A Phase 1, Open-Label, Single-Dose Study to Evaluate the Pharmacokinetics and Safety of Pretomanid in Participants With Renal Impairment Compared to Participants With Normal Renal Function
Phase: PHASE1
Conditions: Renal Impairment, Tuberculosis
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

DMID Protocol 15-0037 
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Renal Pharmacokinetics 
11 April 2024 
 
A Phase 1, Open-Label, Single-Dose Study to Evaluate the 
Pharmacokinetics and Safety of Pretomanid in Participants with 
Renal Impairment Compared to Participants with Normal Renal 
Function 
 
Division of Microbiology and Infectious Diseases (DMID) Protocol Number: 
15-0037 
 
 
DMID Funding Mechanism: Vaccine and Treatment Evaluation Units 
 
 
Pharmaceutical Support: TB Alliance 
 
 
Investigational New Drug (IND) Sponsor: DMID, National Institute of Allergy 
and Infectious Diseases (NIAID) 
 
 
Principal Investigators: William Smith, MD and Kimberly Cruz, MD 
 
 
 
 
DMID Clinical Project Manager: Erica Sondergaard, RN, BSN, CCRC 
 
 
Version: 11.0 
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i 

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STATEMENT OF ASSURANCE 
 
Each Institution will hold a current Federal Wide Assurance (FWA) issued by the Office of Human 
Research Protections (OHRP) for federally funded human participants research. Each FWA will 
designate at least one Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
registered with OHRP, for which the research will be reviewed and approved by the IRB/IEC and 
will be participant to continuing review [45 CFR 46.103(b)]. The IRB/IEC designated under an FWA 
may include an institution’s IRB/IEC, an independent IRB/IEC, or an IRB/IEC of another institution 
after establishing a written agreement with that other institution. 

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STATEMENT OF COMPLIANCE 
 
The study trial will be carried out in accordance with Good Clinical Practice (GCP) and as 
required by the following: 
• United States Code of Federal Regulations (CFR) 45 CFR Part 46 (Protection of Human 
Subjects) 
• Food and Drug Administration (FDA) Regulations, as applicable: 21 CFR Part 50 (Protection of 
Human Subjects), 21 CFR Part 54 (Financial Disclosure by Clinical Investigators), 21 CFR Part 
56 (Institutional Review Boards), 21 CFR Part 312 (Investigational New Drug Application 
[IND] Application), 21 CFR 812 (Investigational Device Exemptions) 
• 
International Council for Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use (ICH) E6(R2) GCP: Integrated Addendum to ICH E6(R1) 
Guidance for Industry, published in the Federal Register (83 FR 8882 [2018]), including the 
latest finalized revision 
• Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of 
Research, Report of the National Commission for the Protection of Human Subjects of 
Biomedical and Behavioral Research 
• National Institutes of Health (NIH) Office of Extramural Research, Research Involving Human 
Subjects, as applicable 
• National Institute of Allergy and Infectious Diseases (NIAID) Clinical Terms of Award, as 
applicable 
• Applicable federal, state, and local regulations and guidance 

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SIGNATURE PAGE 
 
The signature below provides the necessary assurances that this trial will be conducted according to 
all stipulations of the protocol, including all statements regarding confidentiality, and according to 
local legal and regulatory requirements and applicable United States federal regulations and ICH E6 
GCP guidelines. 
I agree to conduct the study in compliance with GCP and applicable regulatory requirements. 
I agree to conduct the study in accordance with the current protocol and will not make changes to 
the protocol without obtaining the sponsor’s approval and IRB/IEC approval, except when necessary 
to protect the safety, rights, or welfare of participants. 
 
 
Site Inve stigator Signature: 
Signed: 
Date: 
William Smith, MD 
Alliance for Multispecialty Research (AMR) 
1928 Alcoa Hwy, Suite 107 
Knoxville, TN 37920 

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SIGNATURE PAGE 
 
The signature below provides the necessary assurances that this trial will be conducted according to 
all stipulations of the protocol, including all statements regarding confidentiality, and according to 
local legal and regulatory requirements and applicable United States federal regulations and ICH E6 
GCP guidelines. 
I agree to conduct the study in compliance with GCP and applicable regulatory requirements. 
I agree to conduct the study in accordance with the current protocol and will not make changes to 
the protocol without obtaining the sponsor’s approval and IRB/IEC approval, except when necessary 
to protect the safety, rights, or welfare of participants. 
 
 
Site Inve stigator Signature: 
Signed: 
Date: 
Kimberly Cruz, MD 
Advanced Pharma CR 
2950 NW 83rd St 
Miami, FL 33147 

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TABLE OF CONTENTS 
STATEMENT OF ASSURANCE ................................................................................................... 2 
STATEMENT OF COMPLIANCE ................................................................................................. 3 
SIGNATURE PAGE ........................................................................................................................ 4 
SIGNATURE PAGE ........................................................................................................................ 5 
TABLE OF CONTENTS ................................................................................................................. 6 
LIST OF TABLES ......................................................................................................................... 10 
LIST OF FIGURES ........................................................................................................................ 11 
LIST OF ABBREVIATIONS ........................................................................................................ 12 
PROTOCOL SUMMARY ............................................................................................................. 15 
1 
KEY ROLES ......................................................................................................................... 20 
2 
BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE .............................. 21 
Background ............................................................................................................... 21 
 
Tuberculosis .................................................................................................. 21 
 Tuberculosis in Patients with Renal Impairment .......................................... 22 
 
Pretomanid .................................................................................................... 22 
 Pre-Clinical Animal Studies .......................................................................... 23 
 
Clinical Trials for Safety and Pharmacokinetics ........................................... 24 
 Efficacy Studies ............................................................................................ 26 
Scientific Rationale ................................................................................................... 30 
 
Purpose of Study ........................................................................................... 30 
 Study Population ........................................................................................... 31 
Potential Risks and Benefits ...................................................................................... 31 
 
Potential Risks ............................................................................................... 31 
 Potential Benefits .......................................................................................... 33 
3 
STUDY DESIGN, OBJECTIVES, AND ENDPOINTS OR OUTCOME MEASURES ..... 34 
Study Design Description .......................................................................................... 34 
Study Objectives ....................................................................................................... 35 
 
Primary .......................................................................................................... 35 
 
Secondary ...................................................................................................... 35 
Study Endpoints or Outcome Measures .................................................................... 35 
 
Primary .......................................................................................................... 35 
 
Secondary ...................................................................................................... 36 
4 
STUDY INTERVENTION/INVESTIGATIONAL PRODUCT .......................................... 37 
Study Product Description ........................................................................................ 37 
 
Formulation, Packaging, and Labeling ......................................................... 37 
 Product Storage and Stability ........................................................................ 37 
Acquisition/Distribution ............................................................................................ 38 

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Dosage/Regimen, Preparation, Dispensing, and Administration of Study 
Intervention/Investigational Product ......................................................................... 38 
Pre-determined Modification of Study Intervention/Investigational Product for an 
Individual Participant ................................................................................................ 39 
Accountability Procedures for the Study Intervention/ Investigational Product(s) ... 39 
5 
SELECTION OF PARTICIPANTS AND STUDY ENROLLMENT AND WITHDRAWAL 
. .............................................................................................................................................. 40 
Eligibility Criteria ..................................................................................................... 40 
 
Participant Inclusion Criteria ........................................................................ 40 
 
Participant Exclusion Criteria ....................................................................... 42 
Withdrawal from the Study or Study Termination .................................................... 46 
 
Withdrawal from the Study ........................................................................... 46 
 
Participant Replacement ................................................................................ 47 
 
Study Termination ......................................................................................... 47 
6 
STUDY PROCEDURES ....................................................................................................... 48 
Screening ................................................................................................................... 48 
 
Visit 00A, Screening Clinic Visit (Day -28 to -7)......................................... 48 
 
Visit 00B, 2nd Screening Clinic Visit (Day -28 to -7) ................................... 48 
 
Visit 00C, Hospital Admission, Day -1 ........................................................ 49 
Dosing (Day 1) and In-house Confinement/ PK Collection ..................................... 50 
 
Visit 01A, Administration of Study Product ................................................. 50 
 
Visit 01B, Day 1, Time 1 Hour ± 10 Minutes Post-dose; Hospital Stay ...... 51 
 
Visit 01C, Day 1, Time 2 Hours ± 10 Minutes Post-dose; Hospital Stay ..... 51 
 
Visit 01D, Day 1, Time 4 Hours ± 10 Minutes Post-dose; Hospital Stay ..... 52 
 
Visit 01E, Day 1, Time 5 Hour ± 10 Minutes Post-dose; Hospital Stay ....... 52 
 
Visit 01F, Day 1, Time 6 Hours ± 10 Minutes Post-dose; Hospital Stay ..... 52 
 
Visit 01G, Day 1, Time 8 Hour ± 10 Minutes Post-dose; Hospital Stay ...... 53 
 
Visit 01H, Day 1, Time 12 Hours ± 10 Minutes Post-dose; Hospital Stay ... 53 
 
Visit 01I, Day 1, Time 16 Hour ± 10 Minutes Post-dose; Hospital Stay ...... 53 
 Visit 01J, Day 2, Time 24 Hour ± 1 Hour Post-dose; Hospital Stay ............ 54 
 Visit 01K, Day 2, Time 36 Hour ± 1 Hour Post-dose; Hospital Stay .......... 54 
 Visit 01L, Day 3, Time 48 Hours ± 1 Hour Post-dose, Hospital Stay .......... 54 
Follow-Up ................................................................................................................. 55 
 
Visit 01M, Day 4, Time 72 Hours ± 4 Hours Post-dose, Clinic Visit .......... 55 
 
Visit 01N, Day 5, Time 96 Hours ± 4 Hours Post-dose, Clinic Visit ........... 56 
 
Visit 02, Day 12 ± 2 Days Post-dose, Clinic Visit ........................................ 56 
Final Visit, Visit 03, Day 85+7 Days Post-dose, Phone Visit ................................... 57 
Early Termination Visit (if needed) .......................................................................... 57 
Unscheduled Visit (if needed) ................................................................................... 58 
Protocol Deviations ................................................................................................... 58 
7 
DESCRIPTION OF CLINICAL AND LABORATORY EVALUATIONS ........................ 59 

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Clinical Evaluations .................................................................................................. 59 
 
Assessment of Concomitant Medications/Treatments Other Than Study 
Product .......................................................................................................... 60 
Laboratory Evaluations ............................................................................................. 62 
 
Clinical Laboratory Evaluations .................................................................... 62 
 
Research Assays ............................................................................................ 62 
8 
ASSESSMENT OF SAFETY ............................................................................................... 64 
Assessing and Recording Safety Parameters ............................................................. 64 
 
Adverse Events .............................................................................................. 64 
 
Serious Adverse Events ................................................................................. 65 
Specification of Safety Parameters............................................................................ 66 
Reporting Procedures ................................................................................................ 67 
 
Reporting SAEs ............................................................................................. 67 
 
Regulatory Reporting for Studies Conducted Under DMID-Sponsored IND68 
 
Reporting of Pregnancy ................................................................................ 68 
Type and Duration of Follow-up of Participants After Adverse Events ................... 68 
Procedures to be Followed in the Event of Abnormal Laboratory Test Values or 
Abnormal Clinical Findings ...................................................................................... 69 
Halting Rules ............................................................................................................. 69 
 
Study Halting Criteria ................................................................................... 69 
Safety Oversight ........................................................................................................ 70 
 
Safety Monitoring Committee (SMC) .......................................................... 70 
9 
HUMAN PARTICIPANT PROTECTION ........................................................................... 71 
Institutional Review Board ....................................................................................... 71 
Informed Consent Process ......................................................................................... 71 
Special Populations ................................................................................................... 73 
Participant Confidentiality ........................................................................................ 73 
Certificate of Confidentiality ..................................................................................... 74 
Costs, Participant Compensation, and Research Related Injuries ............................. 74 
10 
STATISTICAL CONSIDERATIONS .................................................................................. 76 
 
Study Hypotheses ...................................................................................................... 76 
 
Sample Size Considerations ...................................................................................... 76 
 
Treatment Assignment Procedures ............................................................................ 77 
 Randomization Procedures ............................................................................ 77 
10.3.2 Masking Procedures ...................................................................................... 78 
 
Planned Interim Analyses .......................................................................................... 78 
 Interim Safety and PK Review ...................................................................... 78 
 
Final Analysis Plan .................................................................................................... 78 
 Analysis Populations ..................................................................................... 78 
 Analysis of Primary Endpoint (PK for Pretomanid) ..................................... 78 
 Analysis of Secondary Endpoint (Safety) ..................................................... 79 

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 Analysis of Secondary Endpoint (PK for M19 and M50) ............................ 81 
11 
ELECTRONIC CASE REPORT FORMS AND ACCESS TO SOURCE 
DATA/DOCUMENTS .......................................................................................................... 82 
12 
QUALITY CONTROL AND QUALITY ASSURANCE .................................................... 83 
13 
DATA HANDLING AND RECORD KEEPING ................................................................. 84 
 
Data Management Responsibilities ........................................................................... 84 
 
Data Coordinating Center/Biostatistician Responsibilities ....................................... 84 
 
Data Capture Methods ............................................................................................... 84 
 
Types of Data ............................................................................................................ 84 
 
Study Records Retention ........................................................................................... 84 
14 
CLINICAL MONITORING ................................................................................................. 86 
15 
PUBLICATION POLICY ..................................................................................................... 87 
16 
LITERATURE REFERENCES ............................................................................................ 88 
17 
APPENDICES ....................................................................................................................... 91 
APPENDIX A: Schedule of Study Procedures and Evaluations ................................................... 92 
APPENDIX B: Venipuncture Volumes (mL) ................................................................................ 95 

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LIST OF TABLES 
 
Table 1: 
Study Design ............................................................................................................... 18 
Table 2: 
Summary of Phase 2 studies using Pretomanid .......................................................... 28 
Table 3: 
Pretomanid Formulation.............................................................................................. 37 
Table 4: 
Prohibited Strong and Moderate CYP450 Enzyme Inducer or Inhibitor 
Medications/Substances per Participant Exclusion Criteria ....................................... 61 

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LIST OF FIGURES 
Figure 1: 
Schematic of Study Design ......................................................................................... 19 
Figure 2: 
Chemical Structure of Pretomanid .............................................................................. 22 
Figure 3: 
Probability of Observing at Least 50% Increase by Varying CV and True 
Percent Increase .......................................................................................................... 77 

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LIST OF ABBREVIATIONS 
 
Advantage eClinical® 
Electronic Data Capture System 
AE 
Adverse Event/Adverse Experience 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
AUC 
Area under the plasma concentration-time curve 
AUC∞ 
Area under the plasma concentration-time curve from time 0 to infinity 
AUClast 
Area under the plasma concentration-time curve from time 0 to the last 
measurement 
A-V 
Atrioventricular 
BCG 
Bacillus Calmette-Guérin 
BDQ 
Bedaquiline 
BMI 
Body Mass Index 
BPaL 
Pretomanid, Bedaquiline, and Linezolid 
BPM 
Beats Per Minute 
BUN 
Blood Urea Nitrogen 
Cavg 
Average Concentration Over a Dosing Interval 
CFR 
Code of Federal Regulations 
CFU 
Colony Forming Unit 
CG 
Cockcroft-Gault 
CHF 
Congestive Heart Failure 
CI 
Confidence Interval 
CKD 
Chronic Kidney Disease 
CL/F 
Apparent Clearance 
CLR 
Renal Clearance 
Cmax 
Maximum plasma concentration 
CMS 
Clinical Materials Services 
CROMS 
Clinical Research Operations & Management Support 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
Coefficients of Variation 
CYP450 
Cytochrome P450 
°C 
Degrees Celsius 
°F 
Degrees Fahrenheit 
DCC 
Data Coordinating Center 
DCF 
Data Collection Form 
DHHS 
Department of Health and Human Services 
dL 
Deciliter 
DMID 
Division of Microbiology and Infectious Diseases, NIAID, NIH 
DOTS 
Directly Observed Therapy Short Course 
EBA 
Early Bactericidal Activity 
ECG 
Electrocardiogram 

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eCRF 
Electronic Case Report Form 
ED 
Emergency Department 
EDTA 
Ethylenediaminetetraacetic acid 
eGFR 
Estimated Glomerular Filtration Rate 
EHR 
Electronic Health Record 
EMA 
European Medicines Agency 
EMEA 
Europe, the Middle East, and Africa 
ESRD 
End Stage Renal Disease 
ET 
Early Termination 
FDA 
Food and Drug Administration 
FWA 
Federal Wide Assurance 
g/dL 
Grams per Deciliter 
GCP 
Good Clinical Practice 
GFR 
Glomerular Filtration Rate 
HBsAg 
Hepatitis B surface antigen 
HBV 
Hepatitis B virus 
HCG 
Human Chorionic Gonadotropin 
HCV 
Hepatitis C virus 
Hgb 
Hemoglobin 
HRZE 
Standard Treatment with Isoniazid, Rifampin, Pyrazinamide, and 
Ethambutol 
IATA 
International Air Transport Association 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug Application 
INH 
Isoniazid 
IRB 
Institutional Review Board 
kg 
Kilogram 
LLT 
Low Level Term 
LZD 
Linezolid 
µg 
Microgram(s) 
µL 
Microliter(s) 
MDRD 
Modification of Diet in Renal Disease 
MDR-TB 
Multidrug-Resistant Tuberculosis 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
mg/dL 
Milligram(s) per Deciliter 
MIC 
Minimum Inhibitory Concentration 
mL 
Milliliter(s) 
mm 
Millimeter(s) 

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mmHg 
Millimeters of Mercury 
msec 
Millisecond 
MOP 
Manual of Procedures 
Mtb 
Mycobacterium tuberculosis 
N 
Number of Participants 
NIAID 
National Institute of Allergy and Infectious Diseases, NIH, DHHS 
NIH 
National Institutes of Health 
NO 
Nitric Oxide 
OER 
Office of Extramural Research 
OHRP 
Office for Human Research Protections 
PHI 
Personal Health Information 
PI 
Principal Investigator 
PK 
Pharmacokinetics 
Qc 
Quality Control 
RH 
Relative Humidity 
SAE 
Serious Adverse Event/Serious Adverse Experience 
SDCC 
Statistical and Data Coordinating Center 
SMC 
Safety Monitoring Committee 
SOC 
System Organ Class 
SZD 
Sutezolid 
t1/2 
Elimination Half-life 
TB 
Tuberculosis 
TEAE 
Treatment Emergent Adverse Event 
TI 
Treatment-intolerant 
Tmax 
Time to maximum (peak) plasma drug concentration 
ULN 
Upper Limit of Normal 
US 
United States 
Vd/F 
Volume of distribution 
WHO 
World Health Organization 
XDR-TB 
Extensively Drug-Resistant TB 

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PROTOCOL SUMMARY 
 
 
Title: 
A Phase 1, Open-Label, Single-Dose Study to Evaluate the 
Pharmacokinetics and Safety of Pretomanid in Participants with 
Renal Impairment Compared to Participants with Normal Renal 
Function 
Design of the Study: 
This is a Phase 1, open-label, single-dose, sequential group study to 
compare the safety and pharmacokinetics (PK) of pretomanid in the 
following groups of participants: 1) participants with severe renal 
impairment including those with end stage renal disease (ESRD) not 
on dialysis, and participants with mild or moderate renal 
impairment, designated as Groups 2, 3, and 4, respectively; and 2) 
participants with normal renal function matched to the above renal 
impairment groups, designated as Groups 1A, 1B, and 1C, 
respectively. 
The study will be conducted following a reduced PK study design 
in Part A, see Table 1 and Figure 1. Part A will enroll participants 
from Group 1A (i.e., 6 healthy matched controls) and Group 2 (i.e., 
6 participants with severe renal impairment and ESRD, not on 
dialysis). A decision to proceed to Part B will be made after the PK 
of pretomanid, and safety in participants enrolled in Part A have 
been reviewed. If Part A demonstrates at least a 50% increase in 
pretomanid area under the plasma concentration-time curve (AUC) 
in Group 2 (severe renal impairments and ESRD, not on dialysis) 
relative to the exposures in Group 1A (matched participants with 
normal renal function), then the reduced PK study will extend to the 
full PK study to enroll participants into Part B (i.e., to investigate 
mild and moderate renal impairment). All Part B groups (1B, 1C, 3, 
and 4) will be enrolled concurrently. 
If the reduced PK study shows at least a 50% increase in AUC in 
patients with severe renal impairment and patients with ESRD not 
yet on dialysis relative to the matched healthy controls, a “full PK” 
renal impairment study in patients with all intermediate levels of 
renal function impairment should be conducted. Otherwise, no 
further study is recommended. 
Study Population: 
Total 36 male and female adult participants ages of 18 to 85 years 
inclusive, including 18 participants with normal renal function 
matched against each of the renal impairment groups, and 18 renal 

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impaired participants (N=6 mild renal impairment, N=6 moderate 
renal impairment, and N=6 severe renal impairment) as defined by 
estimated glomerular filtration rate (eGFR) (see Table 1). 
Six participants with normal renal function in each group (1A, 1B, 
1C) will be matched by race, gender, age (± 10 years, but between 
18 to 85 years of age), and body mass index (BMI) (18 to 40 kg/m2) 
at enrollment; eGFR ≥90 mL/min as calculated by Modification of 
Diet in Renal Disease (MDRD) to each renal impairment Group 2, 
3, and 4, respectively. 
Group 2: Severe renal impairment: Stage 4 (eGFR 15-29 mL/min) 
and ESRD not on dialysis: Stage 5, MDRD (eGFR <15 mL/min). 
Group  3:  Mild  renal  impairment:  Stage  2,  MDRD (eGFR 
60-89 mL/min). 
Group 4: Moderate renal impairment: Stage 3, MDRD (eGFR 
30-59 mL/min). 
Number of Sites: 
2 
Description of Study 
Product or Intervention: 
A single oral dose of pretomanid 200 mg 
Study Objectives: 
Primary: 
• To evaluate the PK profiles of pretomanid in plasma and 
urine after a single oral dose of 200 mg in participants with 
renal impairment compared to matched healthy controls. 
Secondary: 
• To assess the safety profile of a single oral dose of 200 mg 
pretomanid in renally impaired participants compared to 
matched healthy controls. 
• To evaluate the PK profiles of representative pretomanid 
metabolites (M19 and M50) in plasma and urine. 
Duration of Individual 
Participant Participation: 
Approximately 3 months not including the initial screening visit. 

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Estimated Time to Last 
Participant/Last Study Day: 
Part A: 12 months 
Part B: 18 months 

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Table 1: Study Design 
Part A 
Group 
N 
Participant Characteristics 
Stagea 
eGFRb 
mL/min 
1A 
6 
Healthy matched participants 
(controls) with normal renal function 
N/A 
≥90 
2 
6 
Severe renal impairment and ESRD 
not on dialysis 
4 
5 
15-29 mL/min 
<15 mL/min 
Total 
12 
 
Part B 
Group 
N 
Participant Characteristics 
Stagea 
eGFRb 
mL/min 
1B 
6 
Matched participants with normal 
renal function 
N/A 
≥90 
3 
6 
Mild renal impairment 
2 
60-89 
1C 
6 
Matched participants with normal 
renal function 
N/A 
≥90 
4 
6 
Moderate renal impairment 
3 
30-59 
Total 
24 
CKD=chronic kidney disease; eGFR=electronic case report form; ESRD=end stage renal disease; MDRD=Modification 
of Diet in Renal Disease; N/A=not applicable. 
a Stage based on Clinical Practice Guidelines for CKD (National Kidney Foundation, 2002) and Guidance for Industry 
Pharmacokinetics in Patients with Impaired Renal Function- Study Design, Data analysis and Impact on Dosing 
(DHHS, FDA, and CDER 2020 Draft Guidance). 
b 
eGFR: estimated glomerular filtration rate based on an MDRD equation. Different mathematical formulas 
have been developed to determine eGFR. The MDRD eGFR formula was developed to adjust for body surface area 
and ethnicity, as well as considerations such as age and gender. In many ways the MDRD is superior to the Cockcroft- 
Gault calculation as it is more precise and reliable in predicting GFR. eGFR for this study is automatically calculated 
by clinical laboratories. 

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Figure 1: 
Schematic of Study Design 
 
ESRD=end stage renal disease; PK=pharmacokinetics 
Group 1A: Matched controls to Group 2, with normal renal function 
Group 2: Severe renal impairment and ESRD, not on dialysis 
Group 1B: Matched controls to Group 3, with normal renal function 
Group 3: Mild renal impairment 
Group 1C: Matched controls to Group 4, with normal renal function 
Group 4: Moderate renal impairment 

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1 
KEY ROLES 
 
 
 
Lead Principal Investigators: 
William Smith, MD 
Alliance for Multispecialty Research (AMR) 
1928 Alcoa Hwy, Suite 107 
Knoxville, TN 37920 
Kimberly Cruz, MD 
Advanced Pharma CR 
2950 NW 83rd St 
Miami, FL 33147 
DMID Clinical Project 
Manager: 
Erica Sondergaard, RN, BSN, CCRC 
Statistical and Data 
Coordinating Center: 
The Emmes Company, LLC 

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2 
BACKGROUND 
INFORMATION 
AND 
SCIENTIFIC 
RATIONALE 
 
Background 
 
Tuberculosis 
 
Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) is an age-old disease and remains 
a major public health problem worldwide. It is estimated that one-third of the world’s population is 
infected with Mtb, with about 10 million new cases of TB and 1.2 million deaths annually [1]. For 
the past 5 years, TB has been the leading cause of death from a single infectious agent, ranking above 
HIV/AIDS [1]. Bacillus Calmette-Guérin (also known as BCG), an attenuated strain of 
Mycobacterium bovis, is the only available TB vaccine. The efficacy of this vaccine varies from 
place to place and is generally low [2, 3]. However, it is used by many countries because it protects 
against severe forms of TB in children [2, 3]. Therefore, TB control relies on case detection, 
chemoprophylaxis for newly infected individuals, and directly observed therapy short course 
(DOTS) for TB patients. DOTS, despite its name, is not really a short course. Under DOTS, patients 
are required to take multiple drugs for at least 6 months [4]. Similarly, chemoprophylaxis for newly 
infected individuals takes 3 to 9 months [5, 6]. Long duration of treatment is associated with 
increased cost for follow-up, increased side effects of drugs and increased risk of default that may 
lead to emergence of drug-resistant TB. The World Health Organization (WHO) reports that several 
countries have large numbers of patients with multidrug-resistant tuberculosis (MDR-TB), resistant 
to at least isoniazid (INH) and rifampin [7]. Further, less than 50% of those who started second-line 
drugs had successful treatment outcome [1] and the number of MDR-TB cases is increasing mainly 
due to lack of effective treatment [7]. In addition, several countries with high prevalence of MDR- 
TB also show increasing numbers of extensively drug-resistant (XDR-TB) cases. These are resistant 
not only to INH and rifampin, but fluoroquinolones and aminoglycosides as well. Treatment of 
XDR-TB is even more difficult and the outcome is unpredictable [1, 8]. Thus, MDR- and XDR-TB 
are global problems because of the lack of effective treatment, the need for much longer treatment 
with second-line or experimental drugs, and the risk of further spread through travel and 
immigration. This calls for enhanced efforts to develop new drugs. 
Pretomanid is approved by the United States (US) Food and Drug Administration (FDA) and by the 
European Medicines Agency (EMA) for treating adult patients with extensively drug-resistant, 
treatment-intolerant (TI) or nonresponsive (NR) multidrug-resistant pulmonary TB, in combination 
with bedaquiline (BDQ) and linezolid (LZD) (pretomanid, bedaquiline, and linezolid [BPaL] 
regimen). Pretomanid is administered orally 200 mg once daily for 26 weeks; the BPaL regimen is 
taken with food. 

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Tuberculosis in Patients with Renal Impairment 
 
Chronic kidney disease (CKD) is defined as a reduced glomerular filtration rate (GFR), increased 
urinary albumin excretion, or both, for 3 or more months and is an increasing public health issue 
with estimated prevalence of 8 to16% worldwide [9]. Patients with CKD and kidney transplant have 
a higher risk of developing TB compared with the general population presumably due to associated 
immunodeficiency [10-13]. Immunodeficiency associated with renal impairment appears to be 
multifactorial including defects in oxidative stress, inflammation, vitamin D deficiency, 
malnutrition, and functional abnormalities in immune cells, particularly B and T cells [11, 13]. 
Changes in immunity begin as early as Stage 3 CKD (eGFR 30-59 mL/min/1.73 m2) and worsen in 
later stages as kidney function deteriorates and waste products accumulate. 
The treatment of new drug-susceptible pulmonary TB in patients with renal impairment includes 
4 first-line drugs such as INH, rifampin, ethambutol, and pyrazinamide, similar to the treatment of 
patients with normal renal function. However, the doses of pyrazinamide and ethambutol have to be 
adjusted for renal function [14]. Approximately 80% of ethambutol is cleared by the kidneys and 
may accumulate in patients with renal impairment [15, 16]. Pyrazinamide is metabolized in the liver 
and its metabolites such as pyrazinoic acid and 5-hydroxy-pyrazinoic acid may accumulate in 
patients with renal insufficiency [15, 16]. Despite appropriate use of first-line anti-TB drugs, patients 
with renal impairment have worse clinical outcomes than those without renal impairment, and 
require close monitoring [14, 17]. 
 
Pretomanid 
 
2.1.3.1 
Structure and Molecular Weight 
 
Pretomanid, a nitroimidazooxazine, is a chemical entity with a molecular weight of 359 Daltons [18, 
19]. Figure 2 shows the chemical structure. 
Figure 2: Chemical Structure of Pretomanid 
 

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2.1.3.2 
Mechanism of Action 
 
The mechanism of action of pretomanid is not fully understood, but it appears to have multiple 
activities. Under aerobic conditions, it inhibits Mtb cell wall biosynthesis by inhibiting the oxidation 
of hydroxymycolate to ketomycolate [20, 21]. Under anaerobic conditions, pretomanid generates 
reactive nitrogen species, including nitric oxide (NO) [22]. These known mechanisms under aerobic 
and anaerobic conditions explain why pretomanid has excellent early bactericidal and sterilizing 
activities [23, 24]. Early bactericidal activity (EBA) refers to an agent's ability to kill most of 
mycobacteria in the lung during the first few weeks of treatment [23]. Sterilizing activity measures 
the ability of the drug to kill persisting forms of Mtb, and therefore decrease relapse rates [24, 25]. 
2.1.3.3 
Microbiologic Activities in Vitro 
 
In vitro studies demonstrated that the pretomanid was active against actively growing drug-sensitive 
Mtb isolates with the minimum inhibitory concentration (MIC) ranging from ≤0.0015 to 0.3 µg/mL 
[20, 21], which is comparable to the MIC of INH, one of the key first-line anti-TB drugs. Pretomanid 
was also tested in vitro against a broad panel of multidrug-resistant (MDR) clinical isolates of Mtb 
and was found to be highly active against all tested isolates with MIC <1 µg/mL [26]. Interestingly, 
in addition to its ability to kill actively growing Mtb, pretomanid demonstrated 85%, 89.6%, and 
93.5% killing of Mtb persisting under anaerobic conditions at 2, 10, and 30 µg/mL, respectively [26]. 
 
Pre-Clinical Animal Studies 
 
2.1.4.1 
Toxicology 
 
Before advancement to human trials, the potential adverse effects of pretomanid were evaluated in 
repeat-dose toxicity studies up to 13 weeks in duration in mice, up to 26 weeks in duration in Sprague 
Dawley rats, up to 13 weeks in duration in cynomolgus monkeys. Adverse effects were uncommon 
at doses ≤50mg/kg [18]. 
2.1.4.2 
Pharmacokinetics 
 
The PK profile of pretomanid following single-dose administration has been determined in mice, 
Sprague Dawley rats, cynomolgus monkeys, and New Zealand white rabbits, and the PK profile 
following repeated oral doses of pretomanid has been determined in Sprague Dawley rats and 
cynomolgus monkeys [18]. Systemic exposure to pretomanid following a single oral dose in mice, 
rats, monkeys, and rabbits increased with increasing dose, but the increase was less than dose 
proportional. The elimination half-life (t½) of pretomanid following a single oral dose was 
approximately 3 to 7 hours in male rats, monkeys, and rabbits. The t½ in female rats following single 
oral doses was longer (7 to 9 hours). In multiple studies in rats, the time to peak plasma concentration 
(Tmax) generally ranged from 3.3 to 8 hours. In 14-day studies in rats and monkeys, pretomanid levels 

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in plasma were comparable on Days 1 and 14, indicating no accumulation of pretomanid after 
repeated dosing. Elimination kinetics in rats, rabbits, and monkeys were comparable to values 
observed after single doses, suggesting sustained pretomanid exposure in these animal species does 
not induce drug metabolic systems or other means of eliminating the drug from the body. 
The elimination kinetics were determined in rats and monkeys using radiolabeled pretomanid 
preparations [18]. The findings suggest that pretomanid is subjected to both hepatic metabolism and 
renal excretion. The majority of the excretion was into urine. An average of 88.1% and 67.5% of the 
dose was recovered in the urine and feces for rats and monkeys, respectively. 
2.1.4.3 
Efficacy 
 
In a dose fractionation study in a murine model of active TB, total pretomanid doses from 144 to 
4608 mg/kg were administered as 3, 4, 8, 12, 24, or 48 divided doses over 24 days beginning 2 weeks 
after aerosol infection with Mtb [27]. In this model, pretomanid exhibited time-dependent 
bactericidal activity, with a maximum observed bactericidal effect of 0.1 log colony forming unit 
(CFU)/day over 24 days. Lung CFU counts strongly correlated with the free drug time above MIC 
(T>MIC) and free drug area under the plasma concentration-time curve (AUC)/MIC, where T>MIC 
is the cumulative percentage of the dosing interval that the drug concentration exceeds the MIC 
under steady-state exposure conditions. 
The effectiveness of various 3-drug combinations involving pretomanid was further evaluated in a 
murine model of TB. The combination of pretomanid (50 mg/kg) with BDQ and sutezolid (SZD) or 
LZD was superior to that of the first-line regimen for drug-susceptible TB (rifampin, pyrazinamide, 
and INH in reducing lung mean CFU counts in BALB/c mice infected with Mtb. The addition of 
SZD significantly increased the initial bactericidal activity of pretomanid + BDQ, rendering all mice 
culture-negative between 1 and 2 months of treatment. Although the decline in CFU counts with the 
3-drug regimen containing LZD was not as rapid as that for the regimen containing SZD, the 
combination of LZD + BDQ + pretomanid was also significantly superior to the standard regimen 
after 2 months of treatment [28]. Both 3-drug combinations (pretomanid + BDQ + [SZD or LZD]) 
resulted in significantly fewer relapses after 3 months of treatment compared to either the first-line 
regimen or the 2-drug combination of pretomanid + BDQ. 
 
Clinical Trials for Safety and Pharmacokinetics 
 
2.1.5.1 
Safety 
 
Based on unpublished safety data of the Phase 1 pooling group (i.e., pooled data from all Phase 1 
studies in healthy volunteers) from the Integrated Summary of Safety for the pretomanid New Drug 
Application, the most frequently (≥10% of participants) reported preferred terms of treatment-
emergent adverse events (TEAEs) in the all-pretomanid group (single dose or multiple doses) were 
headache (31.5%), nausea (11.8%), hemoglobin decreased (10.7%), and dermatitis 

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contact (11.4%). Hemoglobin decreased and dermatitis contact were driven by the data from the 
thorough QT study where multiple blood samples were taken. Participants from all the treatment 
groups shared the same trending with decreased hemoglobin levels. Dermatitis contact reported were 
associated with electrocardiogram (ECG) patches. In the control group, the only AE reported in at 
least 10% of participants was headache, with an incidence lower than that in the all-pretomanid 
group (22.9% versus 31.5%). 
2.1.5.2 
Pharmacokinetics 
 
The Investigator Brochure (IB) [18] includes data from the Phase 1 studies in healthy volunteers and 
Phase 2 studies in participants with pulmonary TB. These data indicate that the PK profile for 
pretomanid following oral dosing was consistent for healthy participants and participants with 
pulmonary TB. In both populations, pretomanid was readily absorbed after oral administration and 
slowly eliminated from plasma. Pretomanid plasma concentrations increased in a dose-dependent 
manner after single-dose administration of up to 1000 mg in healthy participants and participants 
with TB, but the increase was less than dose proportional, particularly at doses above 200 mg/day. 
The hypothesis that absorption decreases (i.e., is saturated) at high doses of pretomanid was further 
supported by the observations that mean apparent clearance (CL/F) and volume of distribution (Vd/F) 
at steady-state (Day 7) values increased with dose, while the mean elimination half-life (t1/2) values 
remained similar across dose levels. This suggests that the apparent lack of dose proportionality in 
exposure is most likely related to the decreased bioavailability with increasing dose. 
In both healthy participants and participants with pulmonary TB, steady-state concentrations of 
pretomanid in plasma were achieved within approximately 5 days of once-daily dosing, and the 
accumulation factor was approximately 2. Both findings support the observed elimination t½ of 
approximately 18 hours in healthy participants and participants with pulmonary TB. The mean peak 
concentration (Cmax) and AUC from time 0 to 24 hours (AUC0-24hr) values following a 200 mg dose 
of pretomanid in participants with pulmonary TB ranged from 1.1 to 1.2 μg/mL and 17 to 19 
μg·hr/mL, respectively, after single-dose administration and from 2.2 to 2.4 μg/mL and 38 to 40 
μg·hr/mL, respectively, after 14 days of dosing. 
Based on the IB [18], pretomanid is moderately absorbed following oral administration, with a Tmax 
of 4 to 5 hours after single- or multiple-dose administration under fasted conditions. Dosing with a 
high-calorie, high-fat meal increased the Tmax by approximately 1 hour, and the drug exposure was 
about half in the fasted state comparing with that in the fed state. It is recommended that the clinical 
dose of 200 mg be administered in the fed state. 
Overall, oral CL/F values (~8 L/hr) for pretomanid at a 200 mg dose are considerably less than the 
hepatic blood flow for a 70 kg human (1450 mL/min, 87.0 L/hr), suggesting that pretomanid is not 
highly extracted by the liver. Furthermore, the apparent Vd/F after a 200 mg dose was approximately 

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175 L, which is considerably higher than the total volume of body water (~42 L), indicating that 
pretomanid is distributed out of plasma. 
Pretomanid binding to human plasma protein is 86.4%, with the majority of the binding to human 
serum albumin [18]. In the presence of rifampicin (strong cytochrome [CYP] 3A4 inducer) and 
efavirenz (moderate CYP3A4 inducer), pretomanid average concentration over a dosing interval 
(Cavg) is reduced by 66% and 35%, respectively. Therefore, strong and moderate CYP3A4 inducers 
should be avoided with pretomanid. 
Once-daily oral administration of pretomanid 400 mg for 14 days did not appear to significantly 
inhibit CYP3A4 in healthy participants, based on the results of a drug-drug interaction study with 
midazolam, a sensitive probe substrate for drugs metabolized by CYP3A enzymes. Results of in 
vitro investigations using human liver microsomes also support a low risk of drug-drug interactions 
with pretomanid. In 2 mass-balance studies in healthy participants [18], approximately 91% of the 
administered radioactive dose was recovered in the urine (65% and 53%) and feces (26% and 38%). 
The majority of urinary and fecal radioactivity elimination occurred within 6 to 7 days after dosing. 
Comparisons of plasma and whole blood total radioactivity PK parameters to plasma pretomanid PK 
parameters suggest that the majority of the administered dose is converted to pretomanid 
metabolites, after which time total radioactivity in blood is eliminated slowly from the body. 
No clinically significant differences in the PK of pretomanid were observed based on sex, body 
weight, race, pulmonary TB status, or HIV status. 
The effect of renal or hepatic impairment on the PK of pretomanid is unknown. 
 
Efficacy Studies 
 
2.1.6.1 
Efficacy As a Single Agent 
 
Different doses of pretomanid, given as a single agent, were evaluated in 2 studies [23, 29]. In the 
first study, doses of 200, 600, 1000, and 1200 mg/day were used [23]. In the second study, lower 
doses including 50, 100, 150, and 200 mg/day were used [29]. Both studies produced a measurable 
decrease in sputum CFU counts over the 14-day treatment period. The results, summarized in Table 
2, indicate that there were no meaningful differences among the pretomanid dose groups of 200 to 
1200 mg/day also supported by formal dose trend analyses. There was a dose-related trend with 
respect to changes in mean logCFU values over time in the second study, with a smaller reduction 
seen in the 50 mg/day dose group compared with the 100, 150, or 200 mg/day dose groups. This latter 
study, however, was not powered to detect significant differences between the dose groups. 

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2.1.6.2 
Efficacy When Administered in a Multidrug Regimen 
 
Three Phase 2 studies evaluated pretomanid efficacy in a multidrug regimen [18, 30-32]. The 
treatment regimens studied, and results are summarized in Table 2. The first multidrug regimen [30] 
compared 6 regimens: 
• BDQ (alone). 
• BDQ + pyrazinamide. 
• pretomanid + BDQ. 
• pretomanid + pyrazinamide. 
• pretomanid + moxifloxacin + pyrazinamide. 
• standard treatment regimen (INH, rifampin, pyrazinamide, and ethambutol). 
In this trial, the mean daily rate of decline in logCFU in the first 14 days of treatment was highest 
for pretomanid + moxifloxacin + pyrazinamide combination. The second multidrug regimen [32] 
was a 7-arm study of the following treatments: 
• pretomanid + BDQ + pyrazinamide + clofazimine. 
• pretomanid + BDQ + pyrazinamide. 
• pretomanid + BDQ + clofazimine. 
• BDQ + pyrazinamide + clofazimine. 
• pyrazinamide alone. 
• clofazimine alone. 
• standard treatment with INH, rifampin, and pyrazinamide. 
The study showed that a regimen containing pretomanid + BDQ + pyrazinamide resulted in a marked 
daily rate of decline in logCFU (mean 0.167) comparable to standard treatment (mean 0.151), 
indicating that the pretomanid-containing regimen is a potential new TB treatment regimen. In the 
third trial, 3 regimens were compared, and the mean daily rate of decline of logCFU with a regimen 
containing pretomanid 200 mg + moxifloxacin + pyrazinamide was significantly greater than 
standard treatment (0.155 vs 0.112, respectively) [31]. 

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2.1.6.3 
Efficacy on Drug-Resistant TB 
 
In a Phase 2 trial by Dawson et al [31], 26 patients with MDR-TB were treated with pretomanid + 
moxifloxacin + pyrazinamide. The mean daily rate of decline in logCFU over 56 days in MDR-TB 
patients was comparable to treatment-naïve patients treated with standard treatment (0.117 vs 0.112, 
respectively). These results indicate that pretomanid is useful for treatment of MDR-TB. 
A Phase 3, pivotal, open-label trial Nix-TB assessed the safety, tolerability, efficacy, and PK of 
BPaL regimen in the treatment of patients with either pulmonary XDR-TB or TI/NR MDR-TB. A 
total of 109 patients aged 17 to 60 years old with pulmonary XDR-TB or TI/NR MDR-TB were 
enrolled at 3 centers in South Africa. Patients received study treatment for a minimum of 6 months 
(i.e., until Week 26). If patients were culture positive or reverted to being culture positive between 
Month 4 and Month 6 and their clinical condition suggested they may have ongoing TB infection, 
the study treatment may have been extended to 9 months (i.e., Week 39) or the patient may have 
been withdrawn from the trial. The primary endpoint was the incidence of an unfavorable outcome, 
defined as treatment failure (bacteriologic or clinical) or disease relapse. Clinical treatment failure 
was defined as a change from the protocol-specified TB treatment as a result of a lack of clinical 
efficacy, retreatment for TB, or TB-related death through follow-up until 6 months after the end of 
treatment. The success rate was 89% at 6-month post end of treatment. FDA and EMA approval of 
pretomanid, in the context of the BPaL regimen, was based on the Nix-TB data [33]. 
Table 2:  Summary of Phase 2 studies using Pretomanid 
Outcome 
measure 
N* 
Regimens 
Results 
Conclusions 
Ref. 
Single Agent 
Daily rate 
of decline 
in logCFU 
over 14 
days (Mean 
± SD) 
69 
Pretomanid 200 mg 
0.098 ± 0.07 
Outcome measure the same 
for all 4 pretomanid dosages. 
[23] 
Pretomanid 600 mg 
Pretomanid 1000 mg 
Pretomanid 1200 mg 
Standard (HRZE)¥ 
0.148 ± 0.055 
Daily rate 
of decline 
in logCFU 
over 14 
days (Mean 
± SD) 
69 
Pretomanid 50 mg 
0.063 ± 0.058 
-Dose-related trend with a 
smaller reduction seen in the 
50 mg/day group. 
-Study not powered to detect 
significant differences 
between the dose groups. 
[29] 
Pretomanid 100 mg 
0.09 ± 0.073 
Pretomanid 150 mg 
0.078 ± 0.074 
Pretomanid 200 mg 
0.112 ± 0.070 
Standard (HRZE)¥ 
0.177 ± 0.042 
Multidrug Regimen 
Daily rate 
of decline 
in logCFU 
over 14 
85 
Bedaquiline 
0.061 ± 0.068 
-The mean decline in CFU in 
pretomanid + moxifloxacin + 
pyrazinamide group was 
significantly higher than the 
decline in all other groups 
[30] 
Bedaquiline + 
pyrazinamide 
0.131 ± 0.102 
Pretomanid + 
Bedaquiline 
0.114 ± 0.050 

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Outcome 
measure 
N* 
Regimens 
Results 
Conclusions 
Ref. 
days (Mean 
± SD) 
Pretomanid + 
Pyrazinamide 
0.154 ± 0.040 
except pretomanid + 
pyrazinamide and standard 
treatment groups. 
Pretomanid + 
Moxifloxacin + 
Pyrazinamide 
0.233 ± 0.128 
Standard (HRZE)¥ 
0.14 ± 0.094 
Daily rate 
of decline 
in logCFU 
over 14 
days, Mean 
(95% CI) 
105 
Pretomanid + 
Bedaquiline + 
Pyrazinamide + 
Clofazimine 
0.115 
(0.039-0.189) 
[32] 
Pretomanid + 
Bedaquiline + 
Pyrazinamide 
0.167 
(0.075-0.257) 
This regimen is a potential 
new TB treatment. 
Pretomanid + 
Bedaquiline + 
Clofazimine 
0.076 
(0.005-0.145) 
Bedaquiline + 
Pyrazinamide + 
Clofazimine 
0.124 
(0.035-0.214) 
Pyrazinamide 
0.036 
(-0.026-0.099) 
Clofazimine 
-0.017 
(-0.085-0.053) 
Clofazimine has no activity 
alone. 
Standard (HRZE)¥ 
0.151 
(0.071-0.232) 
Daily rate 
of decline 
in logCFU 
over 56 
days, Mean 
(95% 
Bayesian 
credibility 
interval) 
207 
Pretomanid (100 mg) 
+ Moxifloxacin + 
Pyrazinamide 
0.133 
(0.109-0.155) 
[31] 
Pretomanid (200 mg) 
+ Moxifloxacin + 
Pyrazinamide 
0.155 
(0.133-0.178) 
-Daily CFU decline 
significantly greater than that 
for standard treatment. 
Standard (HRZE)¥ 
0.112 (0.093- 
0.131) 
Pretomanid (200 mg) 
+ Moxifloxacin + 
Pyrazinamide 
0.117 (0.070- 
0.174) 
-Only MDR-TB patients 
included. 
-Daily reduction in CFU was 
comparable to that of standard 
treatment for patients with 
drug-susceptible TB. 
CI=confidence interval; CFU=colony forming unit; HRZE=standard treatment with isoniazid, rifampin, pyrazinamide, 
and ethambutol; MDR-TB=multidrug-resistant tuberculosis; TB=tuberculosis. 

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*N includes all volunteers randomized to the different study groups. ¥, Standard (HRZE) indicates standard treatment 
with isoniazid, rifampin, pyrazinamide, and ethambutol. 
§All pretomanid doses were once daily and all-pretomanid doses were 200 mg unless specified. Unless specified, all 
studies were on treatment-naïve patients with pulmonary TB. 
 
Scientific Rationale 
 
Purpose of Study 
 
TB is a major public health problem worldwide. Treatment of drug-susceptible TB requires the use 
of 4 first-line anti-TB drugs for at least 6 months [4]. New drug treatments may help shorten the 
duration of treatment and potentially increase patient compliance, and therefore, have a direct impact 
on the control of TB. Furthermore, MDR and XDR-TB have made the prevalence of TB more 
challenging. Up to 50% of MDR-TB cases fail treatment and treatment outcome of XDR-TB is 
unpredictable [1], indicating that development of new anti-TB drugs is an essential component of 
TB control. 
Pretomanid is one of a few anti-TB drugs with the following unique and attractive characteristics: 
 
1. It has early bactericidal and sterilizing activity, with a potential to shorten the duration of 
treatment for drug-susceptible TB [23, 24]. It shortens the duration of treatment for 
MDR-TB in the context of the BPaL regimen [33], 
2. It has excellent activities against both drug-sensitive and MDR-isolates of Mtb [26], 
3. It has been shown to have a low incidence of AEs in multiple clinical trials [18], 
4. It has narrow spectrum of activity limited primarily to Mtb with no significant activity 
against a broad range of Gram-positive and Gram-negative bacteria [34], 
5. It has no demonstrable cross resistance to a variety of anti-TB drugs [25], 
6. It is administered orally [18, 19], and 
7. It neither inhibits nor is metabolized by major CYP450 enzyme isoforms except for 
CYP3A4 in vitro, importantly indicating a low potential for drug-drug interactions, 
including with presently used antiretrovirals for treatment of HIV [35, 36]. 
Patients with renal impairment, particularly severe renal impairment or end stage renal disease 
(ESRD), may have an increased risk of drug exposure and may require lower doses of certain drugs 
compared to patients with normal renal function [37]. According to FDA and Europe, the Middle 
East, and Africa (EMEA) guidelines, a PK study should be carried out during the development phase 
of a new drug that is likely to be used in patients with renal dysfunction and whose pharmacokinetics 
are likely to be significantly altered in renally impaired patients [38, 39]. Less than 1% of 

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unmetabolized pretomanid is excreted in the urine. [18]. Therefore, like other commonly used anti-
TB drugs such as ethambutol and pyrazinamide, which are at least partly eliminated through kidneys, 
the PK of pretomanid must be studied in patients with CKD. CKD is a very common clinical disease 
with estimated prevalence of 8 to 16%, and CKD patients globally, particularly those in advanced 
stages, have significantly increased risk of developing TB [11-13]. 
Regarding pretomanid metabolites, no single metabolic pathway can be considered major. Two 
metabolites have been selected for quantification: M19 (4-Trifluoromethoxybenzoic acid) and M50 
(hydroxy imidazole). In one mass-balance study, M19 was the largest drug-derived metabolite, 
representing up to 35% of the sample radioactivity at 24 hours post-dose. However, it has no activity 
or toxicity. In another mass-balance study, M50 was found to account for 6.3% of the parent area 
under the AUC and it has been identified as potentially genotoxic based on an in vitro Ames test. In 
2 mouse genotoxicity studies, no genotoxicity was observed up to a 2000 mg/kg dose. In a recently 
completed carcinogenicity study in transgenic mice with M50 exposure 2-3 times the expected 
human exposure, no pretomanid-related deaths, tumors, or gross necropsy findings were seen. There 
is no evidence suggestive of any potential carcinogenic hazard in rat toxicity studies up to 6 months 
and in monkey toxicity studies up to 9 months. No metabolites have been found to represent more 
than 13% of the total dose in urine and feces. Therefore, based on results from previous studies and 
expected excretion in urine, measuring the plasma exposures of pretomanid metabolites (M50 and 
M19) in this patient population will be valuable. 
The results from this study will help determine future dosing and frequency of administration of 
pretomanid that can be safely used in patients with different stages of renal impairment. 
 
Study Population 
 
The study population will be representative of participants with varying degrees of renal disease as 
defined by eGFR as well as participants who are healthy matched controls. Children will not be 
included as this study is designed for adult participants between the ages of 18-85 years (for detailed 
information see Section 5.1 Eligibility Criteria). 
 
Potential Risks and Benefits 
 
Potential Risks 
 
The potential risks of this trial are those associated with having blood drawn, adverse reactions to 
pretomanid, and breach of confidentiality. 
Potential adverse drug reactions include mild to moderate nausea and vomiting, mild to moderate 
rash, and increased transaminases. These are listed as adverse drug reactions in the pretomanid IB 
[18]. 

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In pooled Phase 1 trials (i.e., pooled data from all Phase 1 studies in healthy volunteers) where 
pretomanid was dosed as single or multiple doses, the most frequently observed AEs were headache 
and nausea. 
A study on the effects of pretomanid in healthy volunteers determined that increases in creatinine 
were noted at high repeat doses in healthy volunteers. A follow-up intensive renal function study 
revealed that the drug does not adversely affect GFR, renal plasma flow, or filtration fraction but 
appeared to decrease tubular renal secretion of creatinine. A single dose of pretomanid did not affect 
kidney function in healthy participants and it is not anticipated that kidney function will change from 
a single dose. 
Testicular toxicity is considered as a potential risk based on pre-clinical studies. TB Alliance is 
currently conducting a study to further investigate pretomanid and testicular toxicity. A single dose 
of pretomanid is however, not anticipated to have an impact on testicular function in general. 
After administering the pretomanid, patients will be closely observed and asked about any new 
symptoms before each blood draw. Clinical evaluation will be done when necessary, during the first 
24 hours of hospital admission, and during follow-up visits. Life-threatening side effects, although 
not anticipated, will be reported immediately to the hospital emergency medical team and standard 
procedures will be followed. Volunteers with serious side effects identified during the follow-up 
visits will be transported to the Emergency Department (ED) of the local hospital where they will 
be examined by an ED physician and admitted to the hospital for further management if required. 
To limit possible adverse reactions to study participants, volunteers who donated blood or blood 
products >500 mL within 30 days from screening or who plans to donate during the study or up to 
14 days after dosing will be excluded from the study. 
Blood Draw 
 
Drawing blood may cause transient discomfort and fainting. Fainting is usually transient and 
managed by having the participant lie down and elevate his/her legs. Bruising at the blood draw site 
may occur but can be prevented or lessened by applying pressure to the blood draw site for a few 
minutes after the blood is taken. Rarely, drawing blood may cause infection (thrombophlebitis). The 
use of aseptic (sterile) technique will make infection at the site where blood will be drawn extremely 
unlikely. 
Peripheral Catheter (if needed) 
 
Inserting a peripheral catheter may cause pain, bleeding, hematoma, vein irritation, infiltration, 
extravasation, phlebitis, air embolism, and/or infection. Use of proper aseptic technique during the 
insertion provides protection against infection. 

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Pregnancy 
 
It is unknown if the study drug poses any risks to an unborn child. As such, females of childbearing 
potential, i.e., women who have started menses, must agree to use an effective method of birth 
control for the duration of the study (Section 5.1.1). Males who are sexually active with a female of 
childbearing potential must agree not to father a child or donate sperm for the duration of the study. 
Other Risks 
 
Personal Health Information (PHI) 
 
Participants will be asked to provide PHI. All attempts will be made to keep this PHI confidential 
within the limits of the law. However, there is a chance that unauthorized persons will see the 
participants’ PHI. All study records will be kept in a locked file cabinet or maintained in a locked 
room at the participating sites. Electronic files will be password-protected. Only people who are 
involved in the conduct, oversight, monitoring, or auditing of this trial will be allowed access to the 
PHI that is collected. Any publications from this trial will use de-identified information. 
Organizations that may inspect and/or copy research records maintained at the participating site for 
quality assurance and data analysis include groups such as the local Institutional Review Boards 
(IRBs), National Institute of Allergy and Infectious Diseases (NIAID), and FDA. 
As required by US law, a description of this clinical trial will be available on 
https://clinicaltrials.gov/ct2/show/NCT03896750. This website will not include information that can 
be used to identify participants. At most, this website will include a summary of the results. 
There may be other risks, discomforts, or side effects that are unknown at this time. 
 
Potential Benefits 
 
There is no direct benefit to participants who will receive the study product. This study is a PK study 
in patients with renal impairment. Patients with renal impairment have a higher risk of developing 
TB and participation will not prevent or reduce the risk of contracting TB. The results from this 
study will help determine the safe and effective dose of pretomanid for treatment of TB in patients 
with renal impairment. Pretomanid, in the context of the BPaL regimen, shortens the treatment of TI 
or NR MDR and XDR-TB to 6 months. 

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3 
STUDY DESIGN, OBJECTIVES, AND ENDPOINTS OR 
OUTCOME MEASURES 
 
Study Design Description 
 
This is a Phase 1, open-label, single-dose, sequential group study to evaluate the PK and safety 
profile of pretomanid in participants with renal impairment (excluding those with ESRD needing 
dialysis) compared to matched participants with normal renal function. 
The study will be conducted following a reduced PK study design in Part A, see Table 1 and Figure 
1. Part A will enroll participants from Group 1A (i.e., 6 healthy matched controls) and Group 2 (i.e., 
6 participants with severe renal impairment and ESRD, not on dialysis). 
A decision to proceed to Part B will be made after the PK of pretomanid and safety of participants 
enrolled in Part A have been reviewed. If Part A demonstrates at least a 50% increase in pretomanid 
AUC in Group 2 (severe renal impairment and ESRD, not on dialysis) relative to the exposures in 
Group 1A (matched participants with normal renal function), then the reduced PK study will extend 
to the full PK study to enroll participants into Part B (i.e., to investigate mild and moderate renal 
impairment) and all enrollment will be initiated concurrently in Part B groups (1B, 1C, 3, and 4). 
Otherwise, no further study is recommended. 
Study Population 
Part A 
Group 1A: 6 healthy participants (matched controls) with normal renal function: MDRD (eGFR 
≥90 mL/min). Participants will be matched by race, gender, age (± 10 years, but between 18 to 
85 years of age) and body mass index (BMI) (18 to 40 kg/m2). 
Group 2: 6 severe renal impairment participants: Stage 4, MDRD (eGFR 15-29 mL/min), and ESRD 
not on dialysis, Stage 5, MDRD (eGFR <15 mL/min). 

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Part B 
 
Groups 1B and 1C: 6 healthy participants (matched controls) each, for Groups 3 and 4, respectively: 
MDRD (eGFR ≥90 mL/min). Participants will be matched by race, gender, age (± 10 years, but 
between 18 to 85 years of age) and BMI (18 to 40 kg/m2). 
Group 3: 6 mild renal impairment participants: Stage 2, MDRD (eGFR 60-89 mL/min). 
 
Group 4: 6 moderate renal impairment participants: Stage 3, MDRD (eGFR 30-59 mL/min). 
 
Study Objectives 
 
Primary 
 
• To evaluate the PK profiles of pretomanid in plasma and urine after a single oral dose of 200 mg 
in participants with renal impairment compared to matched healthy controls. 
 
Secondary 
 
• To assess the safety profile of a single oral dose of 200 mg pretomanid in renally impaired 
participants to matched healthy controls. 
• To evaluate the PK profiles of representative pretomanid metabolites (M19 and M50) in plasma 
and urine. 
 
Study Endpoints or Outcome Measures 
 
Primary 
 
3.3.1.1 
Plasma PK of Pretomanid (see Section 10.5 for specific PK parameters) 
 
The plasma PK of a single dose of pretomanid will be assessed from serial blood samples collected 
up to 1 hour pre-dose (Day 1) and at multiple time points post dosing: 1, 2, 4, 5, 6, 8, 12, 16, 24, 36, 
48, 72, and 96 hours. The primary outcome measure will be total plasma concentration of 
pretomanid. 
3.3.1.2 
Urine PK of Pretomanid (see Section 10.5 for specific PK parameters) 
 
The urine PK of a single dose of pretomanid will be assessed from urine collected up to 1 hour pre-
dose, 0-4, 4-8, 8-12, 12-24, 24-48, 48-72, and 72-96 hours post-dose. Volume of urine will be 
measured and recorded at each of these time intervals. Urine samples will be stored at room 
temperature and then frozen at -20°C within 24 hours. Urine samples will be stored in ≤100 mL 
aliquots at -20°C until shipped to Fisher Bioservices for storage. 

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The concentrations of pretomanid in plasma and urine will be measured by the validated 
bioanalytical methods. The pretomanid PK profiles in plasma and urine estimated through a 
non-compartmental analysis. 
 
Secondary 
 
• Safety – Number of participants reporting AEs. (Time Frame: Time of dosing [Day 1] to 
Day 12). 
• Safety – Mean change from baseline in hemoglobin (Hgb), alanine aminotransferase (ALT), 
aspartate aminotransferase (AST), total bilirubin, blood urea nitrogen (BUN), creatinine 
(includes eGFR), serum potassium and magnesium (Time Frame: Screening [Days -28 to -7], 
Day 5 and Day 12). 
• Safety – Mean change from baseline in oral temperature, pulse, and sitting blood pressure (Time 
Frame: Day 1 [pre-dose], 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, and Day 12). 
• Safety – Mean change from baseline in ECG corrected QT interval by Fridericia (QTcF) (Time 
Frame: Screening [Days -28 to -7] and Day 5). 
• The concentrations of pretomanid metabolites (M19 and M50) in plasma will be measured by 
validated bioanalytical methods. PK – area under the plasma concentration-time curve from time 
0 to the last measurement (AUClast), and any other parameters considered to be of interest, of 
representative metabolites M19 and M50 in plasma (Time Frame: Up to 96 hours post-dose). 
• Excretion of representative metabolites M19 and M50 in urine. The amounts of M19 and M50 
will be calculated in urine (i.e., M19 and M50 concentrations measured using validated 
bioanalytical methods multiplied by collected urine volume). 

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4 
STUDY INTERVENTION/INVESTIGATIONAL PRODUCT 
 
Study Product Description 
 
Pretomanid, a nitroimidazooxazine, is a novel TB treatment that is being investigated for use with 
other TB drugs to shorten and/or simplify regimens to treat either drug-susceptible or resistant 
disease, which may improve the current high rate of noncompliance for TB treatment. Pretomanid 
acts by inhibiting Mtb cell wall biosynthesis, as well as generating NO. 
 
Formulation, Packaging, and Labeling 
 
For this study, pretomanid 200 mg tablets are white to off-white, oval-shaped tablet debossed with 
M on one side and P200. The formulation of pretomanid tablets is summarized in Table 3. 
Table 3: Pretomanid Formulation 
Ingredient 
% 
Weight per Unit (mg) 
Pretomanid, Micronized 
25.0 
200.0 
Lactose Monohydrate NF (Foremost FastFlo 316) 
36.8 
294.4 
Microcrystalline Cellulose NF (Avicel PH102) 
29.4 
235.2 
Sodium Starch Glycolate NF (Explotab) 
5.0 
40.0 
Magnesium Stearate NF (Hyqual) 
1.0 
8.0 
Colloidal Silicon Dioxide NF (Cab-O-Sil M-5P) 
0.3 
2.4 
Sodium Lauryl Sulfate USP 
0.5 
4.0 
Povidone USP (PVP K30) 
2.0 
16.0 
Purified Water USP 
-- 
-- 
Total 
100% 
800.0 mg 
NF=National Formulary; USP=United States Pharmacopeia. 
Note: Water is removed during drug product manufacture. 
TB Alliance or its designee will package the study product. Study product will be labeled and 
supplied according to applicable regulatory requirements. 
 
 
Product Storage and Stability 
 
The investigator or an approved designee (e.g., pharmacist) will ensure that the study product is 
stored in a locked, secure area (with access limited to authorized study personnel only) under 

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recommended storage conditions and in accordance with applicable regulatory requirements. 
Pretomanid will be stored at 15-30°C (59-86°F). 
 
Acquisition/Distribution 
 
Pretomanid will be provided by Global Alliance for TB Drug Development according to the terms 
of the Clinical Trial Agreement between the TB Alliance and NIAID. 
Upon request by Division of Microbiology and Infectious Diseases (DMID), pretomanid will be 
transferred to the following address: 
DMID Clinical Materials Services Contract 
Fisher BioServices 
20439 Seneca Meadows Parkway 
Germantown, MD 20876 
Phone: 240-477-1350 
Fax: 240-477-1360 
Email: DMID.CMS@ThermoFisher.com 
 
All study products (i.e., pretomanid) will be shipped to the participating sites prior to the start of this 
study upon request and with prior approval from DMID. Should the site principal investigator (PI) 
require additional study product during this trial, further instructions are provided in the protocol-
specific manual of procedures (MOP). 
 
Dosage/Regimen, Preparation, Dispensing, and Administration of 
Study Intervention/Investigational Product 
Pretomanid will be administered in the fed state in this study because there is a food effect for the 
drug. Following an overnight fast of at least 8 hours, participants should start the recommended meal 
prior to administration of pretomanid [40]. Study participants should eat this meal in 30 ± 10 minutes 
or less; however, pretomanid should be administered 30 ± 10 minutes after start of the meal. 
Participants will be given one dose of 200 mg of pretomanid orally under direct supervision with 
240 mL of water and a mouth check will be done. All participants will receive the same study 
product. After dosing, participants will have no food, water, or medications for 2 hours post-dose. If 
a participant vomits >2 hours post-dose, no redosing or exclusion is required. If a participant vomits 
within 2 hours of dosing, the participant will be excluded from the study with a plan to replace or 
rescreen and admit another time, if necessary. When a participant vomits soon after swallowing the 
drug, part or all of the drug may be lost. There is no way of knowing how much of the drug is already 
absorbed and redosing with the full dose may affect PK results. 
See the protocol-specific MOP Appendices for detailed information on the preparation, labeling, 
storage, and administration of study product. 

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Pre-determined Modification of Study Intervention/Investigational 
Product for an Individual Participant 
Since a single oral dose of pretomanid will be given, there will be no dose modifications. 
 
Accountability Procedures for the Study Intervention/ Investigational 
Product(s) 
Pretomanid will be sent to the DMID Clinical Materials Services (CMS) contractor, and then 
supplied to the participating sites prior to the start of the study. Should the site PI require additional 
doses of pretomanid during the trial, further instructions are provided in the protocol-specific MOP. 
After receipt of pretomanid, the site PI is responsible for study product distribution and disposition 
and has ultimate responsibility for drug accountability. The site PI may delegate to the participating 
site’s research pharmacist responsibility for study product accountability. The site research 
pharmacist will be responsible for maintaining complete records and documentation of study product 
receipt, accountability, dispensation, storage conditions, and final disposition of the study product. 
For this study, all study product, pretomanid tablets, should be stored at 15-30°C (59-86°F) in blister-
strips comprising a thermoformable-film and a lidding foil configuration. All doses of pretomanid, 
whether administered or not, must be documented on the appropriate study product accountability 
record or dispensing log. The sponsor's monitoring staff will verify the participating sites’ study 
product accountability records and dispensing logs per the site monitoring plan. 
Unused tablets should be retained within the container in which they are supplied from the CMS. 
Unused pretomanid tablets will be monitored and released for final disposition. Final disposition of 
the pretomanid will be determined by DMID and the TB Alliance and communicated to the 
participating sites by the DMID Clinical Project Manager. 

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5 
SELECTION 
OF 
PARTICIPANTS 
AND 
STUDY 
ENROLLMENT AND WITHDRAWAL 
The study population will be represented by participants with varying degrees of renal disease as 
defined by eGFR. Part A will enroll participants into Groups 1A (i.e., 6 healthy matched controls) 
and 2 (i.e., 6 participants with severe renal impairment and ESRD, not on dialysis). 
In this study, participants with renal impairment will be mainly identified from sites’ exhaustive 
database and through referral from local renal clinics. Non-renally impaired participants will be 
identified from participants who have previously participated in clinical trials and through the 
community. 
The decision to proceed from Part A to Part B will be made jointly by representatives from DMID 
and TB Alliance. An independent safety review will be carried out by the Safety Monitoring 
Committee (SMC) and the DMID Medical Monitor. This review will inform the decision to proceed 
from Part A to Part B. 
Part B will be conducted only if the Part A results demonstrate that participants with severe renal 
impairment and ESRD (not on dialysis) have different exposures to pretomanid that may impact 
safety or efficacy relative to the exposures of healthy participants. If no difference in PK is observed 
in Part A, then no further study (Part B) will be recommended. 
If the decision is made to conduct Part B, 12 participants (6 participants in each group) with mild 
and moderate renal impairment will be enrolled in Groups 3 and 4, respectively, along with 12 
healthy matched participants (Groups 1B and 1C). Participants in Part B will receive the same single 
200 mg dose of pretomanid as participants in Part A. 
Participant inclusion and exclusion criteria must be assessed by a study clinician licensed to make 
medical diagnoses and listed on the Form FDA 1572 as the site PI or sub-investigator. 
No exemptions are granted for participant inclusion or exclusion criteria in DMID-sponsored 
studies. Questions about eligibility will be directed to the DMID Medical Officer. 
 
Eligibility Criteria 
 
Participant Inclusion Criteria 
 
5.1.1.1 
Participant Inclusion Criteria for Patients with Renal Impairment (Groups 2-4) 
 
Participants eligible to participate in this trial must meet all of the following inclusion criteria: 

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1. Have the ability to understand the requirements of the study and have provided written informed 
consent1 before any study-related procedure is performed. 
1As evidence by signature on an informed consent document approved by the IRB 
 
2. Agree to abide by the study restrictions. 
3. Are between the ages of 18 and 85 years, inclusive, at the time of enrollment. 
4. Must have mild, moderate, or severe renal impairment or ESRD, but are not on dialysis. See 
Table 1 for staging of renal disease. 
5. Have no history of chronic tobacco/nicotine usage (i.e., >10 cigarettes per day for 3 months 
minimum prior to admission). 
6. Have QTc interval <460 msec on ECG. 
7. Have a BMI of 18 to 40 kg/m2 at enrollment. 
8. Women of childbearing potential2 must use an acceptable contraception method3 for the duration 
of the study. 
2Not sterilized via tubal ligation, bilateral oophorectomy, bilateral salpingectomy, hysterectomy, 
implanted contraceptive device placement (permanent, non-surgical, non-hormonal sterilization) with 
documented radiological confirmation test at least 90 days after the procedure, and still menstruating or 
<1 year has passed since the last menses if menopausal. 
 
3Includes non-male sexual relationships, abstinence from sexual intercourse with a male partner, 
monogamous relationship with vasectomized partner who has been vasectomized for 180 days or more 
prior to the participant receiving study product, barrier methods such as condoms with spermicide or 
diaphragms/cervical caps with spermicide, effective intrauterine devices, NuvaRing®, and licensed 
hormonal methods such as implants, injectables, or oral contraceptives (“the pill”). 
9. If participant is male and capable of reproduction, agrees to avoid fathering a child for the 
duration of the study by using an acceptable method of birth control4. 
4In addition to the use of a barrier method (condom) unless vasectomized, acceptable methods of birth 
control are restricted to a monogamous relationship with a woman who agrees to use acceptable 
contraception as outlined in inclusion criterion #8, and/or abstinence from sexual intercourse with 
women. 
10. Women of childbearing potential must have a negative urine pregnancy test within 24 hours prior 
to receipt of study product. 
5.1.1.2 
Participant Inclusion Criteria for Healthy Participants (Groups 1A-1C) 
 
Healthy participants eligible to participate in this trial must meet all of the following inclusion 
criteria: 

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1. Have the ability to understand the requirements of the study and have provided written informed 
consent1 before any study-related procedure is performed. 
1As evidence by signature on an informed consent document approved by the IRB. 
 
2. Agree to abide by the study restrictions. 
3. Are healthy male or non-pregnant female, between the ages of 18 and 85 years, inclusive, with 
normal GFR >90 at screening. 
4. Have no history of chronic tobacco/nicotine usage (i.e., >10 cigarettes per day for 3 months 
minimum prior to admission). 
5. Have a normal QTc interval <460 msec on ECG. 
6. Have a BMI of 18 to 40 kg/m2 at enrollment. 
7. Women of childbearing potential2 must use an acceptable contraception method3 for the duration 
of the study. 
2Not sterilized via tubal ligation, bilateral oophorectomy, bilateral salpingectomy, hysterectomy, 
implanted contraceptive device placement (permanent, non-surgical, non-hormonal sterilization) with 
documented radiological confirmation test at least 90 days after the procedure, and still menstruating or 
<1 year has passed since the last menses if menopausal. 
 
3Includes non-male sexual relationships, abstinence from sexual intercourse with a male partner, 
monogamous relationship with vasectomized partner who has been vasectomized for 180 days or more 
prior to the participant receiving study product, barrier methods such as condoms with spermicide or 
diaphragms/cervical caps with spermicide, effective intrauterine devices, NuvaRing®, and licensed 
hormonal methods such as implants, injectables, or oral contraceptives (“the pill”). 
8. If participant is male and capable of reproduction, agrees to avoid fathering a child for the 
duration of the study by using an acceptable method of birth control4. 
4In addition to the use of a barrier method (condom) unless vasectomized, acceptable methods of birth 
control are restricted to a monogamous relationship with a woman who agrees to use acceptable 
contraception as outlined in inclusion criterion #7, and/or abstinence from sexual intercourse with 
women. 
9. Women of childbearing potential must have a negative urine pregnancy test within 24 hours prior 
to receipt of study product. 
 
Participant Exclusion Criteria 
 
5.1.2.1 
Participant Exclusion Criteria for Patients with Renal Impairment (Groups 2-4) 
 
Participants eligible to participate in this trial must not meet any of the following exclusion criteria: 
 
1. History of known active TB. 

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2. History of peptic ulcer disease. 
3. Known hypersensitivity to pretomanid or any of the excipients. 
4. History of any clinically significant uncontrolled cardiac abnormality (as deemed by the PI). 
5. Any clinically significant ECG abnormality at screening1. 
 
1Note: the following can be considered not clinically significant: 
 
• 
Heart rate <50 beats per minute (bpm) (sinus bradycardia with heart rate between 45 and 49, 
inclusive, is acceptable only in younger athletic participants, as determined by the PI) 
• 
Mild first-degree atrioventricular (A-V) block (P-R interval >0.23 seconds) 
• 
Right or left axis deviation 
• 
Incomplete right bundle branch block 
• 
Isolated left anterior fascicular block (left anterior hemiblock) in younger athletic participants 
6. History of, or screening results show a QTc interval ≥460 msec. 
7. Family history of Long-QT Syndrome or sudden death when a cause of death is unknown. 
8. Inability to swallow tablets. 
9. History of fever or documented fever (oral temperature >100.4°F) in the 48 hours prior to 
admission to the hospital. 
10. Resting pulse rate <50 or >110 bpm at Screening. 
11. At Screening, blood pressure >20 mm Hg systolic or >10 mm Hg diastolic above baseline2 
(sitting). 
2Baseline is most recent blood pressure in the last 3 months. 
 
12. Current hyperkalemia or hypomagnesemia. 
13. Positive result of urine drug screen or alcohol screen prior to hospital admission except for 
approved prescriptions that are not opiates and benzodiazepines. 
14. Significant history of drug and/or food allergies (as deemed by the PI). 
15. For women, participant is pregnant (positive test for urine Human Chorionic Gonadotropin 
[HCG]) at screening or Admission, breastfeeding, or planning to conceive for the duration of 
the study. 
16. Any contraindication to the use of nitroimidazoles, or prior treatment with pretomanid or 
delamanid. 
17. Treatment with strong or moderate CYP3A4 inducers or inhibitors3 within 14 days before 
admission and during the study4. 

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3Except hormonal contraceptives 
 
4In the opinion of the site investigator 
 
NOTE: See Table 4 for a list of drugs known to alter the function of CYP3A4 (Section 7.1.1). 
 
18. Use of St. John’s Wort within 7 days prior to admission and during the entire study. 
19. Consumption of products containing grapefruit within 5 days prior to dosing until Visit 01N. 
20. Donation of whole blood or blood products >500 mL within 30 days from screening and/or 
plans to donate during the study or up to 14 days after dosing. 
21. Participation in another interventional clinical trial within 30 days prior to dosing until after 
the last study visit. 
22. Hgb <8.0 g/dL in both men and women at the screening visit. 
23. Positive Screening test for hepatitis C virus (HCV), hepatitis B virus (HBV), or HIV. 
24. Renal transplant. 
25. Scheduled for hemodialysis or peritoneal dialysis. 
26. Presence of any condition or finding5 which would jeopardize participant safety, impact study 
result validity, or diminish the participant’s ability to undergo all study procedures and 
assessments. 
5In the opinion of the investigator 
 
27. For men, semen donation for the duration of the study. 
28. AST and ALT > 2.5 x upper limit of normal (ULN). 
29. Hyperbilirubinemia >1.5 x ULN. 
 
5.1.2.2 
Participant Exclusion Criteria for Healthy Participants (Groups 1A-1C) 
 
Participants eligible to participate in this trial must not meet any of the following exclusion criteria: 
 
1. History of known active TB. 
2. History of peptic ulcer disease. 
3. Known hypersensitivity to pretomanid or any of the excipients. 
4. History of any clinically significant uncontrolled cardiac abnormality (as deemed by the PI). 
5. Any clinically significant ECG abnormality at screening.1 
 
1Note: the following can be considered not clinically significant: 

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• 
Heart rate <50 bpm (sinus bradycardia with heart rate between 45 and 49, inclusive, is acceptable 
only in younger athletic participants) 
• 
Mild first-degree A-V block (P-R interval >0.23 seconds) 
• 
Right or left axis deviation 
• 
Incomplete right bundle branch block 
• 
Isolated left anterior fascicular block (left anterior hemiblock) in younger athletic participants 
6. Family history of Long-QT Syndrome or sudden death when a cause of death is unknown. 
7. Inability to swallow tablets. 
8. History of fever or documented fever (oral temperature >100.4°F) in the 48 hours prior to 
admission to the hospital. 
9. At Screening blood pressure >140/90 mm Hg or <90/65 mm Hg (sitting). 
10. History of, or screening results show a QTc interval ≥460 msec. 
11. Positive result of urine drug screen or alcohol screen prior to hospital admission except for 
approved prescriptions that are not opiates and benzodiazepines. 
12. Significant history of drug and/or food allergies (as deemed by the PI). 
13. Women of childbearing potential with a positive urine pregnancy test within 24 hours prior to 
receipt of study product. 
14. Any contraindication to the use of nitroimidazoles, or prior treatment with pretomanid or 
delamanid. 
15. Treatment with strong or moderate CYP3A4 inducers or inhibitors2 within 14 days before 
admission and during the study3. 
2Except hormonal contraceptives 
 
3In the opinion of the site PI 
 
NOTE: See Table 4 for a list of drugs known to alter the function of CYP3A4 (Section 7.1.1). 
 
16. Use of St. John’s Wort within 7 days prior to admission and during the entire study. 
17. Consumption of products containing grapefruit within 5 days prior to dosing until Visit 01N. 
18. Donation of whole blood or blood products >500 mL within 30 days from screening and/or 
plans to donate during the study or up to 14 days after dosing. 
19. Participation in another interventional clinical trial within 30 days prior to dosing until after 
the last study visit. 
20. Hgb <10.0 g/dL in both men and women at the screening visit. 

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21. Positive Screening test for HCV, HBV, or HIV. 
22. Renal transplant. 
23. Presence of any condition or finding4 which would jeopardize participant safety, impact study 
result validity, or diminish the participant’s ability to undergo all study procedures and 
assessments. 
4In the opinion of the investigator 
 
24. For men, semen donation for the duration of the study. 
25. AST and ALT > ULN. 
26. Bilirubin > ULN 
 
Withdrawal from the Study or Study Termination 
 
Withdrawal from the Study 
 
Participants may voluntarily withdraw their consent for trial participation at any time and for any 
reason, without penalty. 
A participant may withdraw or be withdrawn from this trial for any of the following reasons: 
 
• Medical disease or condition, or any new clinical finding for which continued participation, in 
the opinion of the site PI or appropriate sub-investigator, would compromise the safety of the 
participant, or would interfere with the participant's successful completion of this trial, or would 
interfere with the evaluation of data. 
• Participant no longer meets eligibility criteria (see Section 5.1). 
 
• As deemed necessary by the site PI or appropriate sub-investigator for noncompliance or other 
reasons. 
• Withdrawal of consent. 
 
• Lost to follow-up (defined as 3 unsuccessful attempts to contact the participant; the methods and 
dates contact was attempted will be documented). 
• Termination of this trial. 
 
A participant who is withdrawn or voluntarily withdraws from the study for any reason, whether 
related to the study drug or not, after having received the study drug, will be considered an early 
termination subject. The PI or sub-investigator will make every effort to ensure that early termination 

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participants who have received the study drug complete the early termination assessments and safety 
follow-up assessments. 
 
Participant Replacement 
 
Participants who sign the informed consent form (ICF) and receive study product, and subsequently 
withdraw before the first 24-hour time point will be replaced. All other participants who sign the 
ICF and receive study product, and subsequently withdraw or are withdrawn or terminated from this 
study or are lost to follow-up will not be replaced. If participants withdraw, or are withdrawn or 
terminated from the study, or are lost to follow-up after signing the ICF but before receipt of study 
product, additional participants may be enrolled for replacement. Participants may be rescreened 
once. Participants who miss a PK blood draw due to lack of venous access will be replaced. If the 
healthy matched replaced participant does not match the renally impaired participant, the healthy 
matched participant will be replaced. If a participant vomits within 2 hours of dosing, the participant 
will be excluded from the study with a plan to replace or rescreen and admit another time, if 
necessary. 
 
Study Termination 
 
If the study is prematurely terminated by the sponsor, any regulatory authority, or the investigator 
for any reason, the investigator will promptly inform the study participants and assure appropriate 
therapy or follow-up for the participants, as necessary. The investigator will provide a detailed 
written explanation of the termination to the IRB/ Independent Ethics Committee (IEC). 

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6 
STUDY PROCEDURES 
 
Complete study schedule details listed by type of visit are described below. Refer also to 
APPENDIX A: Schedule of Study Procedures and Evaluations. 
 
Screening 
 
Visit 00A, Screening Clinic Visit (Day -28 to -7) 
 
• Participants will be provided with a description of this trial (purpose and study procedures) and 
asked to read and sign the ICF. The ICF will be signed prior to performing any study procedures. 
• Eligibility criteria will be reviewed with the participant. 
• Demographic variables (age, gender, race and ethnicity) and screening characteristics (height 
and weight) will be collected. 
• Complete medical history will be obtained by interview of the participant to ensure eligibility. 
• All concomitant medications taken within 30 days prior to signing the ICF will be reported on 
the appropriate Data Collection Form (DCF). 
• Oral temperature, sitting blood pressure, and sitting pulse will be obtained. Participants must not 
eat or drink anything hot or cold within 10 minutes prior to taking oral temperature. 
• A complete physical examination will be performed on all participants by a study clinician 
licensed to make medical diagnoses and listed on the Form FDA 1572 as the site PI or 
sub-investigator. 
• A 12-lead ECG will be performed. 
• Height and weight will be obtained for BMI calculations. 
• Approximately 10 mL of venous blood will be collected for safety laboratory assessments 
including Hgb, BUN, serum creatinine (includes eGFR), ALT, AST, total bilirubin, serum 
potassium, and serum magnesium. 
• Approximately 12 mL of venous blood will be collected for HCV, hepatitis B surface antigen 
(HBsAg), and HIV testing. 
• Advise to refrain from alcohol use for at least 72 hours before admission. 
 
Visit 00B, 2nd Screening Clinic Visit (Day -28 to -7) 
 
• Participant’s willingness to participate will be reconfirmed and documented in the participant’s 
study source document records prior to performing any further study procedures. 

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• A urine pregnancy test will be performed on all women of childbearing potential and must be 
negative to ensure eligibility. 
• Urine screen for drugs. 
• Approximately 6 mL of venous blood will be collected to screen for alcohol or breath collection 
if breathalyzer is used for alcohol testing 
• Remind to refrain from use of alcohol for 72 hours prior to hospital admission. 
 
Visit 00C, Hospital Admission, Day -1 
 
• Participants will be admitted to the hospital 12-24 hours before administration of study product. 
• Participant’s willingness to participate will be reconfirmed and documented in the participant’s 
study source document records prior to performing any further study procedures. 
• Eligibility criteria will be reviewed with the participant. 
• Interim medical history, including an assessment for new medical conditions and stability of 
chronic diseases, will be obtained by interview of participants and any changes since the first 
visit (Visit 00A) will be noted. 
• All concomitant medications will be reviewed with participants prior to the administration of 
study medication. Any new concomitant medications taken since the screening visit will be 
reviewed with participants and assessed for continued eligibility. 
• A urine pregnancy test will be performed on all women of childbearing potential and must be 
negative to ensure eligibility. 
• Urine screen for drugs. 
• Approximately 6 mL of venous blood will be collected to screen for alcohol or breath collection 
if a breathalyzer is used for alcohol testing. 
• Alcohol and urine drug screening will be performed, and results will be checked when available. 
Participants with positive results will be discharged unless the participants are on approved 
prescriptions. However, opiates and benzodiazepines, which are CYP3A4 substrates, will not be 
allowed even if prescribed. Participants who are discharged because of a positive alcohol or urine 
drug screen will not be rescreened for enrollment. 
• If applicable, a peripheral intravenous catheter will be placed at this Visit or Visit 01A for 
participants with negative alcohol and drug screening except for participants who are on 
approved prescriptions. However, opiates and benzodiazepines, which are CYP3A4 substrates, 
will not be allowed even if prescribed. 
• Participants will be reminded that they must fast overnight (i.e., at least 8 hours). Participants 
will be required to bring in from home all their medications they take at home. 

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Dosing (Day 1) and In-house Confinement/ PK Collection 
 
Visit 01A, Administration of Study Product 
 
• Eligibility criteria will be reviewed. 
• Interim medical history, including an assessment for new medical conditions and stability of 
chronic diseases, will be obtained by interview of participants and any changes since the previous 
visit (Visit 00C) will be noted. 
• Alcohol and urine drug screening results from Day -1 will be checked for participants whose 
alcohol and drug screening results were not available on time and who are not discharged on Day 
-1. Participants with positive results will be discharged unless the participants are on approved 
prescriptions. However, opiates and benzodiazepines, which are CYP3A4 substrates, will not be 
allowed even if prescribed. Participants who are discharged because of a positive alcohol or urine 
drug screen will not be rescreened for enrollment. 
• Vital signs, including oral temperature, sitting pulse, and sitting blood pressure, will be obtained 
to ensure eligibility of participants with negative alcohol and urine drug screening results. 
• If applicable, a peripheral intravenous catheter will be placed if not already placed on Visit 00C. 
• A targeted physical examination may be performed prior to administration of study product, if 
indicated based on review of complete medical history and any updates obtained by interview of 
participants since the screening visit, by a study clinician licensed to make medical diagnoses 
and listed on the Form FDA 1572 as the site PI or sub-investigator. 
• All concomitant medications will be recorded on the appropriate DCF. 
• Collect and measure urine volume for PK up to 1 hour pre-dose and again after the dose has been 
administered; urine will be collected in collection beakers at 1 hour pre-dose and at intervals 0-4, 
4-8, 8-12, 12-24, 24-48, 48-72, and 72-96 hours post-dose. Urine volume will be measured and 
recorded for each of these time intervals. Urine will be stored at room temperature and then 
frozen at -20°C within 24 hours. Urine will be in ≤100 mL aliquots and stored at -20°C until 
shipped to Fisher Bioservices for storage. Fisher Bioservices will ship samples to bioanalytical 
laboratory for concentration measurements. 
• A urine pregnancy test will be performed prior to administration of the study product on all 
women of childbearing potential. Results must be negative and known prior to receipt of the 
study product. 
• Approximately 4 mL of venous blood will be collected for PK prior to administration of study 
product (up to 1 hour pre-dose). 
• Participants 
should 
start 
the 
recommended 
meal 
(high-fat 
and 
high-calorie, 
https://www.fda.gov/media/121313/download)  30  minutes  prior  to  administration  of 

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pretomanid. Study participants should eat this meal in 30 ± 10 minutes or less; however, 
pretomanid should be administered 30 ± 10 minutes after start of the meal. 
• Participants will receive one dose of 200 mg pretomanid orally with 240 mL water under direct 
supervision and a mouth check will be done. If a participant meets eligibility criteria and is 
admitted, but is not dosed, the participant may be re-evaluated for participation in the study. 
• Liquids, food, and medicine will not be allowed until at least 2 hours after dosing. 
• All AEs/Serious Adverse Events (SAEs) will be recorded on the appropriate DCF/DMID SAE 
Report Form. 
 
Visit 01B, Day 1, Time 1 Hour ± 10 Minutes Post-dose; Hospital Stay 
 
• A targeted physical examination may be performed if indicated based on new symptoms after 
administration of study product, by a study clinician licensed to make medical diagnoses and 
listed on the Form FDA 1572 as the site PI or sub-investigator. 
• All concomitant medications will be recorded on the appropriate DCF. 
• Collect all urine for PK, measure and record urine PK volume, aliquot, label and freeze per 
Section 7.2.2.1. 
• Approximately 4 mL of venous blood will be collected for PK. 
• All AEs/Serious Adverse Events (SAEs) will be recorded on the appropriate DCF/DMID SAE 
Report Form. 
 
Visit 01C, Day 1, Time 2 Hours ± 10 Minutes Post-dose; Hospital Stay 
 
• A targeted physical examination may be performed if indicated based on new symptoms after 
administration of study product, by a study clinician licensed to make medical diagnoses and 
listed on the Form FDA 1572 as the site PI or sub-investigator. 
• All concomitant medications will be recorded on the appropriate DCF. 
• Collect all urine for PK, measure and record urine PK volume, aliquot, label and freeze per 
Section 7.2.2.1. 
• Approximately 4 mL of venous blood will be collected for PK. 
• All AEs/SAEs will be recorded on the appropriate DCF/DMID SAE Report Form. 

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Visit 01D, Day 1, Time 4 Hours ± 10 Minutes Post-dose; Hospital Stay 
 
• A targeted physical examination may be performed if indicated based on new symptoms after 
administration of study product, by a study clinician licensed to make medical diagnoses and 
listed on the Form FDA 1572 as the site PI or sub-investigator. 
• All concomitant medications will be recorded on the appropriate DCF. 
• Collect all urine for PK, measure and record urine PK volume, aliquot, label and freeze per 
Section 7.2.2.1. 
• Approximately 4 mL of venous blood will be collected for PK. 
• All AE/SAEs will be recorded on the appropriate DCF/DMID SAE Report Form. 
 
Visit 01E, Day 1, Time 5 Hour ± 10 Minutes Post-dose; Hospital Stay 
 
• A targeted physical examination may be performed if indicated based on new symptoms after 
administration of study product, by a study clinician licensed to make medical diagnoses and 
listed on the Form FDA 1572 as the site PI or sub-investigator. 
• All concomitant medications will be recorded on the appropriate DCF. 
• Collect all urine for PK, measure and record urine PK volume, aliquot, label and freeze per 
Section 7.2.2.1. 
• Approximately 4 mL of venous blood will be collected for PK. 
• All AEs/SAEs will be recorded on the appropriate DCF/DMID SAE Report Form. 
 
Visit 01F, Day 1, Time 6 Hours ± 10 Minutes Post-dose; Hospital Stay 
 
• A targeted physical examination may be performed if indicated based on new symptoms after 
administration of study product, by a study clinician licensed to make medical diagnoses and 
listed on the Form FDA 1572 as the site PI or sub-investigator. 
• All concomitant medications will be recorded on the appropriate DCF. 
• Collect all urine for PK, measure and record urine PK volume, aliquot, label and freeze per 
Section 7.2.2.1. 
• Approximately 4 mL of venous blood will be collected for PK. 
• All AEs/SAEs will be recorded on the appropriate DCF/DMID SAE Report Form. 

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Visit 01G, Day 1, Time 8 Hour ± 10 Minutes Post-dose; Hospital Stay 
 
• A targeted physical examination may be performed if indicated based on new symptoms after 
administration of study product, by a study clinician licensed to make medical diagnoses and 
listed on the Form FDA 1572 as the site PI or sub-investigator. 
• All concomitant medications will be recorded on the appropriate DCF. 
• Collect all urine for PK, measure and record urine PK volume, aliquot, label and freeze per 
Section 7.2.2.1. 
• Approximately 4 mL of venous blood will be collected for PK. 
• All AE/SAEs will be recorded on the appropriate DCF/DMID SAE Report Form. 
 
Visit 01H, Day 1, Time 12 Hours ± 10 Minutes Post-dose; Hospital Stay 
 
• Vital signs, including oral temperature, sitting blood pressure, and sitting pulse will be obtained. 
Participants must not eat or drink anything hot or cold within 10 minutes prior to taking oral 
temperature. 
• A targeted physical examination may be performed if indicated based on new symptoms after 
administration of study product, by a study clinician licensed to make medical diagnoses and 
listed on the Form FDA 1572 as the site PI or sub-investigator. 
• All concomitant medications will be recorded on the appropriate DCF. 
• Collect all urine for PK, measure and record urine PK volume, aliquot, label and freeze per 
Section 7.2.2.1. 
• Approximately 4 mL of venous blood will be collected for PK. 
• All AEs/SAEs will be recorded on the appropriate DCF/DMID SAE Report Form. 
 
Visit 01I, Day 1, Time 16 Hour ± 10 Minutes Post-dose; Hospital Stay 
 
• A targeted physical examination may be performed if indicated based on new symptoms after 
administration of study product, by a study clinician licensed to make medical diagnoses and 
listed on the Form FDA 1572 as the site PI or sub-investigator. 
• All concomitant medications will be recorded on the appropriate DCF. 
• Collect all urine for PK, measure and record urine PK volume, aliquot, label and freeze per 
Section 7.2.2.1. 
• Approximately 4 mL of venous blood will be collected for PK. 
• All AE/SAEs will be recorded on the appropriate DCF/DMID SAE Report Form. 

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Visit 01J, Day 2, Time 24 Hour ± 1 Hour Post-dose; Hospital Stay 
 
• Vital signs, including oral temperature, sitting blood pressure, and sitting pulse will be obtained. 
Participants must not eat or drink anything hot or cold within 10 minutes prior to taking oral 
temperature. 
• A targeted physical examination may be performed if indicated based on new symptoms after 
administration of study product, by a study clinician licensed to make medical diagnoses and 
listed on the Form FDA 1572 as the site PI or sub-investigator. 
• All concomitant medications will be recorded on the appropriate DCF. 
• Collect all urine for PK, measure and record urine PK volume, aliquot, label and freeze per 
Section 7.2.2.1. 
• Approximately 4 mL of venous blood will be collected for PK. 
• All AEs/SAEs will be recorded on the appropriate DCF/DMID SAE Report Form. 
 
Visit 01K, Day 2, Time 36 Hour ± 1 Hour Post-dose; Hospital Stay 
 
• A targeted physical examination may be performed if indicated based on new symptoms after 
administration of study product, by a study clinician licensed to make medical diagnoses and 
listed on the Form FDA 1572 as the site PI or sub-investigator. 
• All concomitant medications will be recorded on the appropriate DCF. 
• Collect all urine for PK, measure and record urine PK volume, aliquot, label and freeze per 
Section 7.2.2.1. 
• Approximately 4 mL of venous blood will be collected for PK. 
• All AEs/SAEs will be recorded on the appropriate DCF/DMID SAE Report Form. 
 
Visit 01L, Day 3, Time 48 Hours ± 1 Hour Post-dose, Hospital Stay 
 
• A targeted physical examination may be performed if indicated based on new symptoms after 
administration of study product, by a study clinician licensed to make medical diagnoses and 
listed on the Form FDA 1572 as the site PI or sub-investigator. 
• All concomitant medications will be recorded on the appropriate DCF. 
• Vital signs, including oral temperature, sitting blood pressure, and sitting pulse will be obtained. 
Participants must not eat or drink anything hot or cold within 10 minutes prior to taking oral 
temperature. 
• Collect all urine for PK, measure and record urine PK volume, aliquot, label and freeze per 
Section 7.2.2.1. 

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• Approximately 4 mL of venous blood will be collected for PK. 
• If applicable, the intravenous catheter will be removed by a nurse or physician. 
• Provide urine PK collection instructions and containers. Instruct the participant to collect urine 
for 2 more days at home and keep urine container at room temperature with the cap on. 
• Discharge after review by physician licensed to make medical diagnoses and listed on the Form 
FDA 1572 as the site PI or sub-investigator. Note: Participants may remain in the hospital per 
site decision. 
• All AEs/SAEs will be recorded on the appropriate DCF/DMID SAE Report Form. 
 
Follow-Up 
 
Visit 01M, Day 4, Time 72 Hours ± 4 Hours Post-dose, Clinic Visit or Continued 
Hospital Stay, per Site Decision 
• Interim medical history, including an assessment for new medical conditions and stability of 
chronic diseases, will be obtained by interview of participants and any changes since the previous 
visit will be noted. 
• A targeted physical examination may be performed if indicated based on review of interim 
medical history, by a study clinician licensed to make medical diagnoses and listed on the Form 
FDA 1572 as the site PI or sub-investigator. 
• All concomitant medications will be recorded on the appropriate DCF. 
• Vital signs, including oral temperature, sitting blood pressure, and sitting pulse will be obtained. 
Participants must not eat or drink anything hot or cold within 10 minutes prior to taking oral 
temperature. 
• Receive home urine collected jug from subject. Measure and record urine PK volume, aliquot, 
label and freeze per Section 7.2.2.1. 
• Provide urine PK collection container and remind the participant to collect urine at home and 
keep urine container at room temperature with cap on for PK. 
• Approximately 4 mL of venous blood will be collected for PK. 
• All AE/SAEs will be recorded on the appropriate DCF/DMID SAE Report Form. 

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Visit 01N, Day 5, Time 96 Hours ± 4 Hours Post-dose, Clinic Visit or Continued 
Hospital Stay, per Site Decision 
• Interim medical history, including an assessment for new medical conditions and stability of 
chronic diseases, will be obtained by interview of participants and any changes since the previous 
visit will be noted. 
• A targeted physical examination may be performed if indicated based on review of interim 
medical history, by a study clinician licensed to make medical diagnoses and listed on the Form 
FDA 1572 as the site PI or sub-investigator. 
• All concomitant medications will be recorded on the appropriate DCF. 
• Vital signs, including oral temperature, sitting blood pressure, and sitting pulse will be obtained. 
Participants must not eat or drink anything hot or cold within 10 minutes prior to taking oral 
temperature. 
• A 12-Lead ECG will be performed. 
• Receive home urine collected jug from subject. Measure and record urine PK volume, aliquot, 
label and freeze per Section 7.2.2.1. 
• Approximately 4 mL of venous blood will be collected for PK. 
• All AE/SAEs will be recorded on the appropriate DCF/DMID SAE Report Form. 
• Approximately 10 mL of venous blood will be collected for safety laboratory assessments 
including Hgb, BUN, serum creatinine (includes eGFR), ALT, AST, total bilirubin, serum 
potassium, and serum magnesium. 
• If hospitalization was continued, discharge after review by physician licensed to make medical 
diagnoses and listed on the Form FDA 1572 as the site PI or sub-investigator. 
 
 
Visit 02, Day 12 ± 2 Days Post-dose, Clinic Visit 
 
• Interim medical history, including an assessment for new medical conditions and stability of 
chronic diseases, will be obtained by interview of participants and any changes since the previous 
visit will be noted. 
• A targeted physical examination may be performed on all participants by a study clinician 
licensed to make medical diagnoses and listed on the Form FDA 1572 as the site PI or 
sub-investigator. 
• All concomitant medications will be recorded on the appropriate DCF. 

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• Vital signs, including oral temperature, sitting blood pressure, and sitting pulse will be obtained. 
Participants must not eat or drink anything hot or cold within 10 minutes prior to taking oral 
temperature. 
• A urine pregnancy test will be performed on all women of childbearing potential. 
• All AE/SAEs will be recorded on the appropriate DCF/DMID SAE Report Form. 
• Approximately 10 mL of venous blood will be collected for safety laboratory assessments 
including Hgb, BUN, serum creatinine (includes eGFR), ALT, AST, total bilirubin, serum 
potassium, and serum magnesium. 
 
Final Visit, Visit 03, Day 85+7 Days Post-dose, Phone Visit 
• The participant will be asked if they or their partner became pregnant. If the participant became 
pregnant, the Pregnancy Report and Follow-Up forms will be completed. If the participant’s 
partner became pregnant, details about the pregnancy should be reported to the sponsor to 
document the outcome of the pregnancy. All SAEs will be recorded on the appropriate 
DCF/DMID SAE Report Form. 
 
Early Termination Visit (if needed) 
 
The following activities will be performed at the early termination (ET) visit on participants who 
withdraw, or are withdrawn or terminated from this trial: 
• Obtain interim medical history, including an assessment of new symptoms and conditions from 
the patient, and note any changes since the previous visit. 
• A targeted review of systems. For participants with renal impairment, this targeted review of 
systems will also focus on renal disease and will include questions pertaining to changes in the 
frequency and volume of urine, requirement for dialysis, and mental status. 
• Targeted physical examination, if needed. 
• All concomitant medications will be recorded on the appropriate DCF. 
• Assess for AEs/SAEs. 
• Urine pregnancy test for females of childbearing potential. 
• Vital signs including oral temperature, sitting blood pressure, and sitting pulse will be obtained. 
• Approximately 10 mL of venous blood will be collected for safety laboratory assessments 
including Hgb, BUN, serum creatinine (includes eGFR), ALT, AST, total bilirubin, serum 
potassium, and serum magnesium. 

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Unscheduled Visit (if needed) 
Unscheduled visits will be allowed for the following reasons: 
• Management of AEs and SAEs. 
• Performance of repeat or additional laboratory tests for clinically abnormal test values. 
• For a repeat urine pregnancy test if the participant suspects pregnancy. 
• Anytime the investigator believes that it is clinically appropriate for patient safety. 
 
Protocol Deviations 
 
A protocol deviation is any noncompliance with the clinical trial protocol, or protocol-specific MOP 
requirements. The noncompliance may be either on the part of the participant, the site PI, or the site 
personnel. As a result of deviations, corrective actions are to be developed by the site and 
implemented promptly. 
It is the responsibility of the site PI and personnel to use continuous vigilance to identify and report 
deviations within 5 working days of identification of the protocol deviations, or within 5 working 
days of the scheduled protocol-required activity. All deviations must be promptly reported to DMID 
per the Statistical Data Coordinating Center (SDCC) protocol deviation reporting procedures. 
All deviations, as defined above, must be addressed in study participant DCFs. A completed copy 
of the DMID Protocol Deviation Form must be maintained in the regulatory file, as well as the 
participant’s chart. Protocol deviations must be sent to the local IRB/IEC per their guidelines. The 
site PI and personnel are responsible for knowing and adhering to their IRB requirements. 

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7 
DESCRIPTION OF CLINICAL AND LABORATORY 
EVALUATIONS 
 
Clinical Evaluations 
 
Complete medical history will be obtained by interview of participants during the screening visit. 
Participants will be queried regarding a history of significant medical disorders of the head, eyes, 
ears, nose, throat, mouth, cardiovascular system, lungs, gastrointestinal tract, liver, pancreas, 
kidneys, urologic system, nervous system, blood, lymph nodes, endocrine system, musculoskeletal 
system, skin, and genital/reproductive tract. A history of any allergies, cancer, immunodeficiency, 
psychiatric illness, substance abuse, and autoimmune disease will be solicited. 
During the hospital stay, any new symptoms after study product administration will be collected. 
After hospital discharge, an interim medical history will be obtained by interview of participants 
noting any changes since the previous visit or contact. 
Medications history (concomitant medications) will include a review of all current medications and 
medications as specified in Section 7.1.1. Assessment of eligibility will include a review of all 
permitted and prohibited medications per the participant inclusion and exclusion criteria (see 
Sections 5.1.1 and 5.1.2). In addition, the site PI or appropriate sub-investigator may identify other 
medications that should not be used due to a risk to participant safety or possible effects on PK 
parameters. 
At the first visit (Visit 00A) a physical examination will be performed on all participants to include 
the following organs and organ systems: skin, head, eyes, ears, nose and throat, thyroid, neurological 
system, chest and lungs, cardiovascular system, abdomen, lymph nodes, musculoskeletal system, 
and extremities by a study clinician licensed to make medical diagnoses and listed on the Form FDA 
1572 as the site PI or sub-investigator. At Visit 01A, all follow-up visits, and ET visit after 
administration of study product, a targeted physical examination may be performed, if indicated 
based on the participant’s interim medical history, by a study clinician licensed to make medical 
diagnoses and listed on the Form FDA 1572 as the site PI or sub-investigator. At the ET visit, for 
participants with renal impairment, a targeted review of systems focused on renal disease will 
include questions pertaining to changes in frequency and volume of urine, requirement for dialysis, 
and mental status. 
Vital sign measurements must include the participant’s sitting pulse, sitting blood pressure (mm Hg), 
and oral body temperature (ºF) at the screening Visit 00A, 01A, 12, 24, 48, 72, and 96 hours and 
Day 12 or at ET after study product administration. Height and weight will be obtained at screening 
Visit 00A only. If a physiologic parameter, e.g., vital signs, is outside of the protocol-specified range 
(for control participants) or outside the patient’s baseline (for renally impaired participants), then the 
measurement may be repeated once if, in the judgment of the investigator, the abnormality is the 

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result of an acute, short-term, rapidly reversible condition (e.g., stress, anxiety, or “white coat 
syndrome”). The participant’s baseline is the latest vital sign recorded in their electronic health 
record (EHR) in the last 3 months before screening. For participants with CKD but no vital signs 
recorded in their EHR, the protocol-specified range used for control participants will be used. Once 
participants are dosed, the vital signs measured at Visit 01A will be considered their baseline. A 
physiologic parameter may also be repeated if there is a technical problem with the measurement 
caused by a malfunction, or an inappropriate measuring device (i.e., inappropriate-sized blood 
pressure cuff). If there is an abnormal blood pressure measurement, the participant should lay down 
for 10 minutes and then the measurement should be repeated while the participant is awake and 
resting supine. For analyzing secondary safety endpoints in rescreened participants (if any) and that 
include a comparison to screening baseline values should have the rescreening values as baseline. 
In addition, a 12-lead ECG will be performed at Screening Visit 00A and Visit 01N. If at Visit 01N 
the ECG is abnormal, it can be repeated. 
At subsequent visits, assessment for AEs and SAEs will occur and the participant will be interviewed 
about interim AEs/SAEs and medical history. 
Participants will be admitted for multiple blood draws following oral administration of study 
product. Any AEs/SAEs will be recorded on the appropriate DCF/DMID SAE Report Form prior to 
discharge from the hospital. 
 
Assessment of Concomitant Medications/Treatments Other Than Study Product 
 
Administration of any medications, therapies, or vaccines will be recorded on the appropriate DCF. 
Concomitant medications will include all current medications and medications taken in the 30 days 
prior to signing the ICF through approximately 11 days after the study medication is given, ET or 
unscheduled visits (if prior to 11 days after study product administration), whichever occurs first. 
Medications reported are limited to those taken within 30 days prior to the study medication through 
approximately 11 days after the study medication. Prescription and over-the-counter drugs will be 
included as well as vitamins, and supplements (including herbal). 

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Table 4: Prohibited Strong and Moderate CYP450 Enzyme Inducer or Inhibitor 
Medications/Substances per Participant Exclusion Criteria 
CYP3A (including 3A4) inhibitors and inducers 
Strong inhibitors 
Moderate inhibitors 
Strong inducers 
Moderate inducers 
• Adagrasib 
• Atazanavir 
• Ceritinib 
• Clarithromycin 
• Cobicistat and 
cobicistat-containing 
coformulations 
• Darunavir 
• Idelalisib 
• Indinavir 
• Itraconazole 
• Ketoconazole 
• Levoketoconazole 
• Lonafarnib 
• Lopinavir 
• Mifepristoned 
• Nefazodone 
• Nelfinavir 
• Nirmatrelvir-ritonavir 
• Ombitasvir- 
paritaprevir-ritonavir 
• Ombitasvir- 
paritaprevir-ritonavir 
plus dasabuvir 
• Posaconazole 
• Ritonavir and 
ritonavir-containing 
coformulations 
• Saquinavir 
• Tucatinib 
• Voriconazole 
• Amiodaronea 
• Aprepitant 
• Berotralstat 
• Cimetidinea 
• Conivaptan 
• Crizotinib 
• Cyclosporinea 
• Diltiazem 
• Duvelisib 
• Dronedarone 
• Erythromycin 
• Fedratinib 
• Fluconazole 
• Fosamprenavir 
• Fosaprepitanta 
• Fosnetupitant- 
palonosetron 
• Grapefruit juice 
• Imatinib 
• Isavuconazole 
(isavuconazonium 
sulfate) 
• Lefamulin 
• Letermovir 
• Netupitant 
• Nilotinib 
• Ribociclib 
• Schisandra 
• Verapamil 
• Apalutamide 
• Carbamazepine 
• Enzalutamide 
• Fosphenytoin 
• Lumacaftor 
• Lumacaftor- 
ivacaftor 
• Mitotane 
• Phenobarbital 
• Phenytoin 
• Primidone 
• Rifampin 
(rifampicin) 
• Bexarotene 
• Bosentan 
• Cenobamate 
• Dabrafenib 
• Dexamethasoneb 
• Dipyrone 
• Efavirenz 
• Elagolix, estradiol, 
and norethindrone 
therapy packc 
• Eslicarbazepine 
• Etravirine 
• Lorlatinib 
• Mitapivat 
• Modafinil 
• Nafcillin 
• Pexidartinib 
• Rifabutin 
• Rifapentine 
• Sotorasib 
• St. John's wort 
CYP=cytochrome P450; FDA=Food and Drug Administration; US=United States (of America) 
From https://www.uptodate.com/contents/image?imageKey=CARD%2F76992 
For drug interaction purposes, inhibitors and inducers of CYP3A metabolism listed above can alter serum concentrations 
of drugs that are dependent upon the CYP3A subfamily of liver enzymes, including CYP3A4, for elimination or 
activation. 
These classifications are based upon US FDA guidance [41, 42]. Other sources may use a different classification system 
resulting in some agents being classified differently. 
Data are for systemic drug forms. Degree of inhibition or induction may be altered by dose, method, and timing of 
administration. 
Weak inhibitors and inducers are not listed in this table with exception of a few examples. Clinically significant 
interactions can occasionally occur due to weak inhibitors and inducers (e.g., target drug is highly dependent on CYP3A4 
metabolism and has a narrow therapeutic index). Accordingly, specific interactions should be checked using a drug 
interaction program such as the Lexicomp drug interactions program included within UpToDate. 

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Refer to UpToDate topics on specific agents and indications for further details. 
a 
Classified as a weak inhibitor of CYP3A4 according to FDA system [41]. 
b 
Classified as a weak inducer of CYP3A4 according to FDA system [41]. 
c  The fixed-dose combination therapy pack taken in the approved regimen has moderate CYP3A4 induction effects. 
When Elagolix is used as a single agent, it is a weak CYP3A4 inducer. Norethindrone and estradiol are not CYP3A4 
inducers. 
d  Mifepristone is a significant inhibitor of CYP3A4 when used chronically (e.g., for hyperglycemia in patients with 
Cushing syndrome); not in single-dose use. 
 
Laboratory Evaluations 
 
Clinical Laboratory Evaluations 
 
Clinical laboratory parameters to be evaluated prior to the study product administration on screening 
visit (Visit 00A), on Day 5 (Visit 01N) and on Day 12 (Visit 02) will include Hgb, ALT, AST, total 
bilirubin, BUN, serum creatinine (includes eGFR), serum potassium and serum magnesium. HIV, 
HBsAg, and HCV will be obtained at Visit 00A only. Screening laboratory assessments may be 
repeated once per investigator discretion. 
Urine pregnancy tests will be performed locally on all women of childbearing potential by the site 
laboratory at screening (Visit 00B), on the day of hospital admission (Visit 00C), prior to 
administration of study product (Visit 01A), at Visit 02, and ET. Results must be negative and known 
prior to administration of study product. Urine drug screen and alcohol screen will also be done on 
Visit 00B and 00C. 
 
Research Assays 
 
All PK samples collected in the study will be analyzed using validated bioanalytical methods for 
pretomanid, and the metabolites, M19 and M50 in plasma and urine. 
Blood samples will be collected (dipotassium ethylenediaminetetraacetic acid [K2 EDTA] tubes) in 
this study to characterize the PK of pretomanid in non-renally impaired controls and in participants 
with renal impairment (see PK sampling points in APPENDIX A: Schedule of Study Procedures and 
Evaluations. 
The exact date and time of collection of all PK blood and urine samples will be recorded. The pre- 
dose blood sample will be collected up to 1 hour prior to dosing. For the post-dose PK blood samples 
collected through the first 16 hours after dosing, collection times must be ± 10 minutes from the 
nominal time. For post-dose collections at 24, 36, and 48 hours, collection times must be within 
± 1 hour from the nominal time. Post-dose collections at within 72 and 96 hours must be within ± 4 
hours from the nominal time. 
Dates should be recorded in an unambiguous format (e.g., DDMMMYYYY), and time should be 
recorded to the nearest minute (e.g., HH:MM using the 24-hour clock). Blood samples drawn outside 

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of the defined window should not be considered protocol deviations. Blood samples that are not 
drawn should be recorded and reported as protocol deviations. 
7.2.2.1 
Laboratory Specimen Preparation, Handling, and Shipping 
 
Instructions for specimen preparation, handling, and storage are included in the central (clinical) 
laboratory manual and protocol-specific MOP as appropriate. 
Briefly, whole blood will be collected into commercially available anticoagulant (K2 EDTA)-treated 
tubes. Cells including platelets will be removed from plasma by centrifugation for 15 minutes at 
2,000 x g using a refrigerated centrifuge. The resulting supernatant is designated plasma. Following 
centrifugation, the plasma will be transferred into a clean polypropylene tube using sterile pipettes. 
The plasma samples will be apportioned into 0.5 mL aliquots immediately while the samples are 
maintained at 2–8°C. The aliquots will be stored at –20°C or colder. 
The urine PK of a single dose of pretomanid will be assessed from urine collected at up to 1 hour 
pre-dose, 0-4, 4-8, 8-12, 12 24, 24 48, 48-72, and 72-96 hours post-dose. Urine volume will be 
measured and recorded for each of these time intervals. Urine will be stored at room temperature 
and then frozen at -20°C within 24 hours. Urine will be in ≤100 mL aliquots and stored at -20°C 
until shipped to Fisher Bioservices. The rest of the urine will be stored until the study is completed. 
7.2.2.2 
Laboratory Specimen Shipment 
 
Specimen shipment will occur at intervals during the course of this trial following all applicable 
International Air Transport Association (IATA) requirements and according to the specifics for 
storage temperature and documentation as detailed in the protocol-specific MOP as appropriate. 
Plasma and urine PK samples will be shipped on dry ice to Fisher Bioservices prior to sending to 
the bioanalytical laboratory measuring concentrations of pretomanid and its metabolites (M19 and 
M50). 
Instructions for specimen shipment are included in the protocol-specific MOP, as appropriate. 

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8 
ASSESSMENT OF SAFETY 
 
Assessing and Recording Safety Parameters 
 
Safety will be assessed by the frequency and severity of the following: 
 
1. SAEs (Section 8.1.2) occurring from the time of the study product administration through Visit 
03, Day 85+7 days. 
2. Adverse Events occurring from the time of the first study product administration (Visit 01A) 
through Visit 02, Day 12 ± 2 days. 
3. Clinical safety laboratory AEs occurring from the time of the first study product administration 
(Visit 01A) through Visit 02 Day 12 ± 2 days. Parameters to be evaluated include a Hgb, AST, 
ALT, total bilirubin, BUN, serum creatinine, eGFR, and serum potassium and magnesium. 
All AEs/SAEs will be followed until resolution. 
 
Adverse Events 
 
Adverse Event (AE): The International Council for Harmonisation (ICH) E6 defines an AE as any 
untoward medical occurrence in a patient or clinical investigation participant administered a 
pharmaceutical product regardless of its causal relationship to the study treatment. The FDA defines 
an AE as any untoward medical occurrence associated with the use of a drug in humans, whether or 
not considered drug related. 
An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a medicinal (investigational) 
product. The occurrence of an AE may come to the attention of study personnel during study visits 
and interviews of a study participants presenting for medical care, or upon review by a study monitor. 
All AEs, systemic (participative and quantitative) reactions from Day 1 to the end of the study, will 
be captured on the appropriate (source documentation and eCRF) (Section 8.3). Information to be 
collected for AEs includes event description, date of onset, assessment of severity, relationship to 
study product and alternate etiology (assessed only by those with the training and authority to make 
a diagnosis and listed on the Form FDA 1572 as an investigator), date of resolution, seriousness, and 
outcome. AEs occurring during the trial collection and reporting period will be documented 
appropriately regardless of relationship to the study product. AEs will be followed through resolution 
or until stable. 
Any medical condition(s) that is/are present at the time that the participant is screened will be 
considered as baseline and not reported as an AE but must be reported in the medical history 

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(APPENDIX A: Schedule of Study Procedures and Evaluations). However, if the severity of any 
pre-existing medical condition increases, it will be recorded as an AE (Section 8.3). 
8.1.1.1 
Adverse Events Grading 
 
All AEs, including laboratory and clinical symptoms, will be graded for severity according to the 
Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0, November 2017 
(https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm#ctc_50), and 
assessed for relationship to study product. AEs characterized as intermittent require documentation 
of onset and duration of each episode. The start and stop date of each reported AE will be recorded 
on the appropriate DCF and eCRF. 
Severity of Event: 
• Mild (Grade 1): Asymptomatic or mild symptoms, Events require minimal or no treatment and 
do not interfere with the participant’s daily activities. 
• Moderate (Grade 2): Events result in a low level of inconvenience or concern with therapeutic 
measures. Moderate events may cause some interference with functioning and daily activities. 
• Severe (Grade 3): Severe or medically significant but not immediately life threatening, interrupt 
the participant’s daily activities; and may require intervention and hospitalization. Severe events 
are usually incapacitating. 
• Life-threatening (Grade 4): Life-threatening consequences; urgent intervention indicated. 
AEs characterized as intermittent require documentation of onset and duration of each episode. 
 
Relationship to Study Product: The assessment of the AE’s relationship to study product will be 
performed by a delegated, licensed study clinician listed on the Form FDA 1572. The assessment 
will be part of the documentation process. Whether the AE is related or not is not a factor in 
determining what is or is not reported in this trial. If there is any doubt as to whether a clinical 
observation is an AE, the event should be reported. In a clinical trial, the study product must always 
be suspect. To help assess the relationship, the following guidelines will be used: 
• Related – There is a reasonable possibility that the study product caused the AE. Reasonable 
possibility means that there is evidence to suggest a causal relationship between the study 
product and the AE. 
• Not Related – There is not a reasonable possibility that the administration of the study product 
caused the event. 
 
Serious Adverse Events 
 
Serious Adverse Event (SAE): An AE or suspected adverse reaction is considered “serious” if, in 
the view of either the site PI or sponsor, it results in any of the following outcomes: 

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• Death, 
• A life-threatening AE*, 
• Inpatient hospitalization or prolongation of existing hospitalization, 
• A persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions, or 
• A congenital anomaly/birth defect. 
*An AE is considered “life-threatening” if, in the view of either the site PI or sponsor, its occurrence 
places the patient or participant at immediate risk of death. It does not include an AE that, had it 
occurred in a more severe form, might have caused death. 
Important medical events that may not result in death, be life-threatening, or require hospitalizations 
may be considered serious when, based upon appropriate medical judgment they may jeopardize the 
health or safety of the patient or participant and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition. Examples of such medical events include 
allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse. 
SAEs will be: 
 
• Assessed for severity and relationship to study product and alternate etiology (if not related to 
study product). 
• Recorded on the appropriate DCF and eCRF, and on the DMID SAE Report Form. 
• Followed through resolution. 
• Reviewed and evaluated by the DMID, SMC (periodic review unless related), and the IRB per 
reporting requirements. 
At any time after the protocol follow-up period or completion of this study, if the site PI or 
appropriate sub-investigator becomes aware of an SAE that is suspected to be related to study 
product, the site PI or appropriate sub-investigator will report the event to the DMID 
Pharmacovigilance Group. 
 
Specification of Safety Parameters 
 
There are no solicited events to be captured for this study. 

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Reporting Procedures 
Non-serious AEs will be documented and reported from the time of receipt of study product through 
approximately 11 days after receipt of study product. 
SAEs will be documented and reported through approximately 3 months after receipt of study 
product. 
AEs will be followed until resolution even if this extends beyond the study-reporting period. 
Resolution of an AE is defined as the return to pretreatment status or stabilization of the condition 
with the expectation that it will remain chronic. 
 
Reporting SAEs 
 
SAEs will be followed until resolution even if this extends beyond the study-reporting period. 
Resolution of an AE is defined as the return to pretreatment status or stabilization of the condition 
with the expectation that it will remain chronic. 
Any AE that meets a protocol-defined serious criterion must be submitted immediately (within 
24 hours of site awareness) on a PDF-fillable SAE form to the DMID Pharmacovigilance 
Group at the following address: 
DMID Pharmacovigilance Group 
Clinical Research Operations and Management Support (CROMS) 
6500 Rock Spring Dr. Suite 650 
Bethesda, MD 20817, US 
SAE Hot Line: 1-800-537-9979 (US) or 1-301-897-1709 (outside US) 
SAE FAX: 1-800-275-7619 (US) or 1-301-897-1710 (outside US) 
SAE Email Address: PVG@dmidcroms.com 
 
In addition to the SAE form, selected SAE data fields must also be entered into the SDCC system 
(for example Advantage eClinical). Please see the protocol-specific MOP for details regarding this 
procedure. 
Other supporting documentation of the event may be requested by the DMID Pharmacovigilance 
Group and should be provided as soon as possible. 
The site will send a copy of the SAE report(s) to the DMID Pharmacovigilance Group. The DMID 
Medical Monitor and DMID Clinical Project Manager will be notified of the SAE by the DMID 
Pharmacovigilance Group. The DMID Medical Monitor will review and assess the SAE for 
regulatory reporting and potential impact on study participant safety and protocol conduct. 

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At any time after completion of this trial, if the site PI or appropriate sub-investigator becomes aware 
of an SAE that is suspected to be related to study product, the site PI or appropriate sub-investigator 
will report the event to the DMID Pharmacovigilance Group. 
 
Regulatory Reporting for Studies Conducted Under DMID-Sponsored IND 
 
Following notification from the investigator, DMID, the IND sponsor will report any suspected 
adverse reaction that is both serious and unexpected. DMID will report an AE as a suspected adverse 
reaction only if there is evidence to suggest a causal relationship between the study product and the 
AE. DMID will notify the FDA and all participating site investigators (i.e., all investigators to whom 
the sponsor is providing drug under its IND[s] or under any PI’s IND[s]) in an IND safety report of 
potential serious risks from clinical trials or any other source, as soon as possible, but in no case later 
than 15 calendar days after the sponsor determines that the information qualifies for reporting as 
specified in US 21 CFR Part 312.32. DMID will also notify the FDA of any unexpected fatal or life-
threatening suspected adverse reaction as soon as possible, but in no case later than 7 calendar days 
after the sponsor’s initial receipt of the information. Relevant follow-up information to an IND safety 
report will be submitted as soon as the information is available. Upon request from the FDA, DMID 
will submit to FDA any additional data or information that the agency deems necessary, as soon as 
possible, but in no case later than 15 calendar days after receiving the request. 
All serious events designated as “not related” to study product(s), will be reported to FDA at least 
annually in a summary format. 
 
Reporting of Pregnancy 
 
Pregnancies occurring in female study participants will be reported via Advantage eClinical® on the 
Pregnancy Report form. With the participant’s permission all protocol-required venous blood 
samples will be obtained and the participant will continue to be followed for safety for the duration 
of this trial. Efforts will be made to follow all pregnancies reported during the course of this trial to 
pregnancy outcome pending the participant’s permission. 
Male participants will be asked if their female partner has become pregnant during the study and any 
pregnancy will be reported. The outcome of pregnancy in the female partner of male participant will 
be handled through contact with the male participant. 
 
Type and Duration of Follow-up of Participants After Adverse Events 
 
AEs/SAEs will be collected, assessed, and followed through resolution from the time of study 
product administration through approximately 3 months after receipt of study product. 

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Resolution of an AE/SAE is defined as the return to pretreatment status or stabilization of the 
condition with the expectation that it will remain chronic. 
Follow-up procedures, evaluations, and outcomes will be recorded on the appropriate DCF. 
 
Procedures to be Followed in the Event of Abnormal Laboratory Test 
Values or Abnormal Clinical Findings 
The site PI or appropriate sub-investigator is responsible for recording all AE/SAEs that are observed 
or reported during this trial, regardless of the relationship to study product. AE/SAEs, abnormal 
laboratory test values, or abnormal clinical findings will be collected, assessed, documented, 
reported, and followed appropriately, using a local laboratory as necessary. Participants with 
elevated aminotransferase and/or bilirubin will be asked about recent seizures and mental health 
status change. In determining eligibility, refer to Section 5.1 and the protocol-specific MOP. 
Clinical and safety laboratory results will be graded for severity according to the CTCAE 
Version 5.0, November 2017 (see Section 8.1.1.1). 
 
Halting Rules 
 
Study Halting Criteria 
 
The study will be immediately suspended, and no additional doses administered if any of the 
following occurs: 
• Any death occurring during the study that was not the result of trauma or accident. 
• Two or more participants experience an SAE, related to the study product. 
• Three or more participants in each part of the trial (A or B) develop a severe, Grade 3 or higher, 
AE, systemic or laboratory, in the same MedDRA Low Level Term (LLT), assessed as related 
to the study product. 
If any halting criterion is met, the study will be suspended, and a SMC ad hoc meeting will convene. 
The study will not be re-started until the SMC meets and provides its recommendation to DMID, the 
study sponsor. 

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Safety Oversight 
 
Safety Monitoring Committee (SMC) 
 
This study will utilize a SMC, which is an independent group of experts that advises DMID. The 
primary responsibility of the SMC is to monitor participant safety. The SMC is external to DMID 
and is composed of at least 3 voting members. The SMC will consist of members with appropriate 
Phase 1 study expertise to contribute to the interpretation of the data from this trial. Its activities will 
be delineated in a SMC charter that will describe the membership, responsibilities, and the scope 
and frequency of data reviews. The SMC will operate on a conflict-free basis independently of the 
study team. The DMID or the SMC may convene ad hoc meetings of the SMC according to protocol 
criteria or if there are concerns that arise during the study. 
The SMC will review the safety data at the following milestones: 
• Organizational meeting (prior to start of the study). 
• After 6 participants in Group 2 (severe renal impairment and ESRD, not on dialysis) and their 
matching controls are enrolled and complete follow-up through Day 12 (Visit 02). This review 
will be completed prior to determining if Part B will be conducted and opening enrollment for 
Groups 3 and 4 and their matched healthy control participants. 
• An ad hoc SMC meeting will be convened when a halting rule is met, or at the request of the 
investigator and/or DMID if there are safety concerns during the course of the study. 
• Final Data Review Meeting: Approximately 6 to 8 months after final clinical database lock to 
review the cumulative unblinded safety data for this trial. The data will be provided in a standard 
summary format. The SMC may be asked to provide recommendations in response to questions 
posed by DMID. 
• The DMID Medical Monitor is empowered to stop study enrollment if AEs that meet the halting 
criteria are reported or if any serious safety concerns arise. The DMID Medical Monitor will be 
responsible for reviewing SAEs in real time. The SMC will review SAEs on a regular basis and 
ad hoc during the study. 

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9 
HUMAN PARTICIPANT PROTECTION 
 
Institutional Review Board 
 
The site PI will obtain IRB approval for this protocol to be conducted at his/her research site(s) and 
send supporting documentation to the DMID before initiating recruitment of participants. The 
investigator will submit applicable information to the IRB on which it relies for the review, to 
conduct the review in accordance with 45 CFR 46, ICH E6 Good Clinical Practice (GCP), and as 
applicable, 21 CFR 56 (IRB) and 21 CFR 50 (Protection of Human Participants), other federal, state, 
and local regulations. The IRB must be registered with the Office for Human Research Protections 
(OHRP) as applicable to the research. DMID must receive the documentation that verifies IRB 
approval for this protocol, associated informed consent documents, and upon request any recruitment 
material and handouts or surveys intended for the participants, prior to recruitment and enrollment 
of participants. 
Any amendments to the protocol or consent materials will be approved by the IRB before they are 
implemented. IRB review and approval will occur at least annually throughout the enrollment and 
follow-up of participants and may cease if annual review is no longer required by applicable 
regulations. The investigator will notify the IRB of deviations from the protocol and reportable 
SAEs, as applicable to the IRB policy. 
Each institution engaged in this research will hold a current Federal Wide Assurance (FWA) issued 
by the OHRP for federally funded research. 
The IRB/IEC will determine that adequate provisions are made for soliciting the permission of each 
participant. 
 
Informed Consent Process 
 
Informed consent is a process that is initiated prior to an individual agreeing to participate in a trial 
and continuing throughout the individual’s trial participation. Before any study procedures are 
performed, informed consent will be obtained from the participant and documented. Participants will 
receive a concise and focused presentation of key information about the clinical trial, verbally and 
with a written ICF. The explanation will be organized and presented in lay terminology and language 
that facilitates understanding why one might or might not want to participate. 
An investigator or designee will describe the protocol to potential participants face-to-face. The key 
information about the purpose of the study, the procedures, and experimental aspects of the study, 
risks and discomforts, any expected benefits to the participant, and alternative treatment will be 
presented first to the participant. 

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Participants will also receive an explanation that the trial involves research, and a detailed summary 
of the proposed study procedures and study interventions/products. This will include aspects of the 
trial that are experimental, the probability for random assignment to treatment groups, any expected 
benefits, all possible risks (including a statement that the particular treatment or procedure may 
involve risks to the participant or to the unborn child, if the participant is or may become pregnant, 
that are currently unforeseeable), the expected duration of the participant’s participation in the trial, 
alternative procedures that may be available and the important potential benefits and risks of these 
available alternative procedures. 
Participants will be informed that they will be notified in a timely manner if information becomes 
available that may be relevant to their willingness to continue participation in the trial. Participants 
will receive an explanation as to whether any compensation and any medical treatments are available 
if injury occurs, and, if so, what they consist of, or where further information may be obtained. 
Participants will be informed of the anticipated financial expenses, if any, to the participant for 
participating in the trial, as well as any anticipated prorated payments, if any, to the participant for 
participating in the trial. They will be informed of whom to contact (e.g., the investigator) for 
answers to any questions relating to the research project. 
Information will also include the foreseeable circumstances and/or reasons under which the 
participant’s participation in the trial may be terminated. The participants will be informed that 
participation is voluntary and that they are free to withdraw from the study for any reason at any 
time without penalty or loss of benefits to which the participant is otherwise entitled. 
The extent of the confidentiality of the participants’ records will be defined, and participants will be 
informed that applicable data protection legislation will be followed. Participants will be informed 
that the monitor(s), auditors(s), IRB, NIAID, and regulatory authority(ies) will be granted direct 
access to the participant’s original medical records for verification of clinical trial procedures and/or 
data without violating the confidentiality of the participant, to the extent permitted by the applicable 
laws and regulations, and that, by signing a written ICF, the participant is authorizing such access. 
Participants will be informed that records identifying the participant will be kept confidential, and, 
to the extent permitted by the applicable laws and/or regulations, will not be made publicly available 
and, if the results of the trial are published, the participant’s identity will remain confidential. 
Participants will be informed whether private information collected from this research and/or 
specimens will be used for additional research, even if identifiers are removed. 
Participants will be allowed sufficient time to consider participation in this research trial and have 
the opportunity to discuss this trial with their family, friends, or legally authorized representative, or 
think about it prior to agreeing to participate. 
ICFs will be IRB-approved, and participants will be asked to read and review the consent form. 
Participants must sign the ICF prior to starting any study procedures being done specifically for this 
trial. 

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Once signed, a copy of the ICF will be given to the participant(s) for their records. The participant(s) 
may withdraw consent at any time throughout the course of the trial. The rights and welfare of the 
participant(s) will be protected by emphasizing to them that the quality of their medical care will not 
be adversely affected if they decline to participate in this study. 
Study personnel may employ recruitment efforts prior to obtaining study consent if a patient-specific 
screening consent is on record or if the IRB has agreed that chart review is allowed without a fully 
executed screening consent. In cases where there is not a patient-specific screening consent on 
record, site staff may pre-screen via chart review and refer potential participants to the Research 
staff. Research staff would obtain written consent per the standard informed consent process before 
conducting protocol-specific screening activities. 
New information will be communicated by the site PI to participants who consent to participate in 
this trial in accordance with IRB requirements. The ICF will be updated, and participants will be re-
consented per IRB requirements, if necessary. Participants will be given a copy of all ICFs that they 
sign. 
 
Special Populations 
 
This trial will be inclusive of participants age 18-85 years of age who meet the participant inclusion 
criteria (see Section 5.1.1) and do not meet any of the participant exclusion criteria (see Section 
5.1.2), regardless of religion, sex, or ethnic background. CKD is mostly seen in adults, and 
participants enrolled in the control arms must meet certain criteria to match the CKD participants. 
Therefore, no one under the age of 18 years will be enrolled in this study. Should the outcome of 
this trial be deemed acceptable, additional trials may be initiated, including those in other 
populations. 
 
Participant Confidentiality 
 
Participant confidentiality is strictly held in trust by the participating investigators, their staff, and 
the sponsor(s) and their agents. This confidentiality includes documentation, investigation data, 
participant’s clinical information, and all other information generated during participation in the 
study. 
No information concerning the study, or the data generated from the study, will be released to any 
unauthorized third party without prior written approval of the DMID and the participant. Participant 
confidentiality will be maintained when study results are published or discussed at conferences. 
The study monitor or other authorized representatives of the sponsor or governmental regulatory 
agencies may inspect all documents and records required to be maintained by the investigator, 
including but not limited to, medical records (office, clinic, or hospital) and pharmacy records for 
the participants in this study. The clinical study site will permit access to such records. All records 
will be kept locked, and all computer entry and networking programs will be carried out with coded 

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numbers only and with password-protected systems. All non-clinical specimens, evaluation forms, 
reports, and other records that leave the site will be identified only by a coded number. 
 
Certificate of Confidentiality 
 
As this research is funded by the National Institutes of Health (NIH), it is covered by NIH policy 
which effectively issues the research a Certificate of Confidentiality. By this policy, researchers 
cannot be forced to disclose or provide, in any federal, state, or local civil, criminal, administrative, 
legislative, or other proceeding, the name of such individual or any such information, document, or 
biospecimen that contains identifiable, sensitive information about the individual and that was 
created or compiled for purposes of the research, unless such disclosure or use is made with the 
consent of the individual to whom the information, document, or biospecimen pertains. 
The Certificate cannot be used to resist a demand for information from personnel of the US 
Government that is used for auditing or evaluation of federally funded projects, like this trial, or for 
information that must be released to meet the requirements of the Federal FDA. 
A Certificate of Confidentiality does not prevent the participant from voluntarily releasing 
information about themselves or their involvement in this research. If any person or agency obtains 
a written consent to receive research information, then the researchers may not use the Certificate to 
withhold that information. 
The Certificate of Confidentiality does not cover matters that must be legally reported, including 
child and elder abuse, sexual abuse, wanting to harm themselves or others, and certain infectious 
diseases that meet the criteria for reporting. In these cases, researchers may report information that 
would identify a participant without the participant’s consent. 
The release of individual private information or specimens for other research will only occur if 
consent was obtained from the individual to whom the information, document, or biospecimen 
pertains, or for the purposes of other research that the release complies with the applicable Federal 
regulations governing the protection of human participants in research. 
 
Costs, Participant Compensation, and Research Related Injuries 
 
There is no cost to participants for the research tests, procedures, and study product while taking part 
in this trial. Procedures and treatment for clinical care may be billed to the participant, participant’s 
insurance or third party. Participants may be compensated for their participation in this trial. 
Compensation will be in accordance with the local IRB’s policies and procedures, and participant to 
IRB approval. 
If it is determined by the site PI that an injury occurred to a participant as a direct result of the tests 
or treatments that are done for this trial, then referrals to appropriate health care facilities will be 
provided to the participant. Study personnel will try to reduce, control, and treat any complications 
from this trial. Immediate medical treatment may be provided by the participating site. No financial 

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compensation will be provided to the participant by the NIAID, NIH to the participant, or by the 
participating site for any injury suffered due to participation in this trial. 

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10 
STATISTICAL CONSIDERATIONS 
 
Study Hypotheses 
 
FDA guidance document suggests using a reduced PK design for drugs that are predominantly 
metabolized or secreted in the bile [38]. In a reduced PK study design, the trial compares PK in 
patients with normal renal function and to patients with severe renal impairment and patients with 
ESRD not yet on dialysis. If the reduced PK study shows at least a 50% increase in AUC in patients 
with severe renal impairment and patients with ESRD not yet on dialysis relative to the matched 
healthy controls, a “full” renal impairment study in patients with all intermediate levels of renal 
function impairment should be conducted [38]. Otherwise, no further study is recommended. 
In the current study, Part A is considered the reduced PK study in which the geometric mean ratio 
of AUC (AUClast and area under the plasma concentration-time curve from time zero to infinity 
[AUC∞]) will be determined comparing Group 2 participants (Severe renal impairment and ESRD, 
not on dialysis) to matched Group 1A participants (healthy participants with normal GFR). The ratio 
of geometric mean AUCs and 90% confidence interval (CI) of the parent compound will be 
considered in determining whether to continue with a full renal impairment study (enrollment of 
subsequent cohorts in Part B). Interim PK data of the parent compound will be reviewed by some 
members of the study team from DMID and TB Alliance before decision is made to proceed to Part 
B. For further details, please refer to the PK Manual. 
In Part B, the primary intent will be to estimate PK parameters of the parent compound and 
metabolites and model the relationship between measures of renal function and the PK parameters 
to determine whether dosage adjustment is required for patients with impaired renal function. 
Estimates and CIs will be utilized rather than formal hypothesis tests. 
No formal hypothesis tests are planned for safety analyses, but safety data will be collected and 
analyzed. 
 
Sample Size Considerations 
 
A sample size of 6 per group is standard for renal impairment PK studies. Prior studies of pretomanid 
(PA-824) with similar dosing (200 to 250 mg) have estimated coefficients of variation (CV) of 16% 
to 33% for the AUC after a single dose in healthy adult participants. Assuming a 20% CV for the 
AUC of both groups, the probability of observing at least a 50% increase in the geometric mean ratio 
of AUCs given a true 100% increase is >99%. Figure 3 shows the probability of observing at least a 
50% increase in the geometric mean ratio for other potential scenarios. The probability of the lower 
bound of the 90% CI for the geometric mean ratio of AUCs being at least 1.5 in this scenario is 
approximately 70%. 

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Figure 3: Probability of Observing at Least 50% Increase by Varying CV and True Percent 
Increase 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CV=coefficients of variation 
The sample size per arm in Part B was chosen based on feasibility and appropriateness for a PK 
study in renal impaired participants to estimate group differences in PK parameters with adequate 
precision. Assuming an observed 2-fold difference between each renal impairment group and 
matched controls with no correlation between matched pairs and a coefficient of variation of 20%, 
a 90% CI for the fold difference between groups is (1.70, 2.35). 
 
Treatment Assignment Procedures 
 
Randomization Procedures 
 
There will be no randomization performed for this study. Participants will be assigned to study 
groups based on eGFR. 
1.0 
0.8 
0.6 
0.4 
0.2 
0.0 
50 
60 
70 
80 
90 
100 
True Percent Increase 
cv 
0.15 
0.2 
0.25 
0.3 
0.35 
Probability of Observing at Least a 50% Increase 

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10.3.2 
Masking Procedures 
 
Not applicable. This is an open-label study. 
 
Planned Interim Analyses 
 
Interim Safety and PK Review 
 
A study team and SMC safety and PK review will occur after Part A 6 participants in Group 2 (severe 
renal impairment and ESRD, not on dialysis) and Group 1A their matched controls are enrolled and 
completed follow-up through Day 12 (Visit 02). This review will decide if Part B will be conducted 
and whether enrollment for Group 3 (eGFR 60-89), and Group 4 (eGFR 30-59) will occur. The 
interim safety and PK review will present data by group, including AEs, SAEs, clinical laboratory 
tests, vital signs, and 12-lead ECG, and PK analysis of pretomanid. Cumulative data for all 
participants enrolled will be included in the safety and PK reviews. 
 
Final Analysis Plan 
 
Analysis Populations 
 
The following sections define the analysis populations for the analysis and reporting of data. 
 
10.5.1.1 
Safety Analysis Population 
 
The safety analysis population will include all participants who received study product. 
 
10.5.1.2 
PK Analysis Population 
 
The PK analysis population will consist of participants who received pretomanid and provided 
sufficient bioanalytical assessment results to calculate reliable estimates of the PK parameters. Any 
participants or data values excluded from PK analyses will be identified, along with their reason for 
exclusion, in the clinical study report. 
 
Analysis of Primary Endpoint (PK for Pretomanid) 
 
All PK parameters will be estimated through a non-compartmental analysis using a validated 
installation of Phoenix WinNonlin (Certara, Princeton, NJ) version 8.0 or later. The recorded true 
time points will be used for PK calculation. Estimated total plasma PK parameters are listed below. 
Plasma PK of Pretomanid 
The plasma PK of a single dose of pretomanid will be assessed from serial blood samples collected 
up to 1 hour pre-dose (Day 1) and at multiple time points post dosing: 1, 2, 4, 5, 6, 8, 12, 16, 24, 36, 

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48, 72, and 96 hours. The primary outcome measure will be total plasma concentration of 
pretomanid. The following PK parameters will be determined using total pretomanid concentrations: 
Cmax: Maximum plasma concentration 
Tmax : Time to peak (maximum) plasma concentration 
AUClast: Area under the plasma concentration-time curve from time zero to time of last 
measurable concentration 
AUC∞: Area under the plasma concentration-time curve from time zero to infinity 
%AUCex: Percentage of AUC∞ obtained by extrapolation 
t1/2 : Terminal-phase elimination half-life 
λz: Apparent first-order terminal elimination rate constant 
CL/F: Apparent clearance 
Vd/F: Apparent volume of distribution 
Urine PK of Pretomanid 
The urine PK of a single dose of pretomanid will be assessed from urine collected up to 1 hour pre-
dose, 0-4, 4-8, 8-12, 12-24, 24-48, 48-72, and 72-96 hours post-dose. Volume of urine will be 
measured and recorded at each of these time intervals. Urine samples will be stored at room 
temperature and then frozen at -20°C within 24 hours. Urine will be stored in ≤100 mL aliquots 
at -20°C until shipped to Fisher Bioservices for storage. 
Ae(0-t): Cumulative amount excreted into the urine from time 0 to the time t 
Ae%Dose: Fraction of dose excreted into the urine 
CLR: Renal clearance 
Details of the statistical analysis will be included in the statistical analysis plan. 
 
Analysis of Secondary Endpoint (Safety) 
 
All safety analyses will be presented using the safety analysis set. No formal hypothesis testing will 
be conducted. 
10.5.3.1 
Adverse Events 
 
AEs will be coded using Medical Dictionary for Regulatory Activities® (MedDRA). All AEs that 
occur after the receipt of study product will be summarized using the number of events as well as 
the number and percent of participants experiencing the event. Summaries will be presented by 
renally impaired and non-renally impaired groups and MedDRA level hierarchy (system organ class 
[SOC] and preferred term) as follows: 
• Overall (i.e., regardless of severity or relationship to treatment) 

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• By severity grade (mild, moderate, severe, or life-threatening) 
• By relationship to study product 
Unless otherwise specified, at each level of participant summarization in reporting incidence of AEs, 
a participant will be counted only once even if the participant reported one or more events. If more 
than one occurrence of an event is reported, the event of the worst severity or the worst-case 
relationship assessment will be summarized. 
The number of SAEs is expected to be small, as such these events will be reported in detailed listings 
showing the event description, MedDRA preferred term and SOC, event date, severity, relatedness, 
and outcome for each event. 
10.5.3.2 
Laboratory Parameters 
 
Descriptive summary statistics for laboratory data at admission, Day 12, and change from baseline 
will be presented by renal impairment and non-renally impaired control groups. For change from 
baseline summaries, participants with an undefined change from admission, because of missing data, 
will be excluded. Graphs, showing individual participant changes from admission to Day 12 will be 
presented for each laboratory parameter, by renal impairment and non-renally impaired groups. 
Participants with clinically significant outliers will be identified in listings. 
10.5.3.3 
Vital Signs 
 
Descriptive summary statistics of vital signs at Day 1 pre-dose and each post-dose time point (both 
absolute and change) will be summarized by renal impairment group and non-renally impaired 
control group. For change from pre-dose summaries, participants with an undefined change from 
pre-dose, because of missing data, will be excluded. 
10.5.3.4 
ECG Data 
 
ECG intervals (QTcF), including change from baseline, will be summarized at the Screening Visit 
00A and Visit 01N using descriptive statistics. 
10.5.3.5 
Demographics and Screening Summaries 
 
Demographic variables (age, gender, race, and ethnicity) and screening characteristics (height, 
weight) will be summarized by renally impaired and non-renally impaired groups. The comparability 
of the groups for relevant demographic and screening characteristics will be assessed by descriptive 
statistics and/or graphs. No statistical hypothesis tests will be performed. For continuous data, 
summaries will include the number of observations, mean, standard deviation, median, 25th and 75th 
quartiles, minimum and maximum values. For categorical data, frequency counts and percentages 
will be reported. Of note, weight will be measured at specified subsequent visits and therefore will 
be summarized for all available post-dose visits, in addition to screening. 

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Analysis of Secondary Endpoint (PK for M19 and M50) 
 
AUClast, and any other parameters considered to be of interest, of the pretomanid representative 
metabolites M19 and M50 in plasma will be estimated. 
Excretion in urine of metabolites M19 and M50 will be estimated. 

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11 
ELECTRONIC CASE REPORT FORMS AND ACCESS TO 
SOURCE DATA/DOCUMENTS 
Each participating site will maintain appropriate medical and research records in compliance with 
ICH E6, Section 4.9, and regulatory and institutional requirements for the protection of 
confidentiality of participants. Each site will permit authorized representatives of the DMID, its 
designees, and appropriate regulatory agencies to examine (and when required by applicable law, to 
copy) clinical trial records for the purposes of quality assurance reviews, audits, evaluation of the 
study safety and progress. These representatives will be permitted access to all source data and 
source documents. 
Source data are all information in original records (and certified copies of original records) of clinical 
findings, observations, or other activities in a clinical trial necessary for the reconstruction and 
evaluation of the trial. Source data should be attributable, legible, contemporaneous, original, 
accurate, and complete. Each participating site will maintain appropriate medical and research 
records for this trial, in compliance with ICH GCP, regulatory, and institutional requirements. Study 
data will be collected on paper DCFs and entered into the eCRF, or data will be entered into the 
eCRF from electronic source documents. Data recorded in the eCRF derived from source documents 
should be consistent with the data recorded on the source documents. 

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12 
QUALITY CONTROL AND QUALITY ASSURANCE 
 
Following a written DMID-accepted site quality management plan, each participating site is 
responsible for conducting routine quality assurance and quality control (QC) activities to internally 
monitor study progress and protocol compliance. The site PI will provide direct access to all study- 
related sites, source data/DCFs, and reports for the purpose of monitoring and auditing by the 
sponsor, and inspection by local and regulatory authorities. The site PI will ensure all study personnel 
are appropriately trained and training documentation is current and maintained on site. 
The SDCC will implement QC procedures beginning with the data entry system and generate data 
QC checks that will be run on the database. Any missing data or data anomalies will be 
communicated to the participating sites for clarification and resolution. 

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13 
DATA HANDLING AND RECORD KEEPING 
 
Data Management Responsibilities 
 
The investigator is responsible to keep a complete medical history and ensure the accuracy, 
completeness, legibility, and timeliness of the data reported. Section 11 details source data collection 
formats. Site staff will be trained on the use of the data system and error correction procedures. The 
site will include on the Delegation of Authority log personnel trained and authorized to enter original 
source data. 
The sponsor and/or its designee will provide guidance to the site PI and other study personnel on 
making corrections to any DCFs and eCRFs. 
 
Data Coordinating Center/Biostatistician Responsibilities 
 
Data collection is the responsibility of the study personnel at each participating clinical site under 
the supervision of the site PI. During this trial, the site PI must maintain complete and accurate 
documentation for the study. 
The Data Coordinating Center (DCC) for this study will be responsible for data management, quality 
review, analysis, and reporting of the study data. 
 
Data Capture Methods 
 
Clinical data (including, but not limited to, AEs/SAEs, concomitant medications, medical history, 
physical assessments, and clinical laboratory values) will be collected on DCFs by study personnel 
then entered into the corresponding eCRFs via a 21 CFR 11-compliant Internet Data Entry System 
provided by the SDCC. The data system includes password protection and internal quality checks, 
such as automatic range checks, to identify data that appear inconsistent, incomplete, or inaccurate. 
 
Types of Data 
 
Data for this trial will include safety and outcome measures (e.g., clinical and PK data). 
 
Study Records Retention 
 
Study records and reports including, but not limited to, DCFs, source documents, ICFs, laboratory 
test results, and study product disposition records will be retained for a minimum of 2 years after a 
marketing application is approved for the study product for which it is being investigated; or, if no 
application is to be filed or if the application is not approved for the study product, until 2 years after 
the investigation is discontinued and FDA has been notified. These documents will be retained for a 

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longer period, however, if required by local regulations. ICFs for future use will be maintained as 
long as the sample/specimen exists. 
No records will be destroyed without written consent of the sponsor. It is the responsibility of the 
sponsor to inform the investigator when these documents no longer need to be retained. The 
participating sites must contact DMID for authorization prior to the destruction of any study records. 

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14 
CLINICAL MONITORING 
 
Site monitoring is conducted to ensure that the human participants’ protections, study and laboratory 
procedures, study intervention administration, and data collection processes are of high quality and 
meet sponsor, ICH/GCP guidelines and applicable regulations, and that this trial is conducted in 
accordance with the protocol, protocol-specific MOP, and applicable sponsor standard operating 
procedures. DMID, the sponsoring agency, or its designee will conduct site monitoring visits as 
detailed in the clinical monitoring plan. 
Site visits will be made at standard intervals as defined by DMID and may be made more frequently 
as directed by DMID. Monitoring visits will include, but are not limited to, review of regulatory 
files, accountability records, eCRFs, ICFs, medical and laboratory reports, and protocol and GCP 
compliance. Site monitors will have access to each participating site, study personnel, and all study 
documentation according to the DMID-approved site monitoring plan. Study monitors will meet 
with site PIs to discuss any problems and actions to be taken and document visit findings and 
discussions. 

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15 
PUBLICATION POLICY 
 
This trial will be conducted in accordance with the NIH Public Access Policy, which ensures that 
the public has access to the published results of NIH funded research. It requires scientists to submit 
final peer-reviewed journal manuscripts that arise from NIH funds to the digital archive PubMed 
Central (https://www.ncbi.nlm.nih.gov/pmc/) upon acceptance for publication. 
Refer to: 
• NIH Public Access Policy, http://publicaccess.nih.gov/ 
• NIH 
Office 
of 
Extramural 
Research 
(OER) 
Grants 
and 
Funding, 
http://grants.nih.gov/grants/oer.htm 
As of January 2018, all clinical trials supported by the NIH must be registered on ClinicalTrials.gov, 
no later than 21 days after the enrollment of the first participant. Results of all clinical trials supported 
by the NIH, generally, need to be submitted no later than 12 months following the primary completion 
date. A delay of up to 2 years is available for trials that meet certain criteria and have applied for 
certification of delayed posting. 
As part of the result posting a copy of this protocol (and its amendments) and a copy of the Statistical 
Analysis Plan will be posted on ClincialTrials.gov. 
For this trial the responsible party is DMID which will register the trial and post results. 
The responsible party plans not to request certification of delayed posting. 
Refer to: 
• Public Law 110-85, Section 801, Clinical Trial Databases 
• 42CFR11 
• NIH NOT-OD-16-149 

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16 
LITERATURE REFERENCES 
 
1. 
World Health Organization, Global Tuberculosis report. 2020. 
2. 
Rodrigues, L.C., V.K. Diwan, and J.G. Wheeler, Protective effect of BCG against 
tuberculous meningitis and miliary tuberculosis: a meta-analysis. Int J Epidemiol, 1993. 
22(6): p. 1154-8. 
3. 
Colditz, G.A., et al., Efficacy of BCG vaccine in the prevention of tuberculosis. Meta-analysis 
of the published literature. JAMA, 1994. 271(9): p. 698-702. 
4. 
ATS, C., IDSA, Treatment of tuberculosis. MMWR Recommendations and Reports 2003. 
52 (RR-11): p. 1-77. 
5. 
Targeted tuberculin testing and treatment of latent tuberculosis infection. American 
Thoracic Society. MMWR Recomm Rep, 2000. 49(RR-6): p. 1-51. 
6. 
Center for Disease, C.P., Recommendations for use of an isoniazid-rifapentine regimen with 
direct observation to treat latent Mycobacterium tuberculosis infection. MMWR Morb 
Mortal Wkly Rep, 2011. 60(48): p. 1650-3. 
7. 
Organization, W.H., Global Tuberculosis Report 2014. 2014. 
8. 
Pietersen, E., et al., Long-term outcomes of patients with extensively drug-resistant 
tuberculosis in South Africa: a cohort study. Lancet, 2014. 383(9924): p. 1230-9. 
9. 
Jha, V., et al., Chronic kidney disease: global dimension and perspectives. Lancet, 2013. 
382(9888): p. 260-72. 
10. 
Kurts, C., et al., The immune system and kidney disease: basic concepts and clinical 
implications. Nat Rev Immunol, 2013. 13(10): p. 738-53. 
11. 
Romanowski, K., et al., Tuberculosis and chronic kidney disease: an emerging global 
syndemic. Kidney Int, 2016. 90(1): p. 34-40. 
12. 
Zuo, L., M. Wang, and A. Chinese Association of Blood Purification Management of 
Chinese Hospital, Current burden and probable increasing incidence of ESRD in China. Clin 
Nephrol, 2010. 74 Suppl 1: p. S20-2. 
13. 
Carrero, J.J. and P. Stenvinkel, Inflammation in end-stage renal disease--what have we 
learned in 10 years? Semin Dial, 2010. 23(5): p. 498-509. 
14. 
Nahid, P., et al., Official American Thoracic Society/Centers for Disease Control and 
Prevention/Infectious Diseases Society of America Clinical Practice Guidelines: Treatment 
of Drug-Susceptible Tuberculosis. Clin Infect Dis, 2016. 63(7): p. e147-e195. 
15. 
Alsultan, A. and C.A. Peloquin, Therapeutic drug monitoring in the treatment of 
tuberculosis: an update. Drugs, 2014. 74(8): p. 839-54. 
16. 
Launay-Vacher, V., H. Izzedine, and G. Deray, Pharmacokinetic considerations in the 
treatment of tuberculosis in patients with renal failure. Clin Pharmacokinet, 2005. 44(3): p. 
221-35. 
17. 
Baghaei, P., et al., Impact of chronic renal failure on anti-tuberculosis treatment outcomes. 
Int J Tuberc Lung Dis, 2014. 18(3): p. 352-6. 
18. 
Global Alliance for TB Drug Development, Investigator's Brochure: PA-824 (Pretomanid), 
v22. 31 January 2023. 
19. 
Pa-824. Tuberculosis (Edinb), 2008. 88(2): p. 134-6. 
20. 
Stover, C.K., et al., A small-molecule nitroimidazopyran drug candidate for the treatment of 
tuberculosis. Nature, 2000. 405(6789): p. 962-6. 
21. 
Manjunatha, U., H.I. Boshoff, and C.E. Barry, The mechanism of action of PA-824: Novel 
insights from transcriptional profiling. Commun Integr Biol, 2009. 2(3): p. 215-8. 

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22. 
Singh, R., et al., PA-824 kills nonreplicating Mycobacterium tuberculosis by intracellular 
NO release. Science, 2008. 322(5906): p. 1392-5. 
23. 
Diacon, A.H., et al., Early bactericidal activity and pharmacokinetics of PA-824 in smear- 
positive tuberculosis patients. Antimicrob Agents Chemother, 2010. 54(8): p. 3402-7. 
24. 
Tasneen, R., et al., Sterilizing activity of novel TMC207- and PA-824-containing regimens 
in a murine model of tuberculosis. Antimicrob Agents Chemother, 2011. 55(12): p. 5485-92. 
25. 
Tyagi, S., et al., Bactericidal activity of the nitroimidazopyran PA-824 in a murine model of 
tuberculosis. Antimicrob Agents Chemother, 2005. 49(6): p. 2289-93. 
26. 
Lenaerts, A.J., et al., Preclinical testing of the nitroimidazopyran PA-824 for activity against 
Mycobacterium tuberculosis in a series of in vitro and in vivo models. Antimicrob Agents 
Chemother, 2005. 49(6): p. 2294-301. 
27. 
Ahmad, Z., et al., PA-824 exhibits time-dependent activity in a murine model of tuberculosis. 
Antimicrob Agents Chemother, 2011. 55(1): p. 239-45. 
28. 
Tasneen, R., et al., Contribution of Oxazolidinones to the Efficacy of Novel Regimens 
Containing Bedaquiline and Pretomanid in a Mouse Model of Tuberculosis. Antimicrob 
Agents Chemother, 2016. 60(1): p. 270-7. 
29. 
Diacon, A.H., et al., Phase II dose-ranging trial of the early bactericidal activity of PA-824. 
Antimicrob Agents Chemother, 2012. 56(6): p. 3027-31. 
30. 
Diacon, A.H., et al., 14-day bactericidal activity of PA-824, bedaquiline, pyrazinamide, and 
moxifloxacin combinations: a randomised trial. Lancet, 2012. 380(9846): p. 986-93. 
31. 
Dawson, R., et al., Efficiency and safety of the combination of moxifloxacin, pretomanid (PA- 
824), and pyrazinamide during the first 8 weeks of antituberculosis treatment: a phase 2b, 
open-label, partly randomised trial in patients with drug-susceptible or drug-resistant 
pulmonary tuberculosis. Lancet, 2015. 385(9979): p. 1738-1747. 
32. 
Diacon, A.H., et al., Bactericidal activity of pyrazinamide and clofazimine alone and in 
combinations with pretomanid and bedaquiline. Am J Respir Crit Care Med, 2015. 191(8): 
p. 943-53. 
33. 
Conradie, F., et al., Treatment of Highly Drug-Resistant Pulmonary Tuberculosis. N Engl J 
Med, 2020. 382(10): p. 893-902. 
34. 
TB Alliance, PA-824 has a New Generic Name: Pretomanid. 2014. 
35. 
Dooley, K.E., et al., Phase I safety, pharmacokinetics, and pharmacogenetics study of the 
antituberculosis drug PA-824 with concomitant lopinavir-ritonavir, efavirenz, or rifampin. 
Antimicrob Agents Chemother, 2014. 58(9): p. 5245-52. 
36. 
Dogra, M., et al., Comparative bioactivation of the novel anti-tuberculosis agent PA-824 in 
Mycobacteria and a subcellular fraction of human liver. Br J Pharmacol, 2011. 162(1): p. 
226-36. 
37. 
Strunk, A.K., et al., Single- and multiple-dose pharmacokinetics of ethambutol and 
rifampicin in a tuberculosis patient with acute respiratory distress syndrome undergoing 
extended daily dialysis and ECMO treatment. Int J Infect Dis, 2016. 42: p. 1-3. 
38. 
Center for Drug Evaluation and Research, Guidance for Industry Pharmacokinetics in 
Patients with Impaired Renal Function – Study Design, Data Analysis, and Impact on 
Dosing, U.S. Department of Health and Human Services, Editor. 2020, Food and Drug 
Administration 
39. 
Matzke, G.R., et al., Drug dosing consideration in patients with acute and chronic kidney 
disease-a clinical update from Kidney Disease: Improving Global Outcomes (KDIGO). 
Kidney Int, 2011. 80(11): p. 1122-37. 

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40. 
Center for Drug Evaluation and Research, Assessing the Effects of Food on Drugs in INDs 
and NDAs — Clinical Pharmacology Considerations Guidance for Industry, U.S. 
Department of Health and Human Services, Editor. 2019, Food and Drug Administration,. 
41. 
Center for Drug Evaluation and Research, Clinical Drug Interaction Studies — Cytochrome 
P450 Enzyme- and Transporter-Mediated Drug Interactions Guidance for Industry, US 
Department of Health and Human Services, Editor. 2020, Food and Drug Administration,. 
42. 
FDA. Drug Development and Drug Interactions: Table of Substrates, Inhibitors and 
Inducers. 06/05/2023 [cited 2023; Available from: https://www.fda.gov/drugs/drug- 
interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors- 
and-inducers. 

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17 
APPENDICES 
 
APPENDIX A: Schedule of Study Procedures and Evaluations 
APPENDIX B: Venipuncture Volumes (mL) 

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APPENDIX A: Schedule of Study Procedures and Evaluations 
 
Study Visit 
00A 
00B 
00C 
01A 
01B 01C 01D 01E 01F 01G 01H 01I 01J 01K 01L 01M 
01N 
021 
03 
Early 
Term 
Study Day 
Screen 
-28 to -7 
Admit 
-1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
2 
2 
3 
4 
5 
12 
± 2d 
85 
+7d 
PK Time Window 
Up to 1 hour 
Pre-dose8 
1 hr ( ± 10 min) 
2 hr ( ± 10 min) 
4 hr ( ± 10 min) 
5 hr ( ± 10 min) 
6 hr ( ± 10 min) 
8 hr ( ± 10 min) 
12 hr ( ± 10 min) 
16 hr ( ± 10 min) 
24 hrs ( ± 1hr) 
36 hrs ( ± 1hr) 
48 hrs ( ± 1hr) 
72 hrs ( ± 4hrs) 
96 hr ( ± 4hrs) 
Obtain Written Informed 
Consent 
X 
Verify Eligibility 
X 
X 
X 
Reconfirm participant’s 
willingness to participate 
X 
X 
Medical History 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medications 
X 
X2 
X2 
X2 
X2 
X2 
X2 
X2 
X2 
X2 
X2 
X2 
X2 
X2 
X 
X 
X 
X 
12-Lead ECG 
X 
X 
Vital Signs (Oral Temp, 
Sitting Pulse and BP)3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Examination 
X 
Targeted PE if needed 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height and Weight 
X 
Urine Pregnancy Test4 
X 
X 
X 
X 
X 
Placement of Peripheral 
Catheter (if applicable) 
X5 
X5 
HIV, HBsAg, HCV 
X 
Safety and Basic Lab 
Testing6 
X 
X 
X 
X 

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Study Visit 
00A 
00B 
00C 
01A 
01B 01C 01D 01E 01F 01G 01H 01I 01J 01K 01L 01M 
01N 
021 
03 
Early 
Term 
Study Day 
Screen 
-28 to -7 
Admit 
-1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
2 
2 
3 
4 
5 
12 
± 2d 
85 
+7d 
PK Time Window 
Up to 1 hour 
Pre-dose8 
1 hr ( ± 10 min) 
2 hr ( ± 10 min) 
4 hr ( ± 10 min) 
5 hr ( ± 10 min) 
6 hr ( ± 10 min) 
8 hr ( ± 10 min) 
12 hr ( ± 10 
min) 
16 hr ( ± 10 
min) 
24 hrs ( ± 1hr) 
36 hrs ( ± 1hr) 
48 hrs ( ± 1hr) 
72 hrs ( ± 4hrs) 
96 hr ( ± 4hrs) 
Urine Drug Screen and 
Alcohol screening 
X 
X 
In-house Confinement 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study Product 
Administration7 
X 
Blood for PK 
X8 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine collection for PK 
and volume 
measurement9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Discharge from 
Hospital12 
X 
Remove Intravenous 
Catheter (if applicable) 
X 
Targeted Review of 
Systems for Renal 
Participants 
X 
AE/SAE Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X10 
X 
Pregnancy Assessment 
X 
Phone Call 
X 
AE=adverse event; ALT=alanine aminotransferase; AST=aspartate aminotransferase; BUN=blood urea nitrogen; ECG=electrocardiogram; eGFR=estimated 
glomerular filtration rate; HBsAg=hepatitis B surface antigen; HCV=hepatitis C virus; HIV=human immunodeficiency virus; PE=physical examination; 
PK=pharmacokinetic; SAE=serious adverse event 
1 
Study visits 01M-02 may be outpatient at the site. 
2 
Concomitant medications will be recorded during the entire hospital stay. 
3 
Participants must not eat or drink anything hot or cold within 10 minutes prior to taking oral temperature. 
4 
Must be performed on all female participants of childbearing potential prior to receipt of each study product and results must be negative and known prior to 
receipt of study product. 
5 
Can be done at Visit 00C or Visit 01A if applicable. The catheter should be removed after the 36-hour time point. 

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6 
Hemoglobin, AST, ALT, total bilirubin, BUN, serum creatinine (includes eGFR), serum potassium and magnesium will be checked. 
7 
The study product will be administered orally under direct supervision with a high-fat, high-calorie meal and 240 mL water. A mouth check will be done. 
Food, liquids, and medication will be restricted for 2 hours post doses. Study participants should eat this meal in 30 ± 10 minutes or less; however, 
pretomanid should be administered 30 ± 10 minutes after start of the meal. 
8 
Blood can be drawn up to 1 hour prior to dosing. 
9 
The urine PK will be assessed up to 1 hour pre-dose and at 0-4, 4-8, 8-12, 12-24, 24-48, 48-72, and 72-96 hours post-dosing. PK urine sample collection 
during the 48-72 hours and 72-96 hours may be performed at home (i.e., Day 4 and Day 5). 
10 
SAEs only from study drug administration to Day 85 + 7 days. 
11 
Alcohol testing can be done on blood or breath if breathalyzer is used for alcohol testing. 
12 
Participants may remain in the hospital per site decision. 

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APPENDIX B: Venipuncture Volumes (mL) 
 
Study Visit 
00A 
00B 
00C 
01A 
01B 
01C 
01D 
01E 
01F 
01G 
01H 
01I 
01J 
01K 
01L 
01M 
01N 
02 
03 
Study Day 
Screen 
-28 to -7 
Admit - 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
2 
2 
3 
4 
5 
12 ± 
2d 
85+7 
d 
PK Time Window 
Up to 1 hour Pre- 
dose 
1 hr ( ± 10 min) 
2 hr ( ± 10 min) 
4 hr ( ± 10 min) 
5 hr ( ± 10 min) 
6 hr ( ± 10 min) 
8 hr ( ± 10 min) 
12 hr ( ± 10 min) 
16 hr ( ± 10 min) 
24 hrs ( ± 1 hr) 
36 hrs ( ± 1 hr) 
48 hrs ( ± 1 hrs) 
72 hrs ( ± 4 hrs) 
96 hrs ( ± 4 hrs) 
HIV, HBsAg, HCV 
12 
Blood for Safety 
10 
10 
10 
Blood to Screen for 
Alcohol1 
6 
6 
Blood for PK 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
Total 
22 
6 
6 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
10 
0 
Cumulative Total 
(Cumulative total 
plus next total) 
22 
28 
34 
38 
42 
46 
50 
54 
58 
62 
66 
70 
74 
78 
82 
86 
90 
100 
100 
HBsAg=hepatitis B surface antigen; HCV=hepatitis C virus; HIV=human immunodeficiency virus; PK=pharmacokinetic 
 
1 
Alcohol testing can be done on blood or breath if breathalyzer is used for alcohol testing.