. Subjects will be 
discharged from the clinic on Day 8. Subjects will return for one follow-up visit on Day 14 for 
PK and safety. Subjects will receive a follow-up phone call on Day 21. Subjects will complete 
the procedures specified for those study days only. All ECGs performed in Cohort 7 will be 
triplicate ECGs at each time point. 
In addition, subjects will have triplicate ECGs at 16 hours postdose. 
Dose escalation to the next cohort (i.e., dose level) or any changes of PK sampling and safety 
assessment timepoints will not take place until the Sponsor, in conjunction with the Principal 
Investigator and Dose Escalation Committee, has determined that adequate safety, tolerability and PK 
from the previous cohort have been demonstrated to permit proceeding to the next cohort. 
The decision for the study to progress to the planned MAD cohorts (Part 2) will not take place until 
the Sponsor, in conjunction with the Principal Investigator and the Dose Escalation Committee, has 
determined that adequate safety, tolerability, and PKs from the previous cohorts (Part 1) have been 
demonstrated to permit proceeding. 
Part 2: 
Three cohorts are planned. Cohort 1 with 12 subjects per cohort (9 to receive active drug and 3 to 
receive placebo), Cohort 2 with 13 subjects per cohort (9 to receive active drug and 4 to receive 
placebo), and Cohort 3 with 14 subjects per cohort (9 to receive active drug and 5 to receive placebo) 
to receive TBAJ-876 or matching placebo for 14 days, all under fed conditions.  
For Cohorts 2 and 3, an additional ECG extraction will occur at 16 hours postdose on Day 1 and Day 
14. For Cohort 3, all ECGs performed will be triplicate ECGs at each time point listed in the Schedule 
of Assessments. 
Additional cohorts may be enrolled if deemed appropriate by the Sponsor to repeat a dose level or to 
study another dose level. 
Part 3: 
Three groups each consisting of 10 subjects are planned.  
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Test product, dosage, and mode of administration:  
Part 1: 
 
TBAJ-876 Oral Suspension, orally administered  
Dose Level 1: 10 mg TBAJ-876  
Dose Level 2: 25 mg TBAJ-876  
Dose Level 3: 50 mg TBAJ-876  
Dose Level 4 and food-effect cohort: 100 mg TBAJ-876  
Dose Level 5: 200 mg TBAJ-876  
Dose Level 6: 400 mg TBAJ-876  
Dose Level 7: 800 mg TBAJ-876 
Additional cohorts may be enrolled if deemed appropriate by the Sponsor to repeat a dose level or to 
study another dose level. 
Part 2: 
TBAJ-876 Oral Suspension, orally administered  
Dose Level 1: 25 mg TBAJ-876  
Dose Level 2: 75 mg TBAJ-876  
Dose Level 3: TBD mg TBAJ-876  
Doses may change based on what is learned from previous cohorts. Additional cohorts may be 
enrolled if deemed appropriate by the Sponsor to repeat a dose level or to study another dose level. 
Part 3: 
TBAJ-876 Tablets, orally administered 
Group 1: 100 mg TBAJ-876 (1 x 100 mg tablet) under fasted conditions 
Group 2: 100 mg TBAJ-876 (1 x 100 mg tablet) under fed conditions 
Group 3:  100 mg TBAJ-876 (4 x 25 mg tablets) under fasted conditions 
Control product, dosage, and mode of administration:  
Placebo for TBAJ-876 Oral Suspension; orally administered 
All levels (except Part 1 food-effect cohort and Part 3) = Matching dose of placebo for TBAJ-876 
Oral Suspension 
Criteria for evaluation:  
Safety: Safety assessments will include physical examination (including heart murmurs), vital signs, 
electrocardiograms (ECGs), extensive cardiac monitoring including telemetry, adverse events (AEs), 
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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 PK 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, or comparable product, Certara, 
L.P.]) and/or SAS® (Version 9.4 or higher, SAS Institute Inc.). PK parameters will be calculated 
using non-compartmental analysis. The following PK parameters will be determined as appropriate 
for each study part and analyte. 
AUCExtrap (%) 
The percentage of extrapolated AUC (area under the [plasma concentration vs. 
time] curve) to AUCinf based on extrapolation (Parts 1 and 3) 
AUCinf 
Area under the concentration-time curve from time-zero extrapolated to infinity; 
calculated for Parts 1 and 3 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 (Parts 1 
and 3) 
AUCtau 
Area under the concentration-time curve during the dosing interval; calculated 
using the linear trapezoidal rule (Part 2) 
Cavg 
Average concentration during the dosing interval (Part 2) 
Clast 
The last quantifiable concentration determined directly from individual 
concentration-time data (Parts 1, 2, and 3) 
CL/F 
Apparent total clearance after single administration (Parts 1 and 3) 
CLss/F 
Apparent total clearance after multiple administration (Part 2) 
Cmax 
Maximum concentration, determined directly from individual concentration-time 
data (Parts 1, 2, and 3) 
RAUC 
Accumulation factor during multiple dosing, based on AUCtau (Part 2) 
RCmax 
Accumulation factor during multiple dosing, based on Cmax (Part 2) 
Tlast 
Time of the last quantifiable concentration (Parts 1, 2, and 3) 
Tmax 
Time of the maximum concentration (Parts 1, 2, and 3) 
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T1/2 
The observed terminal half-life, calculated for Parts 1 and 3 as: 
z
T
λ
)
2
ln(
2
/
1
=
 
Vz/F 
Apparent volume of distribution in the terminal phase (Parts 1, 2, and 3) 
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 
(Parts 1, 2, and 3) 
Additional PK analysis and modeling with multiple compartment model may be performed and will 
be reported separately, if conducted.  
Food-effect: The effect of food will be assessed comparing PK parameters under fed versus fasting 
conditions using an analysis of variance (ANOVA) approach. 
For Part 2, the following PK parameters will be calculated from plasma concentrations of TBAJ-876 
following doses on Days 1 and 14: 
• 
Day 1: AUCtau, Cmax, Tmax, Clast, Tmax, and Cavg (λz, t1/2, CLss/F, and Vz/F may be calculated as 
reasonable). 
• 
Day 14: AUCtau, Cmax, Cmin, Tmax, Ctrough, Cavg, CLss/F, Vz,/F, RAUC, and RCmax. Parameters such as 
λz, and t1/2 may be calculated as reasonable. 
For Parts 1 and 2, PK parameters will be summarized by cohort using descriptive statistics. Dose 
proportionality will be assessed using the power model approach. 
For Part 3, the following PK parameters will be calculated for Group 1 (1 x 100 mg tablet, fasted), 
Group 2 (1 x 100 mg tablet, fed), and Group 3 (4 x 25 mg tablets, fasted): 
Cmax, Tmax, AUClast, AUCinf, AUCExtrap, Clast, Tlast, λz, t1/2, CL/F, and Vz/F. 
PK parameters will be summarized by group using descriptive statistics. Food effect (Group 2, fed, 1 
x 100 mg tablet vs. Group 1, fasted, 1 x 100 mg tablet) and relative bioavailability of the two fasted 
groups (Group 3, 4 x 25 mg tablets vs. Group 1, 1 x 100 mg tablet) will be assessed 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 ABBREVIATIONS ................................................................................................ xxxviii 
1 
INTRODUCTION ...............................................................................................................1 
1.1 
Background Information ......................................................................................................1 
1.2 
Tuberculosis and Rationale for New Medication ................................................................1 
1.3 
Preclinical Studies and Toxicity Studies..............................................................................2 
1.4 
Safety Pharmacology ...........................................................................................................5 
1.5 
Pharmacokinetics and Product Metabolism in Animals ......................................................7 
1.6 
Potential Adverse Effects in Human Subjects ...................................................................10 
1.7 
Rationale for Dose Selection (MAD) ................................................................................11 
2 
OBJECTIVE ......................................................................................................................13 
3 
STUDY DESIGN SUMMARY .........................................................................................13 
3.1 
Dose Escalation ..................................................................................................................18 
3.2 
Stopping Rules for Cohorts for Participants Receiving Active Drug ................................19 
4 
IDENTITY OF INVESTIGATIONAL PRODUCT ..........................................................20 
5 
SUBJECT SELECTION ....................................................................................................21 
5.1 
Inclusion Criteria ...............................................................................................................21 
5.2 
Exclusion Criteria ..............................................................................................................22 
5.3 
Medication and Activity Restrictions ................................................................................25 
5.4 
Screening............................................................................................................................25 
6 
STUDY PROCEDURES ...................................................................................................26 
6.1 
Subject Assignment ...........................................................................................................26 
6.2 
Blinding (Parts 1 and 2) .....................................................................................................27 
6.2.1 Clinical Research Staff ......................................................................................................28 
6.2.2 Study Subjects ....................................................................................................................28 
6.2.3 Bioanalytical Laboratory ...................................................................................................28 
6.2.4 Pharmacokinetic Analysis ..................................................................................................28 
6.2.5 Cardiac Vendor ..................................................................................................................28 
6.2.6 Unblinding Procedures.......................................................................................................28 
6.3 
Check-In Procedures ..........................................................................................................29 
6.4 
Confinement .......................................................................................................................29 
6.5 
Fasting/Meals/Beverages ...................................................................................................30 
6.5.1 Fasting/Meals .....................................................................................................................30 
6.5.2 Beverages ...........................................................................................................................31 
6.6 
Drug Administration ..........................................................................................................32 
6.6.1 Administration of Oral Care Strips (Parts 1 and 2)............................................................32 
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6.6.2 Administration of TBAJ-876 Oral Suspension or Placebo for TBAJ-876 Oral 
Suspension .....................................................................................................................................32 
6.6.3 Administration of TBAJ-876 Tablet ..................................................................................33 
6.7 
Blood Sampling, Processing and Shipment .......................................................................33 
6.7.1 Part 1 ..................................................................................................................................33 
6.7.2 Part 2 ..................................................................................................................................34 
6.7.3 Part 3 ..................................................................................................................................35 
6.7.4 Pharmacokinetic Sampling Time Windows .......................................................................35 
6.8 
End-of-Study Procedures ...................................................................................................36 
6.9 
Safety Monitoring and Procedures .....................................................................................37 
6.9.1 Adverse Events ..................................................................................................................37 
6.9.2 Clinical Laboratory Evaluations ........................................................................................37 
6.9.3 Vital Signs ..........................................................................................................................38 
6.9.4 Physical Examinations .......................................................................................................38 
6.9.5 Electrocardiograms ............................................................................................................38 
6.9.6 Cardiac Holter Monitoring and Cardiodynamic Assessment ............................................39 
6.9.7 Other Safety Measures .......................................................................................................40 
7 
ADVERSE EVENTS .........................................................................................................40 
7.1 
Definitions..........................................................................................................................40 
7.1.1 Adverse Event ....................................................................................................................40 
7.1.2 Serious Adverse Event .......................................................................................................40 
7.2 
Attribution/Causality..........................................................................................................41 
7.3 
Reporting............................................................................................................................44 
7.3.1 Adverse Event ....................................................................................................................44 
7.4 
Serious Adverse Event Reporting ......................................................................................44 
7.5 
Follow up of Adverse Events .............................................................................................45 
7.6 
Post-Trial Serious Adverse Events ....................................................................................46 
7.7 
Clinical Laboratory Adverse Events ..................................................................................46 
7.8 
Drug Interaction .................................................................................................................47 
7.9 
Pregnancy ...........................................................................................................................47 
7.10 
Monitoring and Safety for Specific Toxicities...................................................................47 
8 
GENERAL CONSIDERATIONS .....................................................................................47 
8.1 
Basic Principles ..................................................................................................................47 
8.2 
Institutional Review Board ................................................................................................48 
8.3 
Informed Consent...............................................................................................................48 
8.4 
Indications for Subject Withdrawal ...................................................................................48 
8.5 
Termination of the Study ...................................................................................................48 
8.6 
Documentation ...................................................................................................................48 
8.7 
Trial Monitoring.................................................................................................................49 
8.8 
Reimbursement, Indemnity, and Insurance .......................................................................49 
9 
PHARMACOKINETIC ANALYSIS ................................................................................49 
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9.1 
Analytical Methodology ....................................................................................................49 
9.2 
Pharmacokinetic Analysis ..................................................................................................49 
9.3 
Statistical Analysis .............................................................................................................51 
10 
FACILITIES ......................................................................................................................52 
11 
DRUG SUPPLIES .............................................................................................................53 
12 
ADMINISTRATIVE ISSUES ...........................................................................................53 
13 
EVENTS SCHEDULES ....................................................................................................54 
14 
REFERENCES ..................................................................................................................65 
APPENDIX 1 PHARMACOKINETIC SAMPLE COLLECTION, PROCESSING, AND 
SHIPMENT INSTRUCTIONS ......................................................................................................66 
APPENDIX 2 DESCRIPTION AND COMPOSITION OF TEST PRODUCT ...........................68 
APPENDIX 3 DIVISION OF MICROBIOLOGY AND INFECTIOUS DISEASE TOXICITY 
TABLE ...........................................................................................................................................70 
APPENDIX 4 HOLTER RECORDING AND ANALYSIS .........................................................78 
 
LIST OF TABLES 
 
Table 1 
Plasma Exposure to TBAJ-876 and Metabolites after the Third Dose at the NOAEL 
(30 mg/kg/day) and Comparison to Predicted Clinical Exposures ................................ 5 
Table 2 
Plasma Exposure to TBAJ-876 and Metabolites after the Last Dose at the 
Cardiovascular NOAEL (15 mg/kg/day) and Comparison to Predicted Clinical 
Exposures ....................................................................................................................... 6 
Table 3 
Plasma Exposure to TBAJ-876 and Metabolites after the 16th and Last Dose at the 
Nervous System NOAEL (60 mg/kg/day) ..................................................................... 6 
Table 4 
Plasma Exposure to TBAJ-876 and Metabolites after the 8th and Last Dose at the 
NOAEL (75 mg/kg/day) ................................................................................................. 7 
Table 5 Plasma Exposure to TBAJ-876 and Metabolites vs. BDQ and BDQ-M2 Following 4-
week Repeated Oral Administration to Mice ................................................................. 8 
Table 6 
Single Ascending Dose Cohorts, Part 1 ....................................................................... 16 
Table 7 
Identity of Investigational Products ............................................................................. 20 
Table 8 
Total Volume of Blood to be Collected for Testing: Part 1 ......................................... 34 
Table 9 
Total Volume of Blood to be Collected for Testing: Part 2 ......................................... 35 
Table 10 Total Volume of Blood to be Collected for Testing: Part 3 ......................................... 35 
Table 11 Acceptable Pharmacokinetic Sampling Time Windows, Part 1 and Part 3 ................. 36 
Table 12 Acceptable Pharmacokinetic Sampling Time Windows, Part 2 ................................... 36 
Table 13 Adverse Event Attribution/Causality Ratings .............................................................. 43 
Table 14 Definitions for Adverse Event Severity Gradings ........................................................ 43 
Table 15 Schedule of Assessments and Procedures, Part 1 SAD ................................................ 54 
Table 16 Schedule of Assessments and Procedures, Part 2 MAD .............................................. 58 
Table 17  Schedule of Assessments and Procedures, Part 3 BA .................................................. 61 
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LIST OF ABBREVIATIONS 
  
ADL 
activity of daily living 
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 
BDQ 
bedaquiline 
BMI 
body mass index 
BP 
blood pressure 
BUN 
blood urea nitrogen  
bpm 
beats per minute 
Ca 
calcium  
CFR 
Code of Federal Regulations 
CI 
confidence interval 
Cl- 
chloride  
Clast 
last quantifiable drug concentration 
CLIA 
Clinical Laboratory Improvement Amendments 
cm 
centimeter(s) 
Cmax 
maximum concentration 
CRF 
case report form 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
DARQ 
diarylquinoline 
dL 
deciliter 
ECG 
electrocardiogram 
EDTA 
ethylenediaminetetraacetic acid 
FDA 
Food and Drug Administration 
FIH 
first-in-human 
fl 
fluid 
FOB 
functional observational battery 
FSH 
follicle-stimulating hormone 
g 
gram(s) 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
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ICD 
informed consent document 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use  
IND 
Investigational New Drug 
IP 
Investigational Product 
IRB 
institutional review board 
ISF 
Investigator Site File  
IUD 
intrauterine device 
IV 
intravenous 
K+ 
potassium  
kg 
kilogram(s) 
L 
liter(s) 
lbs 
pounds 
LDH 
lactate dehydrogenase  
LOQ 
limit of quantitation  
m 
meter(s) 
MAD 
multiple ascending dose  
MAOI 
monoamine oxidase inhibitor 
max. 
maximum 
MDR TB 
multidrug-resistant tuberculosis  
mg 
milligram(s) 
MIC 
minimal inhibitory concentrations 
min. 
minute(s) 
mIU 
milli international units 
mL 
milliliter(s) 
mmHg 
millimeter of mercury 
msec 
millisecond 
Mtb 
Mycobacterium tuberculosis 
n or N 
number of occurrences 
Na+ 
sodium 
NOAEL 
no observed adverse event level 
ng 
nanogram(s) 
OTC 
over-the-counter 
oz 
ounce(s) 
rbc 
red blood cell  
rpm 
revolutions per minute 
SAD 
single ascending dose  
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SOP 
standard operating procedure 
TB 
tuberculosis 
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T½ or t½ 
terminal elimination half-life 
Tlag 
time prior to the first measurable (non-zero) concentration 
Tlast 
time of the last measurable concentration 
Tmax 
time to reach Cmax 
UDS 
urine drug screen 
Worldwide 
Worldwide Clinical Trials Early Phase Services, LLC 
Worldwide Clinical Trials Early Phase Services/Bioanalytical Sciences, LLC 
β-hCG  
beta-human chorionic gonadotropin 
λz or 
Lambda-z 
apparent elimination rate constant in terminal phase 
°C 
degrees Celsius/Centigrade 
 
 
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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 TBAJ-876 is 
summarized below from the Investigator’s Brochure.1 Unless noted otherwise, the 
information in this introduction was provided by TB Alliance. 
1.2 
Tuberculosis and Rationale for New Medication 
Current tuberculosis (TB) treatment regimens are lengthy in duration and involve 
multi-drug therapy. High rates of noncompliance are common, which often result in 
increased mortality and chronic, infectious, drug-resistant cases. The present TB 
epidemic and treatment conditions demonstrate the clear need for new TB drugs and 
drug regimens for patients with drug-sensitive or drug-resistant TB that are safe and 
well tolerated and will shorten the overall treatment duration required for cure. In 
addition, new TB drugs and regimens should be affordable, easy to adopt and 
implement, suitable for pediatric use and for co-administration with antiretroviral 
therapy in individuals co-infected with Mycobacterium tuberculosis (Mtb) and human 
immunodeficiency virus (HIV).  
Bedaquiline is a first-in-class diarylquinoline TB drug approved by the U.S. Food and 
Drug Administration (FDA) for use as part of a combination therapy in adults with 
pulmonary multidrug-resistant tuberculosis (MDR TB) when an effective treatment 
regimen cannot otherwise be provided. TBAJ-876 is a preclinical drug candidate from 
the TB Alliance’s efforts to develop a safer diarylquinoline (DARQ) with the potential 
to safely deliver superior efficacy to bedaquiline (BDQ), as part of novel TB treatment 
regimens. Current data suggest that TBAJ-876 could contribute to a new TB regimen 
with utility for both drug-sensitive and drug-resistant TB and could have significant 
advantages over BDQ. In particular, TBAJ-876 demonstrates a low risk of corrected 
QT (QTc) prolongation (whereas QTc prolongation is observed with BDQ), a higher 
predicted clearance than BDQ (greater suitability for daily dosing), and lower minimal 
inhibitory concentrations (MICs) against Mtb. In preclinical models of TB, TBAJ-876 
demonstrates superior efficacy as monotherapy and within regimens compared to BDQ 
given at the same dose. Taken together, these attributes may allow TBAJ-876 to safely 
deliver superior efficacy compared to BDQ.  
At this stage, only the early clinical studies have been designed in detail. However, the 
overall goal during early clinical development of TBAJ-876 will be to demonstrate that 
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TBAJ-876 is well tolerated and effective as a part of a treatment for TB. TBAJ-876 will 
be studied in a standard Phase 1 safety, tolerability and pharmacokinetic (PK) studies. 
This first-in-human (FIH) study is planned to be a randomized, combined single 
ascending dose (SAD) study with a food-effect cohort (Part 1) and multiple ascending 
dose (MAD) study (Part 2). In addition, a Part 3 will be included that is an open-label 
study to determine the relative bioavailability (BA) of two strengths of TBAJ-
876tablets.  
1.3 
Preclinical Studies and Toxicity Studies 
In primary pharmacology studies, TBAJ-876 had clear and potent anti-mycobacterial 
activity in vitro and in animal models; therefore, it is a good candidate for clinical 
investigation. 
Secondary and safety pharmacology studies suggest that, at the dose levels proposed 
for evaluation in human subjects, TBAJ-876 is unlikely to produce adverse effects due 
to off target pharmacologic activity or to adversely affect the function of important 
organ systems. 
Repeat-dose toxicity studies have identified safe TBAJ-876 dose levels, as well as 
systemic exposures for TBAJ-876 and several of its metabolites, that are safe. This 
information was used to select a safe starting dose for the first clinical trial. The repeat-
dose toxicity studies also have characterized the toxicity profile of TBAJ-876 in rats 
and dogs. This information has been used to identify potential adverse effects in human 
subjects and inform the dose-escalation schedule and clinical safety monitoring plan. 
In rats dosed for 13 weeks, the dose-limiting toxicities were diarrhea and skeletal 
muscle damage. Microscopically, skeletal muscle fiber degeneration/necrosis was 
present in multiple muscles of about 1/3rd of the rats after 13 weeks at 25 mg/kg/day or 
after up to 16 days at 60 mg/kg/day but in no rat after 13 weeks at 10 mg/kg/day. 
Muscle damage was accompanied by changes in several clinical chemistry biomarkers; 
e.g., by very high serum CK, AST, and ALT activities and high serum potassium and 
phosphorus concentrations. Muscle damage was reversible, as it was absent after a 10- 
or 13-week recovery period.   
In dogs dosed for 13 weeks, no dose-limiting toxicity was seen, but cardiac muscle 
damage was present microscopically (as cardiac muscle fiber necrosis/infiltrate) in all 
but one dog at 15 mg/kg/day but in no dogs at ≤7.5 mg/kg/day. While this can be an 
incidental background finding in dogs, the high incidence of this finding at 
15 mg/kg/day was considered to be related to TBAJ-876, in part because the finding 
was accompanied by an increase in serum troponin I concentration. Cardiac muscle 
damage was reversible, as it was absent after a 13-week recovery period. 
Various other TBAJ-876-related findings were seen in one of both species. These 
included: 
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• Microscopic findings in the glandular mucosa of the stomach in both species,  
• Effects on intestinal function (diarrhea) in both species,  
• Effects on the liver in both species,  
• Decreased hematopoiesis in dogs,  
• Effects on the incisors in rats, 
• Effects on the lacrimal glands in rats, 
• Increased serum amylase concentration in dogs.   
In the glandular stomach, hyperplasia was seen in several rats after 13 weeks at 
25 mg/kg/day or after two weeks at 60 mg/kg/day. This finding was reversible, as it 
was absent after a 10- or 13-week recovery period. Degeneration/necrosis was seen in 
two rats after 13 weeks at 25 mg/kg/day and several rats after two weeks at 
60 mg/kg/day. At the end of the recovery period, degeneration/necrosis also was 
present in two rats that had been given TBAJ-876 for 13 weeks at 25 mg/kg/day. 
Finally, erosion of the pyloric mucosa in one rat after 13 weeks at 25 mg/kg/day.  
In dogs, minimal to moderate degeneration/atrophy of the fundic glands in the stomach 
was seen in a pilot study after 2 weeks at 15 or 45 mg/kg/day. This was characterized 
by loss of chief cells with overall atrophy of glands, dilated glands with attenuated 
epithelium, and occasional glands with luminal cell debris. When minimal, the primary 
alteration was individual cell necrosis of chief cells with infrequent, minimally dilated 
glands. The grade of fundic gland degeneration/atrophy increased with dose level. 
Stomach findings were not seen in 8 dogs given daily oral doses of TBAJ-876 for 
13 weeks at 15 mg/kg (the highest dose level tested). One possible explanation is that 
the 2-week study used TBAJ-876 free base, while the 13-week study used TBAJ-876 
tartrate. It may be that the presence of the tartrate di-anion protected the fundic mucosa 
against damage. In any event, the clinical drug product will be made with TBAJ-876 
tartrate, which produced no stomach findings in dogs dosed daily for 13 weeks. 
Diarrhea was seen in rats given two doses of TBAJ-876, approximately 24 hours apart, 
at ≥ 500 mg/kg in a micronucleus study and also during the second week of dosing at 
60 mg/kg/day in the 13-week study. At 60 mg/kg/day, diarrhea was accompanied by 
anogenital staining and dehydration, and contributed to the decision to stop dosing early 
at this dose level. Diarrhea resolved when dosing stopped. In dogs in the 13-week 
study, the frequency of discolored, mucoid or with mucous, watery, and/or soft feces 
was greater at 15 mg/kg/day than in the control group, but this difference was not 
clearly related to TBAJ-876. 
Effects on the liver in rats were limited to single-cell vacuolar degeneration or necrosis 
of hepatocytes and/or vacuolation of periportal hepatocytes in a few females after 
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16 days at 60 mg/kg/day. This finding resolved when dosing stopped, although at the 
end of the recovery phase, single cell necrosis was present in one male that had been 
given TBAJ-876 for 16 days at 60 mg/kg/day. In dogs dosed for 13 weeks, 
hepatocellular vacuolation with greater mean liver weight and lower mean serum 
triglycerides concentration was present at all dose levels. At the lowest dose level 
(25 mg/kg/day), these findings were not considered adverse because they were not 
associated with clinical pathologic or microscopic evidence of hepatocellular 
degeneration or necrosis. At ≥7.5 mg/kg/day, mean serum ALT activity was increased 
after 4 and 13 weeks of dosing, but there still was no microscopic evidence of 
hepatocellular injury.   
Evidence of decreased hematopoiesis was seen in dogs dosed for 13 weeks, where the 
incidence and average grade of decreased cellularity in sternal bone marrow was 
greater at 15 mg/kg/day. This microscopic finding was not associated with any changes 
in peripheral blood cell counts and was absent after a 13-week recovery period. 
In female dogs, mean serum amylase concentration was slightly greater after 4 and 
13 weeks of dosing at 15 mg/kg/day, without associated microscopic findings in the 
pancreas. 
Two findings related to TBAJ-876 were seen only in rats and are of questionable 
relevance for humans: 
• Degeneration/necrosis of ameloblasts was present in the incisors of rats dosed for 
13 weeks. At 25 mg/kg/day, four rats also had acute inflammation in the nasal 
cavity (near tooth root), one rat also had pulp cavity necrosis, another had moderate 
periodontal inflammation, and a third had mild acute gingivitis. These dental 
findings were reversible, as they were absent at the end of the 13-week recovery 
period. While the effects on incisors were clearly adverse in rats, it is unclear if 
these findings are relevant for human subjects, because the incisors of rats grow 
continuously throughout life, unlike human teeth. The teeth were not examined 
microscopically in dogs dosed for 13 weeks; however, there was no clinical 
evidence of an effect on teeth, nor were there any findings involving the teeth or 
oral cavity at necropsy. 
• In the lacrimal glands of rats dosed for 13 weeks, the average grade of acinar cell 
alteration (characterized by histologic characteristics of Harderian gland) was 
greater at all dose levels. After 13 weeks at 25 mg/kg/day, a few rats also had 
lacrimal gland atrophy. The differences in grade showed evidence of reversing 
when dosing stopped. Acinar cell alteration is a rodent-specific finding, and so it is 
unclear if an increase in this finding implies a risk for human subjects. There were 
no effects on lacrimal glands in dogs dosed for 13 weeks. 
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1.4 
Safety Pharmacology  
Cardiovascular Function 
In surgically instrumented dogs given repeated doses of TBAJ-876 for 12 days at 
escalating dose levels up to 30 mg/kg/day, there was no effect on blood pressure, heart 
rate, PR or QT interval duration, QRS complex duration, or qualitative aspects of the 
electrocardiogram (ECG).  There were slight decreases in QTc interval duration at 
30 mg/kg/day, but these appeared to be driven by slight increases in body temperature 
and were not large enough to be considered adverse; therefore, the no observed adverse 
event level (NOAEL) for effects on cardiovascular function was 30 mg/kg/day. Plasma 
exposure to TBAJ-876 and its M2 and M3 metabolites after the third dose at the 
NOAEL are summarized in Table 1. 
Table 1 
Plasma Exposure to TBAJ-876 and Metabolites after the Third Dose at the 
NOAEL (30 mg/kg/day) and Comparison to Predicted Clinical Exposures 
Analyte 
Cmax  
(µg/mL) 
Fold over clinical 
AUC0-23.5h  
(hr*µg/mL) 
Fold over clinical 
TBAJ-876 
2.32 
21*/3** 
26.9 
13*/3* 
TBAJ-876-M2 
0.16 
ND 
3.4 
ND 
TBAJ-876-M3 
1.64 
27*/16** 
33.5 
26*/16** 
*Predicted clinical exposures following daily dosing at 25 mg, estimated to be similar efficacy compared to 
BDQ: steady state Cmax (Day 28) for TBAJ-876 and TBAJ-876-M3 of 0.11 and 0.06 µg/mL, respectively; 
and AUC0-24h = 2.1 and 1.3 µg.hr/mL, respectively. 
**Predicted clinical exposures of the highest proposed single clinical dose of 400 mg: Cmax (Day 1) for 
TBAJ-876 and TBAJ-876-M3 of 0.688 and 0.104 µg/mL, respectively; and AUC0-24h = 10.4 and 
2.08 µg.hr/mL, respectively.  
In a 13-week general toxicology study in dogs, oral administration of TBAJ-876 
tartrate at doses of 2.5, 7.5, and 15 mg/kg/day did not have any adverse effects on ECG 
rhythm, morphology, or quantitative measurements; therefore, the 13-week NOAEL for 
effects on cardiovascular function was 30 mg/kg/day. Plasma exposure to TBAJ-876 
and its M2 and M3 metabolites after the last dose at the cardiovascular NOAEL are 
summarized in Table 2.  
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Table 2 
Plasma Exposure to TBAJ-876 and Metabolites after the Last Dose at the 
Cardiovascular NOAEL (15 mg/kg/day) and Comparison to Predicted Clinical 
Exposures 
Analyte 
Cmax 
(µg/mL) 
Fold over clinical 
AUC0-24hr 
(hr*µg/mL) 
Fold over clinical 
TBAJ-876 
1.7 
15*/2.5** 
25.0 
12*/2* 
TBAJ-876-M2 
0.7 
ND 
15.2 
ND 
TBAJ-876-M3 
4.7 
84*/45** 
102.5 
79*/149** 
*Predicted clinical exposures following daily dosing at 25mg, estimated to be similar efficacy compared to BDQ: 
steady state Cmax (Day 28) for TBAJ-876 and TBAJ-876-M3 of 0.11 and 0.06 µg/mL, respectively; and AUC0-24h 
= 2.1 and 1.3 µg.hr/mL, respectively. 
**Predicted clinical exposures of the highest proposed single clinical dose of 400 mg: Cmax (Day 1) for TBAJ-876 
and TBAJ-876-M3 of 0.688 and 0.104 µg/mL, respectively; and AUC0-24h = 10.4 and 2.08 µg.hr/mL, 
respectively. 
Nervous System Function 
As part of the 13-week general toxicology study in which rats were given daily oral 
doses of TBAJ-876, functional observational battery (FOB) testing was conducted on 
10 rats/sex at approximately 8 hours after the 13th dose. Rats tolerated daily oral doses 
of TBAJ-876 for 13 weeks at 10 or 25 mg/kg but not at 60 mg/kg, where dosing was 
stopped after 16 days due to toxicity. There were no differences between control and 
treated rats in FOB test results; therefore, 2-week NOAEL for effects on nervous 
system function was 60 mg/kg/day. Plasma exposure to TBAJ-876 and its M2 and M3 
metabolites after the last dose at the nervous system NOAEL are summarized in Table 
3. 
Table 3 
Plasma Exposure to TBAJ-876 and Metabolites after the 16th and Last Dose at 
the Nervous System NOAEL (60 mg/kg/day) 
Analyte 
Cmax (µg/mL) 
Fold over clinical 
AUC0-24hr 
(hr*µg/mL) 
Fold over clinical 
TBAJ-876 
4.1 
37*/6** 
64.6 
31*/6* 
TBAJ-876-M2 
0.4 
ND 
6.3 
ND 
TBAJ-876-M3 
2.2 
39*/21** 
47.5 
37*/23** 
*Predicted clinical exposures following daily dosing at 25mg, estimated to be similar efficacy compared to BDQ: 
steady state Cmax (Day 28) for TBAJ-876 and TBAJ-876-M3 of 0.11 and 0.06 µg/mL, respectively; and AUC0-24h 
= 2.1 and 1.3 µg.hr/mL, respectively. 
**Predicted clinical exposures of the highest proposed single clinical dose of 400 mg: Cmax (Day 1) for TBAJ-876 
and TBAJ-876-M3 of 0.688 and 0.104 µg/mL, respectively; and AUC0-24h = 10.4 and 2.08 µg.hr/mL, 
respectively. 
 
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Respiratory Function 
In rats given daily oral doses of TBAJ-876 for 7 days at 10, 30, or 75 mg/kg and 
evaluated by plethysmography, there was no effect on respiratory function at 
≤30 mg/kg/day. At 75 mg/kg/day, TBAJ-876 resulted in slight, recoverable, increases 
in respiratory rate and tidal volume (and therefore in minute volume), which were 
smaller after the 7th dose than after the first dose and had resolved completely within 4 
days after the last dose. These effects on respiratory function were too slight to be 
considered adverse; therefore, the 7-day NOAEL for effects on respiratory function was 
75 mg/kg/day. Plasma exposure to TBAJ-876 and its M2 and M3 metabolites after the 
8th and last dose at the respiratory NOAEL are summarized in Table 4. 
Table 4 
Plasma Exposure to TBAJ-876 and Metabolites after the 8th and Last Dose at 
the NOAEL (75 mg/kg/day) 
Analyte 
Cmax 
(µg/mL) 
Fold over 
clinical 
AUC0-24hr 
(hr*µg/mL) 
Fold over 
clinical 
AUC0-96hr 
(hr*µg/mL) 
TBAJ-876 
6.16 
56*/9** 
92.10 
44*/9** 
123.00 
TBAJ-876-M2 
0.04 
ND 
0.69 
ND 
0.91 
TBAJ-876-M3 
0.87 
16*/8** 
16.20 
13*/8** 
24.90 
*Predicted clinical exposures following daily dosing at 25mg, estimated to be similar efficacy compared to 
BDQ: steady state Cmax (Day 28) for TBAJ-876 and TBAJ-876-M3 of 0.11 and 0.06 µg/mL, respectively; and 
AUC0-24h = 2.1 and 1.3 µg.hr/mL, respectively. 
**Predicted clinical exposures of the highest proposed single clinical dose of 400 mg: Cmax (Day 1) for TBAJ-
876 and TBAJ-876-M3 of 0.688 and 0.104 µg/mL, respectively; and AUC0-24h = 10.4 and 2.08 µg.hr/mL, 
respectively. 
 
1.5 
Pharmacokinetics and Product Metabolism in Animals  
Absorption 
Following intravenous (IV) administration, TBAJ-876 exhibited low clearance and a 
large volume of distribution (≥9.45 L/kg). The plasma disposition of TBAJ-876 in 
nonclinical species was multiexponential and due to differences in PK sampling 
schedule, estimates of terminal half-life (t1/2) of TBAJ-876 varied widely, ranging from 
5 to 12 hr (sampling out to 24 hr postdose) to 26 to 77 hr (sampling out to 96 hr 
postdose). 
TBAJ-876 free base had good oral bioavailability ranging from 36% to 44% in rodents, 
28% to 80% in dogs, and 19% to 24% in monkeys, despite low permeability in the 
Caco-2 cell monolayer. Based on the efflux ratio of 0.2 in Caco-2 cells, TBAJ-876 was 
not a substrate of efflux pumps. 
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When TBAJ-876 was orally administered as tartrate salt to nonclinical species in the 
fasted state, Cmax increased 40% to 70% and AUC0-t increased 39% to 59% in rats and 
dogs, whereas in monkeys Cmax and AUC0-t decreased 43% and 49%, respectively. 
The in vivo exposure to two active metabolites, TBAJ-876-M2 and TBAJ-876-M3, was 
quantified in the PK and toxicokinetic (TK) studies. At the NOAELs in the 13-week 
toxicology studies in the rat and dog, the steady state AUC of TBAJ-876-M3 was 0.6x 
and 1.8x of parent AUC, respectively, while TBAJ-876-M2 was present at lower 
concentrations with AUC representing 0.2 x of parent AUC in both species. There was 
no marked sex-related difference in the systemic exposure to TBAJ-876, TBAJ-876-
M3, or TBAJ-876-M2 in rats and dogs. 
In mice following the last dose of 4-week dosing at 3.125 mg/kg, steady state plasma 
exposure to TBAJ-876 and metabolites was approximately 0.4x of that of BDQ and 
metabolite at 25 mg/kg. After 6 weeks dosing in a mouse model of chronic TB, 3.125 
mg/kg TBAJ-876 showed superior efficacy to 25 mg/kg BDQ indicative of TBAJ-876 
being more potent than BDQ (Table 5). TBAJ-876-M3, TBAJ-876-M2, and BDQ-M2 
AUC0-24 was 5x of parent AUC0-24h. 
 
Table 5 
Plasma Exposure to TBAJ-876 and Metabolites vs. BDQ and BDQ-M2 
Following 4-week Repeated Oral Administration to Mice 
Dose 
Cmax 
AUC0-24h 
Analyte 
(µg/mL) 
(hr*µg/mL) 
3.125 mg/kg/day TBAJ-876 
 
 
TBAJ-876 
0.47 
4.1 
TBAJ-876-M2 
0.93 
20.2 
TBAJ-876-M3 
1.0 
22.1 
25 mg/kg/day BDQ 
 
 
BDQ 
1.9 
10.6 
BDQ-M2 
2.8 
57.2 
 
Distribution  
TBAJ-876 and its metabolite TBAJ-876-M3 were not significantly distributed to red 
blood cells. TBAJ-876 and TBAJ-876-M3 were highly protein-bound in mouse, rat, 
dog, monkey, and human plasma (≥99.8%) and exhibited a species-independent protein 
binding. At steady state, high concentrations of TBAJ-876 and TBAJ-876-M3 were 
observed in the mouse lung at 2 hr and 24 hr postdose with the lung to plasma 
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concentration ratio for TBAJ-876 and TBAJ-876-M3 in the range of 5 to 7 and 12 to 
20, respectively. 
Metabolism 
TBAJ-876 and TBAJ-876-M3 were relatively stable metabolically with TBAJ-876 
showing a half-life of >240 min in rat, dog, and human liver microsomes and a half-life 
of 114 and 31 min in monkey and mouse liver microsomes, respectively, and TBAJ-
876-M3 showing a half-life of >240 min in mouse, rat, dog, monkey, and human liver 
microsomes. The in vitro metabolic stability result is consistent with low in vivo 
clearance observed. TBAJ-876 was mainly metabolized by recombinant human 
CYP3A4 followed by CYP2A6, while both CYP3A4 and CYP2A6 play an equal role 
in the metabolism of TBAJ-876-M3. 
In vitro metabolic profile in liver microsomes from nonclinical species and human 
concluded that TBAJ-876-M3 was the major metabolite and there were no human 
unique metabolites. 
TBAJ-876 showed no or limited inhibition to CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 
2D6 and 3A4 activities in human liver microsomes with IC50 >50 µM. TBAJ-876-M3 
at 30 µM (i.e., nearly 90x the projected TBAJ-876-M3 Cmax,ss in humans at the 
potentially supra-therapeutic TBAJ-876 dose of 100 mg) caused a maximum 78% 
inhibition of CYP2C19 activity in human liver microsomes. Therefore, it can be 
concluded that the risk for TBAJ-876 and TBAJ-9876-M3 to cause PK drug 
interactions in humans by inhibition of the major drug metabolizing enzymes is low. 
The major metabolite TBAJ-876-M3 did not active AhR, CAR, or PXR nuclear 
receptors in vitro. However, TBAJ-876 at 1 µM (i.e., 6 x the projected TBAJ-876 
Cmax,ss in humans at the potentially therapeutic dose of 25 mg) induced CYP3A4 
mRNA in one of three lots of human hepatocytes tested. The relevance of this finding 
to the potential for induction in humans will be addressed during an initial clinical 
development for TBAJ-876.    
In vitro transporter inhibition studies showed that TBAJ-876 at 1 µM did not cause 
notable inhibition of OAT1, OAT3, OCT2, OATP1B1, OATP1B3, MATE1, or 
MATE2-K. The IC50 for BCRP cannot be determined due to insufficient inhibition over 
a concentration range of 0.5 to 30 µM. The IC50 for P-gp was determined to be 5.08 µM 
based on nominal concentrations, equivalent to approximately 2.30 µM after taking into 
account the non-specific binding. Cautions will be exercised in subjects who are 
enrolled in the clinical programs for TBAJ-876 and requiring concomitant medication 
with digoxin. 
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1.6 
Potential Adverse Effects in Human Subjects 
Based on the nonclinical safety studies, human subjects should be monitored for the 
following potential effects:   
• Myocardial damage (seen in dogs) by way of clinical chemistry biomarkers  
• Skeletal muscle myopathy (seen in rats) by way of clinical chemistry biomarkers 
and clinical signs of muscle pain or weakness 
• Damage to the stomach mucosa (seen in both species) by way of clinical signs of 
nausea, vomiting, or dyspepsia 
• Diarrhea (seen in both species) 
• Liver injury, both hepatocellular and biliary (seen in both species) by way of 
clinical chemistry biomarkers 
• Effects on hematopoiesis (seen in dogs) by way of hematology analyses 
• Effects on the pancreas (seen in dogs) by way of clinical chemistry biomarkers 
In animals, all of these effects were reversible when dosing stopped, and they are 
expected to be so in humans, too, if they occur. 
No studies have been done to evaluate the potential effects of TBAJ-876 reproductive 
function in male animals. The following side effects were noted in adult 
subjects/patients in studies of a similar drug in this class (bedaquiline - marketed as 
SirturoTM): nausea, tiredness, headache, vomiting, dizziness, diarrhea, liver injury, heart 
problems; prolongation of QTc interval, and pancreas injury. 2  
Clinical Safety Evaluation (Single Ascending Dose) 
In the SAD part of TBAJ-876 CL-001, 47 healthy volunteers aged 20 to 50 years were 
dosed with a single dose of TBAJ-876 or placebo and followed up to Week 4 (Cohorts 
1 through 3) or up to Week 10 (Cohorts 4 through 6) after dosing . Each cohort enrolled 
8 subjects (6 randomized to active treatment and 2 to placebo), except for Cohort 4, 
which enrolled only 7 subjects. Review of the blinded safety data showed that 
TBAJ-876 was generally safe and well tolerated at doses between 10 mg and 400 mg. 
There were no serious or severe AEs. Most of the AEs were mild and all resolved. 
AEs of interest, based on preclinical findings, included myocardial damage, skeletal 
muscle injury, gastrointestinal irritation, elevated pancreatic enzymes, elevated liver 
enzymes, and cytopenia. 
1) There were 3 subjects with elevated lipase (1 in the 10 mg cohort, and 2 in the 50 
mg cohort) and 1 with elevated amylase (50 mg), who also had an elevated lipase. 
These laboratory abnormalities were not associated with any symptoms and 
resolved completely. 
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2) Two subjects with elevated liver enzymes (10 mg). These laboratory abnormalities 
were not associated with any symptoms and resolved completely.  
3) One subject in the 25 mg cohort experienced rhabdomyolysis 9 days after dosing, 
deemed related to physical exertion and not to study drug.  
4) Treatment with TBAJ-876 at single doses between 10 mg and 400 mg was not 
associated with evidence of QT prolongation or myocardial damage. One subject 
in Cohort 6 (400 mg) had an episode of non-sustained ventricular tachycardia 
observed in the Holter extraction on Study Day 1, approximately 5 hours after 
dosing. Upon questioning, the subject reported a few seconds of “more prominent 
heartbeat” at the same time. There were no symptoms of chest pain, syncope, or 
palpitations, and her physical examination and vital signs were normal. No QT 
prolongation was observed on the Holter or in subsequent ECGs. This event was 
reported as “possibly related”. Another subject in Cohort 6 had a mildly elevated 
troponin I on Day 21, with a value of 0.038 ng/mL, confirmed at 0.034 ng/mL 
(ULN 0.028 ng/mL). The subject was completely asymptomatic, and her physical 
examination, vital signs, and ECG were normal. On the same day of the troponin I 
elevation, her CPK and CPK-Mb were also normal. The subject returned to the 
clinic on Study Day 23, and her troponin I levels were within the normal range. 
The finding of elevated troponin I on Study Day 21 was deemed by the primary 
investigator to be “spurious”. 
Based on a review of the blinded data from the SAD part of the study, there was no 
evidence of myocardial, skeletal muscle, gastrointestinal, hepatic, or hematological 
toxicity associated with single doses of TBAJ-876 between 10 mg and 400 mg. There 
were no clinically significant changes from baseline in vital signs and ECG's including 
no prolongation of QTc's.  
While there were a few subjects with mild to moderate elevations in amylase and/or 
lipase, these abnormalities did not appear to be dose-dependent, were not associated 
with any symptomatology, and resolved rapidly without therapeutic interventions. The 
potential adverse effects of TBAJ-876 in human subjects will be further investigated in 
the MAD part of the study, where subjects will receive treatment with multiple 
ascending doses of the drug for 14 consecutive days. 
1.7 
Rationale for Dose Selection (MAD) 
A mathematical model for the PK of TBAJ-876 and its M3 metabolite was developed 
using data from the single-ascending-dose component of the study under fasting 
conditions. The food-effect component of the study was used to estimate the 
relationship between dosing under fed and fasted conditions. These two inputs were 
used to predict the time course of the daily 24-hour AUCs of TBAJ-876 and M3 with 
dosing under fed conditions for 14 days. These AUCs were predicted to increase 
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through 14 days of dosing. The maximum predicted values on the 14th day were 
compared with safety thresholds determined from the three-month toxicity study in 
dogs where cardiotoxicity was observed. Exposure for the planned dose of 25 mg for 
the first cohort was predicted to remain below those thresholds.   
Upon review of the MAD Cohort 1 (25 mg) PK and safety, the 50 mg dose planned for 
Cohort 2 was changed to 75 mg. This decision was made based on the safety of the 25 
mg dose which was shown to be safe and well tolerated without evidence of cardiac, 
muscle skeletal, gastrointestinal, hepatic, or hematological toxicity, and because the 
total exposure of TBAJ-876 plus M3 at the dose of 75 mg was predicted to still remain 
below thresholds determined by the corresponding sum in the three-month toxicity 
study in dogs. 
 
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2 
OBJECTIVE 
The primary objective of the study is: 
• 
To evaluate the safety and tolerability of single and multiple ascending doses of 
TBAJ-876 oral suspension, and single doses of two strengths of TBAJ-876 tablets 
in healthy subjects. 
The secondary objectives of the study are: 
• 
To determine the pharmacokinetics (PK) of TBAJ-876 and its metabolites (M2 
and M3) after single and multiple doses of TBAJ-876 oral suspension, and single 
doses of two strengths of TBAJ-876 tablets in healthy adult subjects. 
• 
To compare the rate and extent of absorption of a single oral dose of TBAJ-876 
oral suspension and two strengths of TBAJ-876 tablets when administered after a 
high-calorie, high-fat meal versus when it is administered fasting in healthy adult 
subjects. 
• To compare the rate and extent of absorption of the 4 x 25 mg tablets and the 1 x 
100 mg tablet under fasted conditions.  
• To compare the rate and extent of absorption of a single oral dose of 100 mg of 
the TBAJ-876 oral suspension and two strengths of TBAJ-876 tablets under fed 
and/or fasted conditions. 
3 
STUDY DESIGN SUMMARY 
This study is a three-part, partially blinded, placebo controlled, combined single 
ascending dose (SAD) with food-effect, multiple ascending dose (MAD) study, and a 
single dose relative bioavailability (BA) study conducted in one study center in the 
United States.  
Safety will be assessed throughout the study for all subjects. Safety assessments will 
include physical examinations, vital signs, serial ECGs, cardiac monitoring, adverse 
events (AEs), and clinical laboratory tests (including hematology, serum chemistry, 
coagulation, and urinalysis).  
Part 1:  
Part 1 is a SAD design with 6 planned dose levels. Additional cohorts may be enrolled 
if deemed appropriate by the Sponsor to repeat a dose level or study another dose level. 
Interim PK analyses and safety assessments will be performed for the dose escalation 
decisions and to select the dose level at which to assess the food-effect. The food-effect 
cohort is planned with two parallel groups, one fasting and the other fed.  
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Current duration and scheduling of safety and PK sampling assumes that the terminal 
half-life (T1/2) will be approximately 7 days. The number and timing of PK sampling 
and safety assessments may be further revised based on evolving PK and safety 
information. 
Subjects will be housed in the clinic from at least 24 hours prior (from Day -1), until 
7 days after dosing (Day 8).  
Subjects from Dose Level 1 will return to the clinic to have subsequent follow up safety 
(collection of AEs) and PK assessments on Days 10, 14, 17, 21, and 28.  
Food-Effect: Based on exposure levels from the first 4 completed cohorts, the 100 mg 
dose was chosen for the food-effect cohort. In this food-effect cohort, there will be two 
parallel groups, one fasting and the other fed. The fed group will enroll at least 10 
subjects and the fasted group will include data from 6 subjects who completed Cohort 4 
and at least 3 additional subjects who will be enrolled in the fasted group. All subjects 
in the food-effect cohort will receive active drug of TBAJ-876, 100 mg. 
Note: PK sampling for making a decision on escalating to the next dose will be through 
the morning trough sample of Day 8, and a dose escalation meeting will take place 
around Day 15 when interim PK data is available from the bioanalytical lab. Therefore, 
the dose escalation meeting and decision will be based on PK through the morning of 
Day 8 and approximately 14 days of safety data, depending on the turnaround time of 
the bioanalysis. Subjects will continue to be monitored for PK and safety up to 10 
weeks or longer after the dose. The duration of the follow-up period will be based on 
the analysis of interim PK data. Available subjects from Cohorts 4 and 5, and all 
subjects in Cohort 6 will be asked to return bi-weekly (+/- 2 days) up to 10 weeks or 
longer postdose. Subjects will complete the same procedures as required for Day 28 at 
each visit. 
Interim PK analyses and safety assessments will be performed for the dose escalation 
decisions and to select the dose for the food-effect assessment, and to reconsider, if 
needed, the PK sampling time points as the study progresses. All samples will be sent 
for analysis on active treatment, and only the bioanalytical lab will be unblinded and 
will only run the analysis on active treatment subjects. Data from the analysis used for 
the escalation meetings will only include active treatment subjects and will be blinded 
by subject. 
Dose escalation to the next cohort (i.e., dose level) or any changes to PK sampling and 
safety assessment timepoints will not take place until the Sponsor, in conjunction with 
the Principal Investigator and Dose Escalation Committee, has determined that 
adequate safety, tolerability and PK from the previous cohort have been demonstrated 
to permit proceeding to the next cohort.  
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Additional cohort, Cohort 7: Eight (8) subjects will be enrolled, 6 to receive active drug 
and 2 to receive placebo. Subjects will receive a single dose under fasted conditions. 
Subjects will receive 800 mg TBAJ-876 or matching dose of placebo for TBAJ-876 
Oral Suspension. 
Subjects will follow the procedures in the Schedule of Assessments (Table 15) with the 
following clarifications: 
Subjects will check-in to the clinic on Day -1 and be confined through Day 8. 
Subjects will be discharged from the clinic on Day 8. Subjects will return for one 
follow-up visit on Day 14 for PK and safety. Subjects will receive a follow-up 
phone call on Day 21. Subjects will complete the procedures specified for those 
study days only. All ECGs performed in Cohort 7 will be triplicate ECGs at each 
time point. 
In addition, subjects will have triplicate ECGs at 16 hours postdose. 
Additional cohorts may be enrolled if deemed appropriate by the Sponsor to repeat a 
dose level, to study another dose level, or to increase cohort size (subject numbers). 
The number and timing of PK sampling and safety assessments may be further revised 
based on what is learned based on evolving data PK information. 
These decisions concerning additional cohorts will not take place until the Sponsor, in 
conjunction with the Principal Investigator, has determined that adequate safety, 
tolerability, and PK from the previous cohorts have been demonstrated. The 
Institutional Review Board (IRB) should be immediately notified of this revised 
approach. 
During each cohort, blood samples will be obtained before each dose of study drug, and 
at serial timepoints postdose on Days 1-8, 10, 14, 17, 21, and 28. Plasma PK samples 
will be analyzed for TBAJ-876, M2, and M3 using validated analytical methods. 
Appropriate PK parameters will be calculated using non-compartmental methods. 
In addition, blood and urine will be collected for clinical laboratory evaluations. 
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. 
Table 6 presents the planned 6 dose cohorts and the additional Cohort 7 for Part 1 of 
the study. 
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Table 6 Single Ascending Dose Cohorts, Part 1 
Cohort (Dose Level)a 
Dosec 
1 (sentinel group)b 
Single dose of 10 mg TBAJ-876 (n=2) 
Placebo (n=1) 
1 (remainder of cohort)b 
Single dose of 10 mg TBAJ-876 (n=4) 
Placebo (n=1) 
2 
Single dose of 25 mg TBAJ-876 (n=6)  
Placebo (n=2) 
3 
Single dose of 50 mg TBAJ-876 (n=6) 
Placebo (n=2) 
4 
Single dose of 100 mg TBAJ-876 (n=6) 
Placebo (n=2) 
5 
Single dose of 200 mg TBAJ-876 (n=6) 
Placebo (n=2) 
6 
Single dose of 400 mg TBAJ-876) (n=6) 
Placebo (n=2) 
7 
Single dose of 800 mg TBAJ-876 (n=6) 
Placebo (n=2) 
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 sentinel cohort and remainder to occur at least 24 hours apart. 
c. 
Subjects will be dosed at all dose levels under fasted conditions except for the fed group of the food-effect 
cohort. Based upon the exposure levels and PK results, the dose level of Cohort 4 (100 mg) will be used in 
the food-effect cohort. There will be two parallel groups, one fasting and the other fed. The fed group will 
enroll at least 10 subjects and the fasted group will include data from 6 subjects who completed Cohort 4 
and 3 additional subjects who will be enrolled in the fasted group. All subjects in the food-effect cohort will 
receive active drug of TBAJ-876, 100 mg.  
At the end of Part 1, PK and safety data along with reasons for choosing the doses for 
the next part (Part 2) will be sent to the appropriate regulatory authorities and the IRB 
for review and approval. The study will not proceed to Part 2 until the above parties 
have provided approval. 
Part 2:  
The decisions for the study to progress to the planned MAD cohorts (Part 2) will take 
place when the Sponsor, in conjunction with the Principal Investigator and the Dose 
Escalation Committee, has determined that adequate safety, tolerability, and PK from 
the previous cohorts (Part 1) have been demonstrated to permit proceeding. 
For Part 2, MAD design, the dose level of the first cohort will be determined based on 
model predictions of multiple-dose PK behavior, and safety from Part 1. The dose for 
the second cohort will then be informed by safety and PK results from the first cohort 
(see Section 1.7). At the time of this writing, it is expected that the dose of the third 
cohort will be informed by the results from the first two.  
In this multiple ascending dose part, each subject is expected to receive TBAJ-876 or 
matching placebo for 14 days in the fed state with corresponding PK and safety 
measurements. 
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Three dose cohorts are planned. After Cohort 1 and 2, the Sponsor and Principal 
Investigator will review the PK and safety data before proceeding to the next dose 
level. 
Note: PK sampling for deciding to escalate to the next dose will be through the 
morning of Day 15, i.e., will include the profile on Day 14, and the dose escalation 
meeting will take place around Day 28 when interim PK data is available from the 
bioanalysis lab. Therefore, the dose escalation meeting and decision will be based on 
PK through the morning of Day 15 and approximately 28 days of safety data, 
depending on the turnaround time of the bioanalysis.    
Subjects will continue to be dosed up to 14 days and be monitored for safety at 
timepoints indicated in the schedule of assessments (Table 16). After the last dose, 
subjects will remain in the clinic for 7 additional days and will then enter an additional 
follow-up period of 15 weeks or longer, if indicated by interim PK analyses. 
During each cohort, blood samples will be obtained before each dose of study drug, and 
at serial timepoints postdose on Days 1 and 14. Samples will be taken according to the 
schedule provided in Table 16, with the last sample being obtained on Day 126, or 
possibly later if a decision is made to extend monitoring. Plasma PK samples will be 
analyzed for TBAJ-876, M2, and M3 using validated analytical methods. Appropriate 
PK parameters will be calculated using non-compartmental methods. In addition, blood 
and urine will be collected for clinical laboratory evaluations. 
For Cohorts 2 and 3, an additional ECG extraction will occur at 16 hours postdose on 
Day 1 and Day 14. For Cohort 3, all ECGs performed will be triplicate ECGs at each 
time point listed in Table 15, including the additional 16 hour postdose time point. The 
sampling and safety assessment schedule may be revised based on what is learned 
about PK from Part 1 of the study and it may be further revised based on evolving data 
in Part 2. 
Female subjects will have blood collected for serum pregnancy testing. Females 
claiming postmenopausal status will have blood collected to measure FSH levels. 
Subjects who withdraw from the study will not be replaced. 
Part 3: 
Part 3 is a single-dose design study with 3 planned dose groups each consisting of 10 
subjects.  
Subjects will be assigned to one of 3 groups and dose: 
• 
Group 1: TBAJ-876 - 100 mg (1 x 100 mg tablet) under fasted conditions. 
• 
Group 2: TBAJ-876 -100 mg (1 x 100 mg tablet) under fed conditions. 
• 
Group 3: TBAJ-876 - 100 mg (4 x 25 mg tablets) under fasted conditions. 
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Subjects will be confined in the clinic prior to dosing (Day -1) until 7 days after dosing 
(Day 8). Subjects will return to the clinic to have subsequent follow up safety and PK 
measurements on Days 10 and 14. A follow-up phone call to collect any AEs will be 
conducted on Day 21. Refer to the schedule of assessments in Table 17. 
Blood samples will be obtained before each dose of study drug, and at serial time points 
postdose on Days 1-8 and Days 10 and 14. Plasma PK samples will be analyzed for 
TBAJ-876, M2 and M3 using validated analytical methods. 
In addition, blood and urine will be collected for clinical laboratory evaluations. 
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. 
3.1 
Dose Escalation  
The first cohort of the SAD will start with a sentinel group. The decision to continue 
dosing the remainder of Cohort 1 will occur after a minimum of 24 hours following 
sentinel group dosing and after the Sponsor, in conjunction with the Principal 
Investigator, has determined that adequate safety and tolerability have been 
demonstrated. It is not possible to stop dosing during an individual cohort of the SAD, 
except for the first cohort of SAD where dosing may be stopped following the sentinel 
cohort if any safety signal/concern arises, or, if the food effect is assessed by crossing 
over a single cohort, after the dosing of that cohort in the fasting state. 
Dose Escalation Review  
A review period will take place after the dosing of all subjects in each cohort in order 
evaluate and interpret all PK and safety data collected. The review of all pertinent 
blinded safety/tolerability data will include physical examinations, ECGs, vital signs, 
clinical laboratory tests, cardiac monitoring, and AEs or serious adverse events (SAEs) 
through approximately Day 14 (SAD) and Day 21 (MAD). 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 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. PK analysis will be 
completed on the active treatment subjects and will be blinded by subject. 
As data from each cohort is informative for dose escalation decisions in subsequent 
cohorts, review of unblinded data will be conducted after completion of each cohort by 
2 experienced individuals not directly involved in the study, one of whom must be a 
physician. Per protocol, the dose escalation meeting and decision require PK data 
through the morning of Day 8 and approximately 14 days of safety data, depending on 
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the turnaround time of the bioanalysis. Upon completion of the review, they will 
communicate to the study team modifications, if any, that should be implemented for 
subsequent cohorts. See unblinding procedures (Section 6.2.6). 
Note: Although safety data for deciding on escalating to the next dose or cohort will be 
through approximately 14 days (SAD, Part 1) or 28 days (MAD, Part 2), subjects will 
continue to be monitored for safety up to 10 weeks or longer after the last dose. The 
duration of the follow-up period will be based on the analysis of interim PK data. For 
Part 1, available subjects from Cohorts 4 and 5, and all subjects in Cohort 6 will be 
asked to return bi-weekly (+/- 2 days) up to 10 weeks or longer postdose. Subjects will 
complete the same procedures as required for Day 28 at each visit. For Part 2, subjects 
will be discharged 1 week after the last dose and will be asked to return every 3 weeks 
for an additional follow-up period of 15 weeks or longer for safety and PK evaluation.  
Subjects will complete the same procedures as required for Day 21 at each visit. 
Upon review of relevant data, the Sponsor, in conjunction with the Investigator, may 
decide to: 
1. Escalate the dose as planned. 
2. Evaluate an intermediate dose level prior to proceeding to the next planned dose 
level if concerns arise from PK and safety that do not warrant ceasing 
escalation. 
3. Repeat a given dose level in a new cohort of subjects. 
4. Increase the dose of the next cohort if the PK is lower than expected in the 
previous cohort. 
5. Add a cohort if the PK is lower than expected after a cohort and there are no 
safety concerns. 
6. Halt the study. 
During the dose-escalation phase of this first clinical trial, escalation will be guided by 
emerging safety and PK data.  
Dose escalation to the next cohort (i.e., dose level) will not take place until the Sponsor, 
in conjunction with the Principal Investigator and Dose Escalation Committee, has 
determined that adequate safety, tolerability and PK from the previous cohort has been 
demonstrated. The IRB will be notified, and the next cohort will start once IRB 
approval is received. 
3.2 
Stopping Rules for Cohorts for Participants Receiving Active Drug 
If any of the cohort stopping rules are met, cohort dosing must be stopped to allow 
review of the data by the Sponsor and the Investigator. As with dose escalation review, 
the review of data here is also blinded except for review by the 2 experienced 
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individuals not directly involved in the study (see unblinding procedures; 
Section 6.2.6). 
Rules for stopping dosing of a cohort include the following:  
a. One subject experiences one or more drug-related SAEs.   
b. Two or more subjects experience Grade 3 or 4 (per DMID) myalgia in 
combination with increase of CPK (at least 3 times the upper limit of the normal 
range [ULN] confirmed at 48 hours). 
c. Two or more subjects have a QTcF ≥ 500 ms with an increase from baseline 
> 60 ms. 
d. Two or more subjects experience confirmed Grade 3 or 4 AEs (per DMID) in 
any one of the following laboratory parameters: alanine aminotransferase 
(ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), amylase, 
or lipase. 
4 
IDENTITY OF INVESTIGATIONAL PRODUCT 
The Investigational Medicinal Product (IMP) will be supplied as TBAJ-876 Oral 
Suspension, 5 mg/mL formulation or matching placebo, TBAJ-876 tablets 25 mg, and 
TBAJ-876 tablets 100 mg.  
Refer to Appendix 2 for details regarding the description and composition of TBAJ-876 
oral suspension, TBAJ-876 tablets 25 mg, and TBAJ-876 tablets 100 mg. 
Table 7 Identity of Investigational Products 
Test Products:  
TBAJ-876 Oral Suspension 5 mg/mL 
Manufactured for Global Alliance for TB Drug Development 
 
TBAJ-876 Tablets 25 mg  
Manufactured by Piramal Pharma Limited for Global 
Alliance for TB Drug Development 
 
TBAJ-876 Tablets 100 mg  
Manufactured by Piramal Pharma Limited for Global 
Alliance for TB Drug Development 
 
 
Control Product: 
Placebo for TBAJ-876 Oral Suspension  
Manufactured for Global Alliance for TB Drug Development 
 
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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 female, 19 to 50 years of age (inclusive) at the time of 
screening.  
3. Has a body mass index (BMI) ≥18.5 and ≤32.0 (kg/m2) and a body weight of no 
less than 50.0 kg at the time of screening and check-in. 
4. Is medically healthy with no clinically significant screening results (e.g., 
laboratory profiles normal or up to Grade 1 per DMID Toxicity Tables), as 
deemed by the Investigator. Note: Lab results within the testing facility’s normal 
range will not be considered AEs when referenced to the DMID 
assessment/grading scale. 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 FSH levels consistent with postmenopausal status (i.e., greater 
than 40 mIU/mL) at screening.  
7. If female of childbearing potential, must be using effective birth control methods, 
as defined below and is willing to continue practicing birth control methods and 
not planning to conceive throughout treatment until after the last follow-up visit 
(or until at least 12 weeks [male participants] or 6 weeks [female participants] 
after the date of early withdrawal).  The following are allowed birth control 
methods for this study: 
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• 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); 
• Vasectomized partner (at least 6 months before dosing); 
• Non-surgical permanent sterilization (e.g., Essure® procedure) at least 
3 months before dosing; 
• Implanted or intrauterine hormonal contraceptives in use for at least 6 
consecutive months before study dosing; and/or 
8. 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 follow-up visit (or until at least 90 days after the date of 
early withdrawal): 
• Use a condom with spermicide while engaging in sexual activity or be 
sexually abstinent; and  
• 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. 
9. Is willing to answer inclusion and exclusion criteria questionnaire at check-in. 
10. Is able to comply with the protocol and the assessments therein, including all 
restrictions. 
11. Is willing and able to remain in the study unit for the entire duration of the 
assigned confinement period and return for outpatient visits. 
12. If assigned to receive study drug under fed conditions, 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 (heart murmur), 
pulmonary, hepatic, renal, hematologic, gastrointestinal, endocrine, immunologic, 
dermatologic, neurologic, psychiatric disease, or any other condition that, in the 
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opinion of the Investigator, would jeopardize the safety of the subject or the 
validity of the study results. 
2. Any presence of musculoskeletal toxicity (severe tenderness with marked 
impairment of activity, or frank necrosis). 
3. Surgery within the past 90 days prior to dosing as determined by the Investigator 
to be clinically relevant. 
4. History or presence of alcoholism or drug abuse within the past 2 years as 
determined by the Investigator to be clinically relevant. 
5. Participation in another clinical trial within 30 days prior to dosing. 
6. Female subjects who are pregnant or lactating.  
7. Positive result on a urine drug/alcohol screen at screening or check-in. 
8. Positive result on urine cotinine at screening. 
9. Has the following laboratory abnormalities at screening: 
a. ALT or AST Grade 2 or greater (≥ 2.0 times ULN) 
b. Creatinine Grade 2 or greater (≥1.6 times ULN) 
c. Pancreatic lipase Grade 2 or greater (≥1.6 times ULN) 
d. Amylase Grade 2 or greater (≥1.6 times ULN) 
e. Total bilirubin Grade 2 or greater  
f. CPK (> 1.25 times ULN) 
If exclusionary lab criteria are met, values may be confirmed by repeat 
evaluation. 
10. Has a positive test for hepatitis B surface antigen, hepatitis C antibody, or HIV at 
screening. 
11. Seated blood pressure (BP) is less than 90/40 mmHg or greater than 140/90 
mmHg at screening, Day -1 (check-in) or predose. Out-of-range vital signs may 
be repeated once for confirmation. Out of range values will not be considered AEs 
if the repeat assessment is in range. 
12. Seated heart rate is lower than 40 beat per minute (bpm) or higher than 99 bpm at 
screening, Day -1 (check-in) or predose. Out-of-range vital signs may be repeated 
once for confirmation. Out of range values will not be considered AEs if the 
repeat assessment is in range. 
13. Any clinically significant ECG abnormality at screening (as deemed by decision 
of the Investigator and the Sponsor’s Medical Monitor). 
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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  
14. QTcF interval >450 msec for males or >470 msec for females at screening, 
Day -1, or Day 1 (predose), or history of prolonged QT syndrome. For the 
triplicate ECGs taken at screening and on Day -1, the average QTcF interval of 
the 3 ECG recordings will be used to determine qualification. 
15. 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). 
16. Use of any prescription medication within 14 days prior to dosing. 
17. 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 only at occasional use and at the discretion of 
the Investigator prior to dosing. 
18. 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. 
19. Use of any drugs or substances known to be inducers of CYP enzymes and/or 
P-gp, including St. John’s Wort, within 30 days prior to the first dose of study 
drug. 
20. Blood donation or significant blood loss within 56 days before the first dose of 
study medication until the end-of-study visit.  
21. Plasma donation within 7 days before the first dose of study medication until the 
end-of-study visit. 
22. Has been on a significantly abnormal diet during the 4 weeks preceding the first 
dose of study medication. 
23. Unwilling to remove any artificial nails (e.g. acrylic, gel) or fingernail polish and 
not use such products for the duration of the study. 
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24. History or presence of allergic or adverse response to Listerine breath strips or 
aspartame. 
25. Is lactose intolerant. 
5.3 
Medication and Activity Restrictions 
1. Subjects must not donate blood from 56 days or plasma from 7 days prior to the 
first dose of study medication until the last follow-up visit or early withdrawal 
visit is completed. It is recommended that blood/plasma donations not be made 
for at least 30 days after the last follow-up visit or early withdrawal visit. 
2. Subjects must not use tobacco- or nicotine-containing products (including 
smoking cessation products) from 6 months prior to the first dose of study 
medication until the last follow-up visit or early withdrawal visit is completed. 
3. Subjects must not consume alcohol from 72 hours prior to the first dose of study 
medication until the last follow-up visit or early withdrawal visit is completed. 
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. 
4. Subjects 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 24 hours before the first dose of study medication, until 
the last follow-up visit or early withdrawal visit is completed. 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. Subjects must not engage in strenuous exercise from 48 hours prior to the first 
dose of study medication until after discharge from the clinic. For follow-up  
visits, subjects must not engage in strenuous exercise during the 3 days prior to 
the visit. Any report of exercise will be documented and recoded as a protocol 
deviation. Subjects may continue in the study at the discretion of the study 
Investigator.  
6. Subjects 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. 
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 before any study-specific 
procedures being performed. 
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Each potential study participant will have the following assessments by the Investigator 
or designee within 28 days (21 days for Part 3) before study start:   
• Demographic data, including sex, age, race, ethnicity, body weight (kg), 
height (cm), BMI (kg/m2), and smoking habits.  
• Medical history 
• Physical examination 
• Vital signs (blood pressure, pulse rate, respiration rate, temperature, and pulse 
oximetry) 
• Triplicate 12-lead safety ECGs 
• Clinical laboratory tests (hematology, coagulation, chemistry, and urinalysis) 
• Serology tests for HIV, hepatitis B and C 
• Urine test for drugs of abuse and cotinine 
• Serum pregnancy (all female subjects) 
• FSH test (Post-menopausal females)   
• 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, 6 dose levels are planned. For 6 dose levels, 6 cohorts of 8 subjects will be 
used, 6 to receive active drug and 2 to receive placebo, all under fasting conditions.  
In addition, the effect of food on bioavailability of TBAJ-876 will be studied in a food-
effect cohort comprised of two parallel groups, one fasting and the other fed. The fed 
group will enroll at least 10 subjects, which will yield complete data for at least 8 
subjects if at most 2 fail to complete. For the fasted group, the data from the 6 subjects 
previously administered 100 mg TBAJ-876 in Cohort 4 (who have already completed 
the cohort) will be combined with data from 3 additional subjects to be enrolled in this 
fasted group. This will yield a complete data set for at least 8 subjects if at most 1 fails 
to complete. Thus, the total number of subjects planned is at least 50 to 60.  
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Food-Effect: Based on exposure levels from the first 4 completed cohorts, the 100 mg 
dose was chosen for the food-effect cohort. Therefore, all subjects in the food-effect 
cohort will receive active drug of TBAJ-876, 100 mg. In this food-effect cohort, new 
subjects will be enrolled in two parallel groups, one fasting and the other fed. The fed 
group will enroll at least 10 subjects and the fasted group will include data from 6 
subjects who completed Cohort 4 and 3 additional subjects to be enrolled in the fasted 
group.  
Additional cohorts (8 subjects per cohort) may be enrolled if it is deemed appropriate by 
the Sponsor to repeat a dose level, to study another dose level, or to increase cohort size 
(subject numbers). 
Additional cohort, Cohort 7: Eight (8) subjects will be enrolled, 6 to receive active drug 
and 2 to receive placebo. Subjects will receive a single dose under fasted conditions. 
Subjects will receive 800 mg TBAJ-876 or matching dose of placebo for TBAJ-876 
Oral Suspension. 
For Part 2, 39 subjects are planned to be enrolled. There are 3 cohorts planned. Cohort 1 
with 12 subjects per cohort (9 to receive active drug and 3 to receive placebo), Cohort 2 
with 13 subjects per cohort (9 to receive active drug and 4 to receive placebo), and 
Cohort 3 with 14 subjects per cohort (9 to receive active drug and 5 to receive placebo). 
All doses in Part 2 will be under fed conditions. 
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. 
For Part 3, 30 subjects are planned to be enrolled. There are 3 groups planned with 10 
subjects per group. All subjects will receive active drug under fasted or fed conditions.   
6.2 
Blinding (Parts 1 and 2) 
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 
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subject assessments. The pharmacy staff will follow the Standard Operating Procedures 
(SOPs) 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 blinded information will be kept in the pharmacy file. 
Access to the blinded information in the pharmacy file will be restricted.  
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 at the site and will be required to notify the 
Sponsor in the event of any breaking of the blind for any reason.  
Part 3 is open-label.  
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 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 
As data from each cohort is informative for dose escalation decisions in subsequent 
cohorts, review of unblinded data will be conducted after completion of each cohort by 
2 experienced individuals not directly involved in the study, one of whom must be a 
physician. Per protocol, the dose escalation meeting and decision require PK data 
through the morning of Day 8 and approximately 14 days of safety data, depending on 
the turnaround time of the bioanalysis.  Upon completion of the review, they will 
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communicate to the study team modifications, if any, that should be implemented for 
subsequent cohorts. 
The treatment assignment should be unblinded at the clinic only in the case of an 
emergency when knowledge of the study drug assignment is absolutely necessary for 
the clinical management or welfare of the subject. Breaking of the blind at the clinic 
under any other circumstances will be considered a protocol violation.  
The Investigator is strongly encouraged to contact the Sponsor before unblinding the 
study drug assignment prior to the scheduled assessment of tolerance and safety data. If 
the blind is broken for any reason, the Investigator must notify the Sponsor within 
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 -1. 
At check-in, all subjects will be evaluated to confirm they continue to meet all the 
inclusion criteria (Section 5.1) and none of the exclusion criteria (Section 5.2).  
Subjects will undergo the following assessments during the confinement period prior to 
dosing: 
• Physical examinations 
• Weight 
• Vital signs (blood pressure, pulse rate, respiration rate, temperature, and pulse 
oximetry) 
• Triplicate 12-lead ECG 
• Clinical laboratory tests (hematology, coagulation, chemistry, and urinalysis) – 
myoglobin will be collected but results will not be required for dose qualification. 
• 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 
6.4 
Confinement 
For Part 1, subjects will be admitted to the research center on Day -1 and remain in the 
research center until completion of the procedures on Day 8. Subjects will return for 
subsequent follow up visits on Days 10, 14, 17, 21, and 28. Available subjects from 
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Cohorts 4 and 5, and all subjects in Cohort 6 will also return bi-weekly (+/- 2 days) up 
to 10 weeks or longer postdose.  
Additional cohort, Cohort 7: Subjects will check-in to the clinic on Day -1 and be 
confined through Day 8. Subjects will be discharged from the clinic on Day 8. Subjects 
will return for one follow-up visit on Day 14 for PK and safety. Subjects will receive a 
follow-up phone call on Day 21. 
For Part 2, subjects will be admitted to the research center on the evening of Day -1 and 
remain in the research center until completion of the procedures on Day 21.  Subjects 
will return for subsequent follow up visits on Days 42, 63, 84, 105, and 126 (+/- 1 day) 
and will receive a phone call on Day 133 (+/- 1 day). 
For Part 3, subjects will be admitted to the research center on the evening of Day -1 and 
remain in the research center until completion of the procedures on Day 8. Subjects will 
return for subsequent follow-up visits on Days 10 and 14 and will receive a follow-up 
phone call on Day 21. 
6.5 
Fasting/Meals/Beverages 
6.5.1 
Fasting/Meals  
Part 1, SAD 
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. 
In the food-effect cohort of Part 1, the 3 fasted subjects will fast for at least 10 hours 
before dosing and the 10 fed subjects will receive the required FDA standard high-fat, 
high-calorie breakfast to begin 30 minutes before scheduled administration of the dose 
and to end (last bite taken) within 5 minutes before 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 before 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. 
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Standard meals will be provided at approximately 4 and 10 hours after drug 
administration and at appropriate times thereafter. 
Part 2, MAD 
An optional meal or snack will be served the evening of check-in.  
All subjects will then be required to fast for at least 10 hours before consuming a 
required FDA standard high fat, high-calorie breakfast. Subjects will receive the 
required FDA standard high fat, high-calorie breakfast to begin 30 minutes before 
scheduled administration of the dose and to end (last bite taken) within 7 minutes before 
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 before 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. 
Standard meals will be provided at approximately 4 and 10 hours after drug 
administration and at appropriate times thereafter. 
Part 3, BA 
An optional meal or snack will be served the evening of check-in.  
Subjects in Group 1 and Group 3 will be required to fast for at least 10 hours before 
dosing. The subjects will fast for 4 hours after dosing.  
Subjects in Group 2 will fast for at least 10 hours before consuming the required FDA 
standard high-fat, high calorie breakfast as described above in the food effect cohort in 
Part 1.   
Standard meals will be provided at appropriate times after dosing for all groups.  
6.5.2 
Beverages 
Part 1, SAD and Part 2, MAD 
Each dose of TBAJ-876 Oral Suspension and placebo for TBAJ-876 Oral Suspension 
will be administered orally followed by approximately 240 mL of room temperature 
water. 
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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. 
Part 3, BA 
Each dose of TBAJ-876 Tablet(s) will be administered orally with approximately 240 
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 (Parts 1 and 2)  
Listerine® oral care strips (or similar product) will be used to blind subjects to treatment 
(TBAJ-876 Oral Suspension or placebo for TBAJ-876 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 240 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 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 TBAJ-876 Oral Suspension or Placebo for TBAJ-876 Oral 
Suspension  
Note: Detailed instructions for preparing and dispensing TBAJ-876 Oral Suspension 
will be provided in a separate pharmacy manual. Any instructions in the pharmacy 
manual shall supersede those presented in this protocol. 
TBAJ-876 Oral Suspension or placebo for TBAJ-876 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 TBAJ-876 Oral Suspension or Placebo for TBAJ-876 Oral Suspension 
will be administered orally followed by approximately 240 mL of room temperature 
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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 TBAJ-876 Tablet 
Each dose of TBAJ-876 Tablet will be administered orally with approximately 240 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, subjects may be escorted to such procedures or 
activities by research personnel as deemed medically necessary. Subjects will not be 
allowed to lie down, except as directed by clinical staff secondary to AEs, for the first 
4 hours after dosing. 
6.7 
Blood Sampling, Processing and Shipment 
Blood samples will be collected as detailed in Appendix 1. 
Refer to the Schedule of Events (Table 15, Part 1, Table 16, Part 2, or Table 17, Part 3) 
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. Two aliquots of each blood sample will be 
prepared. One set aliquot of the plasma samples will be sent to bioanalytical lab. After 
receiving of the first set of plasma samples, the second set plasma samples (backup 
samples) will also be sent to the bioanalytical lab. 
6.7.1 
Part 1 
For Cohorts 1-6, a total of 140 mL (35 x 4 mL samples) will be collected from each 
subject for PK analysis. Approximately 124.5 mL of blood will be collected for the 
clinical laboratory evaluations and coagulation testing.  
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Table 8 
Total Volume of Blood to be Collected for Testing: Part 1 
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, 6 and 
48 hours and Days 5, 7, 10, 14, 17, 21, and 28 
(end-of-study) a 
10 
8.5 
85.0 
Coagulation a 
10 
2.7 
27.0 
Pharmacokinetic analysis a  
35 
4.0 
140.0 
10 week postdose follow-up (includes clinical 
labs and coagulation) a 
5 
11.2 
56 
Total 
320.5 
a. Subjects in Cohort 7 will not have collections after Day 14.  
The scheduling of PK sample collection will be based on the PK data collected from 
previous cohorts and could involve a different sampling schedule during the first 5 days 
and may require subjects return to the clinic for up to 10 weeks after dosing, depending 
on what is learned about the PK of TBAJ-876. Available subjects from Cohorts 4 and 5, 
and all subjects in Cohort 6 will return bi-weekly (+/- 2 days) up to 10 weeks postdose. 
Subjects will have clinical labs and coagulation tests completed at each visit. The total 
volume of blood collected from each subject during the 10 week postdose follow-up 
will be approximately 56 mL. The total volume of blood collected from each subject in 
Part 1 Cohorts 1-6 will not exceed approximately 320.5 mL.  
For Cohort 7, a total of 124 mL (31 x 4 mL samples) will be collected from each 
subject for PK analysis. Approximately 78.5 mL of blood will be collected for the 
clinical laboratory evaluations and coagulation testing.  The total volume of blood 
collected from each subject in Part 1 Cohort 7 will not exceed approximately 203 mL. 
6.7.2 
Part 2 
A total of 212 mL (53 x 4 mL samples) will be collected from each subject for PK 
analysis. Approximately 110.6 mL of blood will be collected for the clinical laboratory 
evaluations and coagulation testing. The total volume of blood collected from each 
subject in Part 2 is planned not to exceed approximately 322.6 mL, although more may 
be collected if a decision is made to prolong PK monitoring. 
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Table 9 
Total Volume of Blood to be Collected for Testing: Part 2 
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, Days 7, 
14, 21, 42, 63, 84, 105, and 126 (end-of-study) 
9 
8.5 
76.5 
Coagulation 
8 
2.7 
21.6 
Pharmacokinetic analysis (predose trough) 
13 
4.0 
52.0 
Pharmacokinetic analysis (postdose) 
40 
4.0 
160.0 
Total 
322.6 
Additional PK samples may be collected at times to be determined based on the results 
from previous cohorts.  
The Principal Investigator, in conjunction with the Sponsor, may collect additional 
blood if necessary, for repeat laboratory or safety evaluations including AE follow-up. 
6.7.3 
Part 3 
A total of 128 mL (32 x 4ml samples) will be collected for PK Analysis.  
Approximately 91 mL of blood will be collected for the clinical laboratory evaluations 
and coagulation testing. 
Table 10 Total Volume of Blood to be Collected for Testing: Part 3 
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, 6 and 
48 hours and Days 5, 7, 10, and 14 (end-of-
study). 
7 
8.5 
59.5 
Coagulation 
7 
2.7 
18.9 
Pharmacokinetic analysis 
32 
4.0 
128.0 
Total 
218.9 
The Principal Investigator, in conjunction with the Sponsor, may collect additional 
blood if necessary, for repeat laboratory or safety evaluations including AE follow-up. 
6.7.4 
Pharmacokinetic Sampling Time Windows 
Blood samples collected outside the time windows listed below will be considered 
deviations.  
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Table 11 Acceptable Pharmacokinetic Sampling Time Windows, Part 1 and Part 3 
Investigation and examination 
Allowable Time Window 
Postdose 
≤24 hours 
˃24 hours to 
≤Day 7 
>Day 7 
Plasma sample collection for 
pharmacokinetic assessment 
± 2 minutes 
± 5 minutes 
± 10 minutes 
Note: For the food-effect cohort, time windows are relative to dosing in each study 
period. 
Table 12 Acceptable Pharmacokinetic Sampling Time Windows, Part 2 
Investigation and examination 
Allowable Time Window 
Postdose 
≤24 hours and Day 14 
˃24 hours to 
≤Day 13 
>Day 15 
Plasma sample collection for 
pharmacokinetic assessment 
± 5 minutes 
± 5 minutes 
± 10 minutes 
Note: The 24-hour sample of Day 1 must be collected prior to the Day 2 dose. 
6.8 
End-of-Study Procedures 
Subjects will return to the clinic for a follow-up visit after their final dose of study 
medication. During this visit, the following procedures will be conducted: 
• Physical examination 
• Triplicate ECG 
• Vital signs (blood pressure, pulse rate, respiration rate, temperature, and pulse 
oximetry) 
• Blood sample collection for PK 
• Clinical laboratory tests (hematology, coagulation, chemistry, and urinalysis) 
• Urine pregnancy (all female subjects) 
When possible, end-of-study procedures will be performed in the event of a subject’s 
early termination from the study. 
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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 time of signing the ICD 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 
schedule of events (Table 15, Table 16, or Table 17). A Clinical Laboratory 
Improvement Amendments (CLIA) certified laboratory will perform all clinical 
laboratory tests for this study. 
• Hematology: hemoglobin, hematocrit, total and differential leukocyte count, red 
blood cell (RBC) count, reticulocyte count, and platelet count. 
• Serum Chemistry: albumin, blood urea nitrogen (BUN), creatinine, creatine 
phosphokinase (CPK), direct, indirect, and 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, total protein, , magnesium, and bicarbonate, creatine phosphokinase of 
myocardial band (CPK-MB), lipase, and amylase.  
• Serology: hepatitis B surface antigen, hepatitis C antibody, and HIV. 
• Coagulation: prothrombin time (PT2) and activated partial thromboplastin time 
(aPTT2). 
• Other Laboratory Tests: cardiac troponin I and glycosylated hemoglobin 
• Urinalysis - The following will be evaluated by an automated or manual urine 
“dipstick” method: pH, specific gravity, protein, glucose, ketones, bilirubin, 
creatinine, nitrite, sodium, urobilinogen, myoglobin, blood, leukocyte esterase, and 
urobilinogen. If protein, occult blood, nitrite, or leukocyte esterase values are out of 
range, a microscopic examination will be performed. Myoglobin will be collected 
but results will not be required for dose qualification. 
• Urine Drug, Cotinine, and Alcohol Screens - Urine samples will be tested for drugs 
of abuse (amphetamines, benzodiazepines, barbiturates, cannabinoids, cocaine, 
opiates) cotinine, and alcohol. 
• Pregnancy test (all female subjects). 
• FSH (female subjects claiming post-menopausal status). 
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6.9.3 
Vital Signs 
For Part 1, vital signs (blood pressure, pulse rate, temperature, respiration rate, and 
pulse oximetry) will be measured at the times noted on the appropriate events schedule 
(Table 15).  
For Part 2, vital signs (blood pressure, pulse rate, temperature, respiration rate, and 
pulse oximetry) will be measured at the times noted on the appropriate events schedule 
(Table 16). Furthermore, vital signs will also be taken once daily on Day 2 through 
Day 14 (6 hours after dosing) and once daily on Days 15-21 and Days 42, 63, 84, 105, 
and 126 or at early withdrawal (to be done within 15 minutes before review of 
medication and collection of AEs).  
For Part 3, vital signs (blood pressure, pulse rate, temperature, respiration rate, and 
pulse oximetry) will be measured at the times noted on the appropriate events schedule 
(Table 17). 
Vitals signs will be measured within 90 minutes prior to dosing and within 15 minutes 
of the defined time points. Both blood pressure and pulse rate should be captured 
simultaneously. Blood pressure and pulse 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. 
Additional vital signs measurements may be performed as deemed medically necessary 
by research personnel.   
6.9.4 
Physical Examinations 
Physical examinations including height and weight measurements, will be conducted at 
the times noted on the appropriate events schedule (Table 15, Table 16, or Table 17). 
6.9.5 
Electrocardiograms 
For Part 1, triplicate ECGs will be completed at screening, Day -1, 48 hours, and Day 8 
or early withdrawal only. All other time points will be single ECG readings within 
15 minutes of time points on Table 15.  
The predose ECG will be performed prior to the predose blood draw. If a subject 
experiences a postdose 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. 
For Cohort 7, all ECGs will be triplicate at each time point. In addition, subjects in will 
have triplicate ECGs at 16 hours postdose. 
For Part 2, triplicate ECGs will be completed at screening, Day -1, Day 15 or early 
withdrawal only. All other time points on Table 16 will be single ECG readings. ECGs 
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may be done within 2 hours prior to time of dosing and at 6 hours after dosing on 
Days 1, 2, 3, 8, 12, 14, and on Days 42, 63, 84, 105, and 126.  
For Cohorts 2 and 3, an additional ECG extraction will occur at 16 hours postdose on 
Day 1 and Day 14. For Cohort 3, all ECGs performed will be triplicate ECGs at each 
time point listed in Table 16.  
For Part 3, triplicate ECGs will be completed with 15 minutes at all timepoints on 
Table 17. 
NOTE: Where possible, ECG extractions should be taken from the continuous 12-lead 
ECGs (Holter). 
The predose ECG should be completed within 1 hour prior to the predose blood draw. If 
a subject experiences a postdose QTcF >500 ms with a change from baseline QTcF 
>60 ms, after repeat testing, the Principal Investigator should be notified, and additional 
ECGs should be recorded until normalization or return to baseline. 
6.9.6 
Cardiac Holter Monitoring and Cardiodynamic Assessment 
In order to detect potential changes in ECG parameters, study subjects will undergo 
cardiac Holter monitoring. 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). 
On Day -1, subjects should fast until lunch to avoid circadian fluctuations. 
For Part 1, continuous 12-lead ECGs (Holter) will be recorded for 1 hour prior to dose 
and continue for at least 24 hours post dose. 
For Part 2, continuous 12-lead ECGs (Holter) will begin at least 1 hour before and end 
at least 24 hours after dosing first dose (Day 1) and start again at least 1 hour before and 
end at least 24 hours after dosing dose 14 (Day 15). 
For Part 3, continuous 12-lead ECGs (Holter) will be recorded for 1 hour prior to dose 
and continue for at least 24 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 15, Table 16, 
and Table 17. At each time point for ECG extraction, subjects should be resting in the 
supine position for at least 10 minutes.  
NOTE: When ECG extractions from the continuous 12-lead ECGs (Holter) 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.   
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6.9.7 
Other Safety Measures 
Medical emergency personnel trained in advanced cardiac life support will be on site to 
monitor subjects during the confinement period in the research center. Emergency 
medical equipment including but not limited to intubation equipment and pulse 
oximetry shall be maintained on site to administer appropriate medical care should it be 
required.  
Procedures will be completed as specified in this protocol unless contraindicated due to 
a reported AE. 
7 
ADVERSE EVENTS 
Subjects will be monitored for any AEs from the signing of the consent form until the 
end-of-study visit. Adverse events for subjects who fail screening will be recorded in 
the source documents and maintained on site. The Investigator or a medically qualified 
designee will review each event. The Investigator or a Sub-Investigator will assess its 
relationship to the study drug. Each sign or symptom will be graded for severity, and 
the date and time of onset, cessation and resolution will be recorded. Treatment of any 
adverse reactions will be evaluated and managed by a physician, either at the study site 
or at a nearby hospital emergency room, as appropriate. All non-serious AEs will be 
reported on a regular basis or as specified by the Sponsor. 
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 
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observation and/or treatment that would not have been appropriate in the 
physician’s office or outpatient setting. Complications that occur during 
hospitalization are AEs. If a complication prolongs hospitalization or fulfills any 
other serious criteria, the event is serious. When in doubt as to whether 
“hospitalization” occurred or was necessary, the AE should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE; 
• Results in persistent or significant disability/incapacity; the term disability means a 
substantial disruption of a person’s ability to conduct normal life functions. This 
definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g., sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption; 
• Is a congenital anomaly/birth defect; or 
• Is a medically important event. 
Note:  Medical and scientific judgment should be exercised in deciding which is a 
medically important event that may not be immediately life-threatening or result in 
death or hospitalization, but may jeopardize the participant or may require medical or 
surgical intervention to prevent one of the outcomes listed above. Examples of such 
events are intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization, or 
the development of drug dependency or drug abuse.  A “suspected transmission of 
infectious agent by a medicinal product” is also considered a serious adverse event 
under the SAE criterion “Other medically important condition”.  
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. 
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• For each AE/SAE, the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality. 
• There may be situations in which an SAE has occurred, and the investigator has 
minimal information to include in the initial report to the Sponsor/designee. 
However, it is very important that the investigator always assess causality for every 
event before the initial transmission of the SAE data to the Sponsor/designee. 
• The investigator may change his/her opinion of causality in light of follow-up 
information and send a SAE follow-up report with the updated causality 
assessment. 
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Table 13 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 14 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 end-of-study. 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 (CRF). The Investigator will review each AE and assess its relationship to drug 
treatment based on all available information at the time of the completion of the CRF. 
The following information will be recorded for each Adverse Event reported: 
• Diagnosis of the AE, if possible. In the case where an overall diagnosis cannot be 
made, each specific sign and/or symptom will be recorded as individual AEs; 
• Date of onset; 
• Stop date (with duration, if applicable); 
• Severity;   
• Action taken with IMP; 
• Other action taken; 
• Outcome; 
• Relationship to IMP; 
• Occurrence; 
• Seriousness 
7.4 
Serious Adverse Event Reporting 
The Investigator or designee will notify the appropriate Sponsor contact immediately 
after the SAE detection, observation, or report of occurrence (regardless of the 
relationship to test article). The Sponsor contact information for SAE reporting is 
provided below: 
TB Alliance Pharmacovigilance 
Email: AE_inbox@tballiance.org 
Questions relative to SAE case processing may also be sent to the above-mentioned 
email address.  If there is ever an email failure upon trying to report an SAE, please call 
Dr. Lombardi at 1-917-601-0024 and he will notify the Safety team at TB Alliance. 
Medical questions relative to AEs or SAEs can be directed to:  
Antonio (Tony) Lombardi, MD 
Global Alliance for TB Drug Development 
40 Wall Street, 24th Floor 
New York, NY  10005, United States of America 
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Mobile: +1 917.601.0024 
Email: Antonio.Lombardi-Consultant@tballiance.org 
These SAE reports must contain the following information: 
A. Study name/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 IRB will be notified of the alert reports per FDA regulations. 
All AEs, including SAEs, will be followed to resolution when possible. All AEs and 
treatment administered will be recorded on the CRF. 
The Sponsor will be responsible for reporting and processing any SAEs to the FDA or 
other applicable regulatory agency. 
7.5 
Follow up of Adverse Events 
All AEs will be followed until: 
• Satisfactory clinical resolution or stabilization; or 
• End of the follow-up period; and  
• All queries on these AEs have been resolved.   
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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 
International Council for Harmonisation (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 
tests. All laboratory changes greater than or equal to Grade 2 must be reported as an AE 
regardless of clinical significance.   
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7.8 
Drug Interaction 
If the Investigator becomes aware that the subject has experienced a drug interaction 
which has resulted in an AE, 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 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.  
Subjects who discontinue may be replaced at the Principal Investigator and Sponsor’s 
discretion. Subjects who have a positive urine drug, alcohol, or cotinine screen result 
will be evaluated on a case-by-case basis and the Principal Investigator and Sponsor 
will decide whether the subject will continue in the study or will be withdrawn. 
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 PK data. Cases of emesis will be evaluated by the 
Sponsor and Principal Investigator to determine if subject replacement is needed. 
8.5 
Termination of the Study 
The Principal Investigator reserves the right to terminate the study in the interest of 
subject safety and welfare. The Sponsor reserves the right to terminate the study at any 
time for administrative reasons. 
8.6 
Documentation 
All documents pertaining to the study, including a copy of the approved protocol, copy 
of the ICD and Health Insurance Portability and Accountability Act (HIPAA) 
documents, completed CRFs (where applicable), drug accountability and retention 
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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 TBAJ-876, M2, and M3 using validated assays. 
Plasma samples from subjects who receive placebo for TBAJ-876 oral suspension will 
not be analyzed. 
9.2 
Pharmacokinetic Analysis 
Final PK 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, or comparable product, Certara, L.P.]) and/or SAS® (Version 9.4 or 
higher, SAS Institute Inc.). 
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PK parameters will be calculated using non-compartmental analysis. The following PK 
parameters will be determined as appropriate for each study part and analyte. 
AUCExtrap (%) 
The percentage of extrapolated AUC to AUCinf based on extrapolation (Parts 
1 and 3) 
AUCinf 
Area under the concentration-time curve from time-zero extrapolated to 
infinity; calculated for Parts 1 and 3 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 
(Parts 1 and 3) 
AUCtau 
Area under the concentration-time curve during the dosing interval; 
calculated using the linear trapezoidal rule (Part 2) 
Cavg 
Average concentration during the dosing interval (Part 2) 
Clast 
The last quantifiable concentration determined directly from individual 
concentration-time data (Parts 1, 2, and 3) 
CL/F 
Apparent total clearance after single administration (Parts 1 and 3) 
CLss/F 
Apparent total clearance after multiple administration (Part 2) 
Cmax 
Maximum concentration, determined directly from individual 
concentration-time data (Parts 1, 2, and 3) 
RAUC 
Accumulation factor during multiple dosing, based on AUCtau (Part 2) 
RCmax 
Accumulation factor during multiple dosing, based on Cmax (Part 2) 
Tlast 
Time of the last quantifiable concentration (Parts 1, 2, and 3) 
Tmax 
Time of the maximum concentration (Parts 1, 2, and 3) 
T1/2 
The observed terminal half-life, calculated for Parts 1, 2, and 3 as: 
z
T
λ
)
2
ln(
2
/
1
=
 
Vz/F 
Apparent volume of distribution in the terminal phase (Parts 1, 2, and 3) 
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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 (Parts 1, 2, and 3) 
Additional PK analysis and modeling with multiple compartment model may be 
performed and will be reported separately, if conducted.  
Food effect: The effect of food will be assessed comparing PK parameters under fed 
versus fasting conditions using an analysis of variance (ANOVA) approach. 
For Part 2, the following PK parameters will be calculated from plasma concentrations 
of TBAJ-876 following doses on Days 1 and 14: 
• Day 1: AUCtau, Cmax, Tmax, Clast, Tmax, and Cavg λz, t1/2, CLss/F, and Vz/F may be 
calculated as reasonable). 
• Day 14: AUCtau, Cmax, Cmin, Tmax, Ctrough, Cavg, CLss/F, Vz/F, RAUC, and RCmax. 
Parameters such as λz, and t1/2 may be calculated as reasonable. 
For Parts 1 and 2, PK parameters will be summarized by cohort using descriptive 
statistics. Dose proportionality will be assessed using the power model approach.4 
For Part 3, the following PK parameters will be calculated for Group 1 (1 x 100 mg 
tablet, fasted), Group 2 (1 x 100 mg tablet, fed), and Group 3 (4 x 25 mg tablets, 
fasted): 
Cmax, Tmax, AUClast, AUCinf, AUCExtrap, Clast, Tlast, λz, t1/2, CL/F, and Vz/F. 
PK parameters will be summarized by group using descriptive statistics. Food effect 
(Group 2, fed, 1 x 100 mg tablet vs. Group 1, fasted, 1 x 100 mg tablet) and relative 
bioavailability of the two fasted groups (Group 3, 4 x 25 mg tablets vs. Group 1, 
1 x 100 mg tablet) will be assessed using an analysis of variance (ANOVA) approach. 
Additional details will be provided in the Statistical Analysis Plan (SAP). 
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.). 
For Parts 1, 2, and 3, PK parameters will be summarized by cohort using descriptive 
statistics. Summary statistics will also be presented by gender within each cohort.  
For Part 1, dose proportionality for exposure parameters (Cmax, AUCs) will be assessed 
using a power model approach. Food effect will be assessed using an analysis of 
variance (ANOVA) with food condition as the fixed effect. 
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For Part 2, dose proportionality for exposure parameters (Cmax, AUCs) will be assessed 
using a power model approach. Steady state for each dose level will be assessed using 
an appropriate statistical methodology. 
For Part 3, Food effect will be assessed using an ANOVA model with food condition as 
the fixed effect. The relative bioavailability analysis for the two strengths of TBAJ-876 
tablets will be assessed using an ANOVA model with the strength of tablet 
administered under fasting conditions as the fixed effect. 
Additional details will be provided in the SAP. 
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. 
Bioanalytical Principal Investigator: Natalie Auman 
Contact for Sample Shipment: Ruth Guan 
17 Lee Boulevard 
Malvern, PA 19355 
Phone: 610.296.3152 
Fax: 610.296.3153 
Email: rguan@alliancepharmaco.com;  
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, TBAJ-876 for preparation of TBAJ-876 Oral Suspension, TBAJ-876 tablets 25 
mg, and TBAJ-876 tablets 100 mg. Study drug will be shipped to Worldwide Clinical 
Trials Early Phase Services, LLC pursuant to site SOPs. Upon receipt of the study drug, 
the study drug will be inventoried and stored in an environmentally controlled and 
secure, limited access area. For oral suspension, the suspending vehicle (also used as 
Placebo) and other supplies will be procured, inventoried, and stored appropriately by 
Worldwide Clinical Trials Early Phase Services, LLC pursuant to site SOPs. 
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 (TBAJ-876 Oral Suspension 
and Placebo for TBAJ-876 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. 
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 SCHEDULES 
Table 15 Schedule of Assessments and Procedures, Part 1 SAD 
PART 1 
SCR 
 
CONFINEMENT 
*FU 
STUDY 
DAY** 
-28 
to -2 
-1 
CI 
DAY 1 
DAY 2 
3 
4 
5, 
6, 
7, 
8 
10, 
14, 
17, 
21, 
28 
STUDY HOUR 
 
EVENT**  
0 
0.5 
1 
1.5 
2 
3 
4 
5 
6 
7 
8 
10 
12 
16a 
20 
24 28 30 32 
36 
40 
42 
44 
48 
54 
60 
66 
72 
80 
88 
 
N/A 
Informed 
consent and 
medical 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical 
examination 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
Heart 
murmurb 
X 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
Vital signs 
(blood 
pressure, 
pulse, 
temperature, 
respiration 
rate, and 
pulse 
oximetry) 
Xc 
X 
Xc 
X 
X 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
X 
12-lead 
safety ECGs 
Xd 
X 
Xd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Xd 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
Xd 
Xd 
HIV/hepatitis 
B, C 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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PART 1 
SCR 
 
CONFINEMENT 
*FU 
STUDY 
DAY** 
-28 
to -2 
-1 
CI 
DAY 1 
DAY 2 
3 
4 
5, 
6, 
7, 
8 
10, 
14, 
17, 
21, 
28 
STUDY HOUR 
 
EVENT**  
0 
0.5 
1 
1.5 
2 
3 
4 
5 
6 
7 
8 
10 
12 
16a 
20 
24 28 30 32 
36 
40 
42 
44 
48 
54 
60 
66 
72 
80 
88 
 
N/A 
Clinical 
laboratory 
tests 
(hematology, 
chemistry, 
and 
urinalysis)e 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
Coagulation 
testse 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
Urine drug, 
alcohol, 
cotinine 
screen 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Serum 
pregnancy 
(females 
only) 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine 
pregnancy 
(females 
only)f 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
FSH (post-
menopausal 
females 
only) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
medication 
review 
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 
X 
X 
X 
X 
X 
X 
X 
X 
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PART 1 
SCR 
 
CONFINEMENT 
*FU 
STUDY 
DAY** 
-28 
to -2 
-1 
CI 
DAY 1 
DAY 2 
3 
4 
5, 
6, 
7, 
8 
10, 
14, 
17, 
21, 
28 
STUDY HOUR 
 
EVENT**  
0 
0.5 
1 
1.5 
2 
3 
4 
5 
6 
7 
8 
10 
12 
16a 
20 
24 28 30 32 
36 
40 
42 
44 
48 
54 
60 
66 
72 
80 
88 
 
N/A 
Breath strip 
applicationh 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dose 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK blood 
collectioni 
 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Cardiac 
Telemetry; 
12 – lead 
Holter 
monitoringj 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG 
extractions 
from Holter 
recordingk 
 
 
X 
X 
X 
X 
X 
X 
X 
X X 
X 
X 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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 
  *  Available subjects from Cohorts 4 and 5, and all subjects in Cohort 6 will return bi-weekly (+/- 2 days) up to 10 weeks postdose. Subjects 
will complete the same procedures as required for Day 28 at each visit. 
**  Subjects in Cohort 7 will be discharged from the clinic on Day 8. Subjects will return for one follow-up visit on Day 14 for PK and safety. 
Subjects will receive a follow-up phone call on Day 21. Subjects will complete the procedures specified for those study days only.  
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. Heart Murmur: Presence of heart murmur  
c. Vital signs (blood pressure, pule rate, temperature, respiration rate, and pulse oximetry) will be measured at screening and check-in 
(Day -1). Vitals signs will be measured within 90 minutes prior to dosing and within 15 minutes of the defined time points. Both blood 
pressure and pulse rate should be captured simultaneously. Blood pressure and pulse rate will 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. 
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 -1, at 48 hours and on Day 8 or upon early withdrawal only. All other time points will be single ECG readings within 15 
minutes of the time points. The first ECG Day 1 may be done within 2 hours prior to dosing and must be completed 20 minutes prior to 
the predose blood draw. All safety ECGs on Day 1 and Day 2 will be extracted from a continuous 12 lead Holter recording at discrete 
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timepoints as noted in above flow chart. If a subject experiences a postdose QTcF >500 msec or a change-from-baseline QTcF >60 msec, 
after repeat testing, additional ECGs will be recorded until normalization or return to baseline. All ECGs in Cohort 7 will be triplicate at 
each time point. In addition, subjects in Cohort 7 will have triplicate ECGs at 16 hours postdose.  
e. Safety laboratory assessments will be done at check-in (Day -1), 6 and 48 hours postdose and on Days 5, 7, 10, 14, 17, 21, and 28. The 
following analyses will be performed: 
• 
Full blood cell count (hemoglobin, hematocrit, red blood cell count, white blood cell count with differential, reticulocyte count, 
platelet count), reticulocyte count 
• 
Coagulation Tests: Activated partial thromboplastin time (aPTT2), Prothrombin time (PT2)  
• 
Clinical Chemistry (albumin, serum urea, creatinine, direct, indirect, and total bilirubin, uric acid, total protein, alkaline phosphatase, 
aspartate aminotransferase (AST), alanine aminotransferase (ALT), phosphate, sodium, potassium, calcium (corrected for albumin), 
chloride, magnesium, glucose, bicarbonate/CO2, creatine phosphokinase (CPK), creatine phosphokinase myocardial band (CPK-MB), 
lipase, and amylase 
• 
Other laboratory tests: cardiac troponin I and glycosylated hemoglobin 
• 
Urinalysis (pH, specific gravity, protein, glucose, micro-albumin, ketones, bilirubin, creatinine, nitrite, sodium, urobilinogen, 
myoglobin, blood, leukocytes).  If protein, occult blood, nitrite, or leukocyte esterase values are out of range, a microscopic 
examination will be performed. Myoglobin will be collected but results will not be required for dose qualification. 
f. 
Female subjects will have a urine pregnancy test at the end-of-study on Day 28 or early withdrawal. 
g. Subjects will be monitored from the time of signing the informed consent 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 specified postdose and upon return 
to clinic for subsequent visits.  
h. TBAJ-876 or Placebo for TBAJ-876 Oral Suspension will be administered orally followed by 240 mL of water. Listerine® strips will be 
used as a blinding agent. A strip will be added to the subject’s tongue before and after each dose.  
i. 
Subjects will be followed up for safety and PK during follow-up at the following timepoints: Dose Level 1: PK samples to be collected at 
pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 54, 60, 66, 72, 80, 88, 96, 120, 144, and 168 hours after dosing, 
then on Days 10, 14, 17, 21 and 28.  Other Dose Level Cohorts: scheduling of PK sample collection will be based on the PK data 
collected from previous cohorts and could involve a different sampling schedule and require subjects return to the clinic for up to 10 weeks 
or longer after dosing. 
j. 
Continuous 12-lead Holter recording (cardiac telemetry) will begin 1 hour before and end 24 hours after dosing. 
k. ECGs on Day 1 will be extracted from a continuous 12 lead Holter recording at discrete timepoints as noted in above flow chart and will 
be extracted at the same time as vital sign measurements. 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. 
 
NOTE: when ECG extractions coincide with safety ECGs, vital sign assessments, and/or blood draws, then procedures should be carried 
out in said order. 
 
 
 
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Table 16 Schedule of Assessments and Procedures, Part 2 MAD 
PART 2 
SCREEN 
CHECK-
INa 
CONFINEMENTa 
FOLLOW-UP 
EARLY 
WITHDRAWAL 
DAY 
-28 to -2 
-1 
1 to 20 
7, 14 
21 
42 
63, 84, 
105, 126 
133 
 
EVENT 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
Check-in questions 
 
X 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
Height, weight 
X 
 
 
 
 
 
 
 
 
HIV/ Hepatitis B, C 
X 
 
 
 
 
 
 
 
 
Serum pregnancy testb 
X 
X 
 
 
 
 
 
 
 
FSHb 
X 
 
 
 
 
 
 
 
 
Urine pregnancyc 
 
 
 
 
 
 
X 
 
X 
Urine drug/alcohol/ cotinine 
screen 
X 
X 
 
 
 
 
 
 
 
Safety Labs hematology, 
chemistry, urinalysis)d 
X 
X 
 
X 
X 
X 
X 
X 
Coagulation 
X 
X 
 
X 
X 
X 
X 
X 
Physical exam 
X 
X 
 
X 
X 
X 
X 
X 
Heart murmure  
X 
X 
X 
X 
X 
 
X 
X 
X 
Vital signs (blood pressure, 
pulse, temperature, 
respiration rate, and pulse 
oximetry)f 
X 
X 
Xf 
X 
X 
X 
X 
 
X 
Concomitant medication 
review 
X 
X 
X 
X 
X 
 
X 
X 
X 
Adverse eventsg 
 
X 
X 
X 
X 
X 
X 
X 
X 
Breath strip applicationh 
 
 
Xi 
X 
 
 
 
 
 
Dosei 
 
 
Xi 
X 
 
 
 
 
12-lead safety ECGsj 
X 
X 
Xj 
 
X 
X 
X 
X 
Plasma for pre-dose trough 
PKk 
 
 
Xk 
X 
 
 
 
 
 
Plasma for Post-dose PKl 
 
 
Xl 
X 
X 
X 
X 
 
 
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PART 2 
SCREEN 
CHECK-
INa 
CONFINEMENTa 
FOLLOW-UP 
EARLY 
WITHDRAWAL 
DAY 
-28 to -2 
-1 
1 to 20 
7, 14 
21 
42 
63, 84, 
105, 126 
133 
 
EVENT 
 
 
Cardiac telemetry; 12-lead 
Holter monitoringm 
 
 
Xm 
Xm 
 
 
 
 
 
ECG extractions from 
Holter recordingn 
 
 
Xn 
Xn 
 
 
 
 
 
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. 
Confinement to start at check-in (Day -1) until the completion of procedures on Day 21. 
b. Serum pregnancy test done at screening and at check-in for females only. FSH completed for perimenopausal females only. 
c. 
Female subjects will have a urine pregnancy test done at the end-of-study Day 126 or early withdrawal.  
d. Safety laboratory assessments. The following analyses will be performed: 
• 
Full blood cell count (hemoglobin, hematocrit, red blood cell count, white blood cell count with differential, reticulocyte count, 
platelet count) 
• 
Coagulation Tests: Activated partial thromboplastin time (aPTT2), Prothrombin time (PT2) 
• Clinical Chemistry (albumin, serum urea, creatinine, direct, indirect, and total bilirubin, uric acid, total protein, alkaline phosphatase, 
aspartate aminotransferase (AST), alanine aminotransferase (ALT),  phosphate, sodium, potassium, calcium (corrected for albumin), 
chloride, magnesium, glucose, bicarbonate/CO2, creatine phosphokinase (CPK), lipase, and amylase 
• Other laboratory tests: creatine phosphokinase of myocardial band (CPK-MB), cardiac troponin I and glycosylated hemoglobin 
• Urinalysis (pH, specific gravity, protein, glucose, micro-albumin, ketones, bilirubin, creatinine, nitrite, sodium, urobilinogen, blood, 
myoglobin, leukocytes). If protein, occult blood, nitrite, or leukocyte esterase values are out of range, a microscopic examination will 
be performed. Myoglobin will be collected but results will not be required for dose qualification. 
e. 
Heart murmur: Presence of heart murmur 
f. 
Vital signs (blood pressure, pule rate, temperature, respiration rate, and pulse oximetry) will measured at screening and check-in (Day -1). 
Vital sign measurements will be taken within 90 minutes prior to dosing and within 15 minutes of the defined time points at study hours 0, 
1, 6, and 12 on Days 1 and 14. Furthermore, vital signs will also be taken once daily on Day 2 through Day 14 (6 hours after dosing) and 
once daily on Days 15-21 and Days 42, 63, 84, 105, and 126 and at early withdrawal (to be done within 15 minutes before review of 
medication and collection of adverse experiences). Both blood pressure and heart rate will be captured simultaneously. Blood pressure and 
heart rate will be measured after subjects are in a seated position for 2 minutes and then again after standing for 1 minute, except when 
they are supine or semi-reclined because of study procedures and/or adverse events, or as deemed necessary by the Investigator. 
g. AEs will be monitored from the time of signing the informed consent throughout the study via safety assessments, observation and 
participant reporting. Specific AE questions will be posed daily throughout the study until Day 21 and on all follow-up visits including a 
phone call on Day 133.  
h. TBAJ-876 or Placebo to TBAJ-876 Oral Suspension will be administered orally followed by 240 mL of water. Listerine® strips will be 
used as a blinding agent. A strip will be added to the subject’s tongue before and after each dose.  
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i. 
Dosing will only occur on Days 1-14.  
j. 
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 -1, and on Day 15 or upon early withdrawal. All other time points will be single ECG readings. ECGs may be done within 
2 hours prior to time of dosing and at 6 hours after dosing on Days 1, 2, 3, 8, 12, 14, and on Days 21, 42, 63, 84, 105, and 126. The predose 
ECG will be completed within 1 hour prior to the predose blood draw. If a participant experiences a postdose QTcF >500 ms or a change-
from-baseline QTcF >60 ms, after repeat testing, additional ECGs should be recorded until normalization or return to baseline. All ECGs 
in Cohort 3 will be triplicate at each time point. In addition, subjects in Cohort 3 will have triplicate ECGs at 16 hours postdose on Day 1 
and Day 14. 
k. Predose trough plasma samples will be drawn daily Days 1 through 14. 
l. 
Postdose blood plasma samples will be drawn at the following timepoints: 
• Day 1: 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 20, 24 (pre-dose sample for Day 2). 
• Day 14: 0.5, 1, 2, 3, 4, 5, 8, 12, 16, 20, 24, 28 32, 36, 40, 44, 48, 54, 60, 66, 72, 80, 88, 96, 120, 144, and 168 hours after dosing and 
on Days 42, 63, 84, 105, and 126. 
Additional or fewer samples may be collected at times to be determined based on the results from previous cohorts. 
m. Continuous 12 lead Holter recording (cardiac telemetry) will begin at least 1 hour before and end at least 24 hours after dosing (Day 1) and 
start again at least 1 hour before and end at least 24 hours after dosing on Day 14.  
n. ECGs extractions from the 12 lead Holter monitor will occur only on Days 1 and 14 at the following time points: 0, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 
7, 8, 12, 20, and 24 hours postdose. 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. For Cohorts 2 and 3, an additional 
extraction will be done at the 16 hour time point on Days 1 and 14. 
 
NOTE: when ECG extractions coincide with safety ECGs, vital sign assessments, and/or blood draws, then procedures should be carried 
out in said order. 
 
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Table 17  Schedule of Assessments and Procedures, Part 3 BA 
PART 3 
SCR 
 
CONFINEMENT 
*FU 
STUDY 
DAY 
-21 
to -2 
-1 
CI 
DAY 1 
DAY 2 
3 
4 
5, 
6, 
7, 
8 
10, 
14,  
21 
STUDY HOUR 
 
EVENT  
0 
0.5 1 
1.5 
2 
3 
4 
5 
6 
7 
8 
10 
12 
16a 
20 
24 28 30 32 
36 
40 
42 
44 
48 
54 
60 
66 
72 
80 
88 
 
N/A 
Informed 
consent and 
medical 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical 
examination 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
Heart 
murmurb 
X 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
Vital signs 
(blood 
pressure, 
pulse, 
temperature, 
respiration 
rate, and 
pulse 
oximetry) 
Xc 
X 
Xc 
X 
X 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
X 
12-lead 
safety ECGs 
Xd 
X 
Xd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
Xd 
Xd 
HIV/hepatitis 
B, C 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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PART 3 
SCR 
 
CONFINEMENT 
*FU 
STUDY 
DAY 
-21 
to -2 
-1 
CI 
DAY 1 
DAY 2 
3 
4 
5, 
6, 
7, 
8 
10, 
14,  
21 
STUDY HOUR 
 
EVENT  
0 
0.5 1 
1.5 
2 
3 
4 
5 
6 
7 
8 
10 
12 
16a 
20 
24 28 30 32 
36 
40 
42 
44 
48 
54 
60 
66 
72 
80 
88 
 
N/A 
Clinical 
laboratory 
tests 
(hematology, 
chemistry, 
and 
urinalysis)e 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
Coagulation 
testse 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
Urine drug, 
alcohol, 
cotinine 
screen 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Serum 
pregnancy 
(females 
only) 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine 
pregnancy 
(females 
only)f 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
FSH (post-
menopausal 
females 
only) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
medication 
review 
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 
X 
X 
X 
X 
X 
X 
X 
X 
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PART 3 
SCR 
 
CONFINEMENT 
*FU 
STUDY 
DAY 
-21 
to -2 
-1 
CI 
DAY 1 
DAY 2 
3 
4 
5, 
6, 
7, 
8 
10, 
14,  
21 
STUDY HOUR 
 
EVENT  
0 
0.5 1 
1.5 
2 
3 
4 
5 
6 
7 
8 
10 
12 
16a 
20 
24 28 30 32 
36 
40 
42 
44 
48 
54 
60 
66 
72 
80 
88 
 
N/A 
Doseh 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK blood 
collectioni 
 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Cardiac 
Telemetry; 
12 – lead 
Holter 
monitoringj 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG 
extractions 
from Holter 
recordingk 
 
 
X 
X 
X 
X 
X 
X 
X 
X X 
X 
X 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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 
* Subjects will return for follow-up visits on Day 10 and 14. Subjects will receive a follow-up phone call on Day 21. 
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. Heart Murmur: Presence of heart murmur  
c. 
Vital signs (blood pressure, pule rate, temperature, respiration rate, and pulse oximetry) will be measured at screening and check-in 
(Day -1). Vitals signs will be measured within 90 minutes prior to dosing and within 15 minutes of the defined time points. Both blood 
pressure and pulse rate should be captured simultaneously. Blood pressure and pulse rate will 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. 
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 -1, each time point listed, and on Day 8 or upon early withdrawal. ECG readings will be within 15 minutes of the time 
points. The first ECG Day 1 may be done within 2 hours prior to dosing and must be completed 20 minutes prior to the predose 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. If a subject experiences a postdose QTcF >500 msec or a change-from-baseline QTcF >60 msec, after repeat testing, 
additional ECGs will be recorded until normalization or return to baseline.  
e. 
Safety laboratory assessments will be done at check-in (Day -1), 6 and 48 hours postdose and on Days 5, 7, 10, and 14. The following 
analyses will be performed: 
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• 
Full blood cell count (hemoglobin, hematocrit, red blood cell count, white blood cell count with differential, reticulocyte count, 
platelet count), reticulocyte count 
• 
Coagulation Tests: Activated partial thromboplastin time (aPTT2), Prothrombin time (PT2)  
• 
Clinical Chemistry (albumin, serum urea, creatinine, direct, indirect, and total bilirubin, uric acid, total protein, alkaline phosphatase, 
aspartate aminotransferase (AST), alanine aminotransferase (ALT), phosphate, sodium, potassium, calcium (corrected for albumin), 
chloride, magnesium, glucose, bicarbonate/CO2, creatine phosphokinase (CPK), creatine phosphokinase myocardial band (CPK-
MB), lipase, and amylase 
• 
Other laboratory tests: cardiac troponin I and glycosylated hemoglobin 
• 
Urinalysis (pH, specific gravity, protein, glucose, micro-albumin, ketones, bilirubin, creatinine, nitrite, sodium, urobilinogen, 
myoglobin, blood, leukocytes).  If protein, occult blood, nitrite, or leukocyte esterase values are out of range, a microscopic 
examination will be performed. Myoglobin will be collected but results will not be required for dose qualification. 
f. 
Female subjects will have a urine pregnancy test at the end-of-study on Day 14 or early withdrawal. 
g. Subjects will be monitored from the time of signing the informed consent 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 specified postdose and upon return 
to clinic for subsequent visits.  
h. TBAJ-876 Tablet will be administered orally with 240 mL of water.  
i. 
Subjects will be followed up for safety and PK during follow-up at the following timepoints: pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 20, 
24, 28, 32, 36, 40, 44, 48, 54, 60, 66, 72, 80, 88, 96, 120, 144, and 168 hours after dosing, then on Days 10 and 14. 
j. 
Continuous 12-lead Holter recording (cardiac telemetry) will begin 1 hour before and end 24 hours after dosing. 
k. ECGs on Day 1 will be extracted from a continuous 12 lead Holter recording at discrete timepoints as noted in above flow chart and will 
be extracted at the same time as vital sign measurements. 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. 
 
NOTE: when ECG extractions coincide with safety ECGs, vital sign assessments, and/or blood draws, then procedures should be carried 
out in said order. 
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14 
REFERENCES 
1. Investigator’s Brochure, TBAJ-876, TB Alliance, version 1.0, effective 19 Mar 
2020.  
2. Package insert: Sirturo. Janssen Therapeutics, September 2014. Available at: 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/204384s000lbl.pdf. 
3. FDA Guidance for Industry, Estimating the Maximum Safe Starting Dose in Initial 
Clinical Trials for Therapeutics in Adult Healthy Volunteers 
4. Smith, B, Vandenhende, F, DeSante, K, Farid, N, Welch, P, Callaghan, J & Forgue, 
S. (2000). Confidence Interval Criteria for Assessment of Dose Proportionality. 
Pharmaceutical Research. 17. 1278-1283. 10.1023/A:1026451721686. 
5. FDA Food-Effect Guidance 
[https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/
guidances/ucm070241.pdf]. 
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APPENDIX 1 PHARMACOKINETIC SAMPLE COLLECTION, PROCESSING, AND 
SHIPMENT INSTRUCTIONS 
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 1 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 -80°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 TBAJ-
876 and its metabolites (M2 and M3) 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 identification 
c) Period or dosing phase; sampling time (relative to dosing) 
d) Aliquot letter (a or b)  
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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 
3. Before 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. The shipment will be accompanied by documentation containing the following 
information: name of the study drug product, protocol number, number of subjects, and 
number of samples included in the shipment. Expected samples that are not present will 
be identified. 
5. All frozen pharmacokinetic samples will be transferred with accompanying 
documentation to: 
Alliance Pharma, Inc. 
17 Lee Blvd 
Malvern, PA 19355 
Telephone:  610.296.3152 
Fax:  610.296.3153 
Contact name: Ruth Guan 
Contact E-mail: rguan@alliancepharmaco.com 
samples@alliancepharmaco.com  
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APPENDIX 2 DESCRIPTION AND COMPOSITION OF TEST PRODUCT 
Description of the Dosage Form 
TBAJ-876 Oral Suspension is a compounded preparation at 5 mg/mL TBAJ-876 as tartrate, in 
ORA-Sweet®. The suspension is compounded at the clinical study site with TBAJ-876 tartrate 
and ORA-Sweet®, a commercially available flavored suspending vehicle.  
Placebo for TBAJ-876 Oral Suspension is ORA-Sweet®, the same flavored vehicle used in the 
active oral suspension (without TBAJ-876).  The placebo suspension, 100% ORA-Sweet®, is 
purchased commercially by the clinical site. 
The required doses of the suspension drug product are dispensed using commercially available 
oral syringes of suitable capacity. 
TBAJ-876 Tablets 25 mg are white to off white, round uncoated tablets, plain on both sides. 
TBAJ-876 Tablets 100 mg are white to off white, capsule-shaped uncoated tablets, plain on both 
sides. 
Composition of the Drug Product 
TBAJ-876 Oral Suspension  
The quantitative composition, function, and quality of each ingredient in the drug product 
(TBAJ-876 Oral Suspension, 5 mg/mL) is provided in the table below. 
 
Qualitative and Quantitative Composition of the TBAJ-876 Oral Suspension, 5 mg/mL 
Ingredient 
Function 
Quality 
Standard 
Quantity 
in 5 
mg/mL 
Quantity per Dose 
10 mg 
25 mg 
50 mg 
100 mg 
200 mg 
400 mg 
TBAJ-876 
Tartrate1, 
equivalent 
to 
TBAJ-876 
Drug 
Substance 
In-house 
0.5 g 
10 mg 
25 mg 
50 mg 
100 mg 
200 mg 
400 mg 
ORA-
Sweet®2 
Flavored 
Oral 
Suspending 
Vehicle 
Commercially 
available 
q.s to 
100 mL 
q.s. to 
2 mL 
q.s. to 
5 mL 
q.s. to 
10 mL 
q.s. to 
20 mL 
q.s. to 
40 mL 
q.s. to 
80 mL 
Total Volume 
100 mL 
2 mL 
5 mL 
10 mL 
20 mL 
40 mL 
80 mL 
1TBAJ-876 equivalent calculated using the assay value of free base from the certificate of analysis. 
 
 
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2Purified water, sucrose, glycerin, sorbitol, and flavoring.  Buffered with citric acid and sodium phosphate. Preserved with 
methylparaben and potassium sorbate. 
 
TBAJ-876 Tablets 
Each 25 mg tablet contains 25 mg of TBAJ-876 equivalent to 30.7 mg of TBAJ-876 tartrate.  
Each 100 mg tablet contains 100 mg of TBAJ-876 equivalent to 122.8 mg of TBAJ-876 tartrate.  
The composition of the tablets is as follows: lactose monohydrate, microcrystalline cellulose, 
povidone, crospovidone, colloidal silicon dioxide, and magnesium stearate. The formulation of 
the two strengths of tablets is identical and dose proportional. 
Container and Closure System 
TBAJ-876 tartrate drug substance is shipped to the clinical study site in double LDPE bags, with 
each bag individually twist-tied. The bags are then placed in an aluminum foil polybag with a 
silica gel pack in the foil bag, and heat-sealed.  
TBAJ-876 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. 
TBAJ-876 Tablets 25 mg are packaged as 30-count in 30 cc round high-density polyethylene 
(HDPE) bottles induction sealed and with 28 mm polypropylene (PP) child resistant closures 
(CRC). TBAJ-876 Tablets 100 mg are packaged as 30-count in 40 cc round HDPE bottles 
induction sealed and with 33 mm PP CRC.  The tables are stored at 15-30 °C (59-86 °F). 
 
 
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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. 
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• 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 
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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 
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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 
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 
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CARDIOVASCULAR 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
BP, No treatment 
required1 
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 
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GASTROINTESTINAL 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Diarrhea 
mild or transient; 
3-4 loose 
stools/day or mild 
diarrhea last < 1 
week 
moderate or 
persistent; 5-7 
loose stools/day or 
diarrhea lasting >1 
week 
>7 loose 
stools/day or 
bloody diarrhea; or 
orthostatic 
hypotension or 
electrolyte 
imbalance or >2L 
IV fluids required  
hypotensive shock 
or physiologic 
consequences 
requiring 
hospitalization   
Oral 
Discomfort/Dysphagia 
mild discomfort; no 
difficulty 
swallowing 
some limits on 
eating/drinking 
eating/talking very 
limited; unable to 
swallow solid 
foods 
unable to drink 
fluids; requires IV 
fluids 
 
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 
 
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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 
 
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SKIN 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Rash at Injection 
Site 
< 15mm  
15-30 mm 
>30mm 
 
Pruritus 
slight itching at 
injection site 
moderate itching at 
injection extremity 
itching over entire 
body 
 
 
 
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 
 
 
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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 
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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. 
 
 
 
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