Clinical trial NCT02422524
Conditions: Tuberculosis
Keywords: Hepatic impairment PA-824 Pharmacokinetics Safety Tuberculosis
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Start date: 2018-03-29; Completion date: 2023-11-17
Enrollment: 14 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a Phase 1, single dose (200 mg), open-label study comparing the pharmacokinetics and safety of Pretomanid in subjects with mild, moderate, and severe hepatic impairment to matched, non-hepatically impaired subjects. There will be approximately 36 total subjects, adult males and females, 18 to 70 years of age, inclusive. The study will be conducted at 2 sites, study duration is approximately 24 months, and subject participation duration is approximately 5 weeks (including screening). Primary objective: To evaluate the pharmacokinetics of a single oral dose of Pretomanid in subjects with mild, moderate, and severe hepatic impairment (as assessed by Child-Pugh score), relative to matched non-hepatically impaired subjects. Secondary objective: To evaluate the safety of a single oral dose of Pretomanid in subjects with mild, moderate, and severe hepatic impairment (as assessed by Child-Pugh score), relative to matched non-hepatically impaired subjects.

Detailed description:
This is a Phase 1, single dose (200 mg), open-label study comparing the pharmacokinetics and safety of Pretomanid in subjects with mild, moderate, and severe hepatic impairment to matched, non-hepatically impaired subjects. This study will enroll approximately 6 subjects with mild hepatic impairment (Child-Pugh A), approximately 6 subjects with moderate hepatic impairment (Child-Pugh B), approximately 6 subjects with severe hepatic impairment (Child-Pugh C), and approximately 18 matched non-hepatically impaired subjects. Non-hepatically impaired subjects in the control group will be matched to subjects with hepatic impairment based on age (+/- 10 years) and body weight (+/- 20 percent) as measured at screening (Visit 00A). There will be approximately 36 total subjects, adult males and females, 18 to 70 years of age, inclusive. The study will be conducted at 2 sites, study duration is approximately 24 months, and subject participation duration is approximately 5 weeks (including screening). Primary objective: To evaluate the pharmacokinetics of a single oral dose of Pretomanid in subjects with mild, moderate, and severe hepatic impairment (as assessed by Child-Pugh score), relative to matched non-hepatically impaired subjects. Secondary objective: To evaluate the safety of a single oral dose of Pretomanid in subjects with mild, moderate, and severe hepatic impairment (as assessed by Child-Pugh score), relative to matched non-hepatically impaired subjects.

Arms: arm 1: 6 Subjects will receive a single oral dose of 200mg Pretomanid tablets on day 1 arm 2: 6 Subjects will receive a single oral dose of 200mg Pretomanid tablets on day 1 arm 3: 6 Subjects will receive a single oral dose of 200mg Pretomanid tablets on day 1 arm 4: 18 matched Subjects will receive a single oral dose of 200mg Pretomanid tablets on day 1
Interventions: intervention 1: PA-824
Intervention descriptions: intervention 1: Pretomanid (PA-824) is a nitroimidazooxazine. All subjects will receive a single oral dose of 200 mg Pretomanid on day 1.

Protocol documents:
Prot_000.pdf: 
DMID Protocol 13-0053  
Version 7.0 
Pretomanid in Adults with Hepatic Impairment 
19 October 2022 
________________________________________________________________________________________________________ 
 
DMID/NIAID/NIH 
1 
CONFIDENTIAL 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 15, 2018 
A Phase I, Single Dose, Open-label Study Comparing the 
Pharmacokinetics and Safety of Pretomanid in Subjects with Mild, 
Moderate, and Severe Hepatic Impairment to Matched, Non-
Hepatically Impaired Subjects 
DMID Protocol Number: 13-0053 
 
 
 
DMID Funding Mechanism: Vaccine and Treatment Evaluation Units 
 
Pharmaceutical Support: Global Alliance for TB Drug Development 
Other Identifying Numbers:  
IND Sponsor: Division of Microbiology and Infectious Diseases, National Institute of Allergy 
and Infectious Diseases, National Institutes of Health 
Principal Investigators: Julius Wilder, MD, PhD and Emmanuel Walter, MD, MPH; 
  Getahun Abate, MD, PhD, MSc 
DMID Clinical Project Manager: Erica Sondergaard, RN, BSN 
 
Version Number: 7.0 
 
19 October 2022  
 
 
 
 


DMID Protocol 13-0053  
Version 7.0 
Pretomanid in Adults with Hepatic Impairment 
19 October 2022 
________________________________________________________________________________________________________ 
 
DMID/NIAID/NIH 
2 
CONFIDENTIAL 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 15, 2018 
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 subjects 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 subject 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. 
 


DMID Protocol 13-0053  
Version 7.0 
Pretomanid in Adults with Hepatic Impairment 
19 October 2022 
________________________________________________________________________________________________________ 
 
DMID/NIAID/NIH 
3 
CONFIDENTIAL 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 15, 2018 
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 11, and 21 CFR Part 312 
(Investigational New Drug Application), 21 CFR 812 (Investigational Device Exemptions) 
• 
International Conference on Harmonisation: Good Clinical Practice (ICH E6); 62 Federal 
Register 25691 (1997); and future revisions 
• 
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 


DMID Protocol 13-0053  
Version 7.0 
Pretomanid in Adults with Hepatic Impairment 
19 October 2022 
________________________________________________________________________________________________________ 
 
DMID/NIAID/NIH 
4 
CONFIDENTIAL 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 15, 2018 
SIGNATURE PAGE 
The signature below provides the necessary assurance 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 US federal regulations and 
ICH E6 Good Clinical Practice (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 subjects. 
Site Investigator Signature: 
 
Signed: 
 
Date: 
 
 
Name 
Title 
 
 
 
 
Site Investigator Signature: 
 
Signed: 
 
Date: 
 
 
Name 
Title 
 
 
 
 


DMID Protocol 13-0053  
Version 7.0 
Pretomanid in Adults with Hepatic Impairment 
19 October 2022 
________________________________________________________________________________________________________ 
 
DMID/NIAID/NIH 
5 
CONFIDENTIAL 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 15, 2018 
TABLE OF CONTENTS 
STATEMENT OF ASSURANCE ...................................................................................................2 
STATEMENT OF COMPLIANCE .................................................................................................3 
SIGNATURE PAGE .......................................................................................................................4 
TABLE OF CONTENTS .................................................................................................................5 
LIST OF TABLES .........................................................................................................................11 
LIST OF FIGURES .......................................................................................................................12 
LIST OF ABBREVIATIONS ........................................................................................................13 
PROTOCOL SUMMARY .............................................................................................................17 
Table 1: Study Groups ..........................................................................................................20 
 
KEY ROLES.........................................................................................................................21 
 
BACKGROUND AND SCIENTIFIC RATIONALE ..........................................................22 
 
Background .................................................................................................................22 
2.1.1 Tuberculosis ...................................................................................................22 
2.1.1.1 
Mechanism of action .........................................................................23 
2.1.1.2 
In Vitro Microbiological Activity .....................................................23 
2.1.1.3 
Pharmacology and toxicology ..........................................................23 
2.1.1.4 
Clinical Pharmacology and Biopharmaceutics .................................24 
2.1.1.4.1 
In vitro ........................................................................................................................24 
2.1.1.4.2 
In vivo .........................................................................................................................24 
2.1.1.5 
Efficacy studies .................................................................................25 
Table 2: Summary of 4 Pretomanid Phase 2 studies ............................................................27 
Table 3: Mean log CFU for Pretomanid in the 5th Phase 2 multidrug trial (NC-003) .........29 
2.1.2 Summary of safety .........................................................................................29 
 
Scientific Rationale .....................................................................................................30 
2.2.1 Purpose of Study ............................................................................................30 
2.2.2 Study Population ............................................................................................30 


DMID Protocol 13-0053  
Version 7.0 
Pretomanid in Adults with Hepatic Impairment 
19 October 2022 
________________________________________________________________________________________________________ 
 
DMID/NIAID/NIH 
6 
CONFIDENTIAL 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 15, 2018 
 
Potential Risks and Benefits .......................................................................................31 
2.3.1 Potential Risks ...............................................................................................31 
2.3.2 Known Potential Benefits ..............................................................................37 
 
STUDY DESIGN, OBJECTIVES AND ENDPOINTS OR OUTCOME MEASURES .....38 
 
Study Design Description ...........................................................................................38 
Table 4: Study Groups ..........................................................................................................39 
 
Study Objectives .........................................................................................................40 
3.2.1 Primary ...........................................................................................................40 
3.2.2 Secondary .......................................................................................................40 
 
Study Endpoints or Outcome Measures .....................................................................40 
3.3.1 Primary ...........................................................................................................40 
3.3.2 Secondary .......................................................................................................41 
 
STUDY INTERVENTION/INVESTIGATIONAL PRODUCT..........................................42 
 
Study Product Description ..........................................................................................42 
4.1.1 Acquisition .....................................................................................................42 
 
Formulation, Packaging, and Labeling .......................................................................42 
Table 5: Pretomanid Formulation .........................................................................................42 
4.2.1 Product Storage and Stability .........................................................................43 
 
Acquisition/Distribution .............................................................................................43 
 
Dosage/Regimen, Preparation, Dispensing and Administration of Study 
Intervention/Investigational Product .........................................................................43 
 
Pre-determined Modification of Study Intervention/Investigational Product for an 
Individual Subject .....................................................................................................44 
 
Accountability Procedures for the Study Intervention/Investigational Product(s) .....44 
 
Assessment of Subject Compliance with Study Intervention/Investigational Product
 ..................................................................................................................................45 
 
Concomitant Medications/Treatments ........................................................................45 
Table 6: Prohibited CYP450 Enzyme Altering Medications/Substances per Subject 
Exclusion Criteria .....................................................................................................46 


DMID Protocol 13-0053  
Version 7.0 
Pretomanid in Adults with Hepatic Impairment 
19 October 2022 
________________________________________________________________________________________________________ 
 
DMID/NIAID/NIH 
7 
CONFIDENTIAL 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 15, 2018 
 
STUDY ENROLLMENT AND WITHDRAWAL ..............................................................47 
 
Eligibility Criteria .......................................................................................................47 
5.1.1 Subject Inclusion Criteria ..............................................................................47 
5.1.2 Subject Exclusion Criteria .............................................................................49 
 
Withdrawal from the Study, Discontinuation of Study Product, or Study Termination
 ..................................................................................................................................53 
5.2.1 Reasons for Withdrawal .................................................................................53 
5.2.2 Handling of Withdrawals ...............................................................................54 
5.2.3 Study Termination .........................................................................................55 
 
STUDY SCHEDULE ...........................................................................................................56 
 
Screening (Visit 00A) (Day -22 to Day -2) ................................................................56 
 
Admission (Visit 00B) (Day -1) .................................................................................57 
 
Planned Study Visits ...................................................................................................58 
6.3.1 Dosing (Visit 01) (Day 1) and Confinement/Hospitalization (Visit 01A to 
Visit 01J) (Day 1 and Day 2) .........................................................................58 
6.3.2 Follow-up (Visits 02, 03, and 04) (Day 3, Day 4, and Day 5) .......................59 
6.3.3 Final Study Visit (Visit 05) (Day 12) ............................................................60 
6.3.4 Early Termination Visit .................................................................................61 
 
Unscheduled Study Visits ...........................................................................................61 
 
Protocol Deviations ....................................................................................................62 
 
DESCRIPTION OF CLINICAL AND LABORATORY EVALUATIONS .......................63 
 
Clinical Evaluations ....................................................................................................63 
7.1.1 Assessment of Subject Compliance with Study Intervention/Investigational 
Product ...........................................................................................................64 
 
Laboratory Evaluations ...............................................................................................64 
7.2.1 Clinical Laboratory Evaluations ....................................................................64 
7.2.2 Special Assays or Procedures ........................................................................65 
7.2.2.1 
ECG ..................................................................................................65 
7.2.2.2 
PK Samples .......................................................................................66 


DMID Protocol 13-0053  
Version 7.0 
Pretomanid in Adults with Hepatic Impairment 
19 October 2022 
________________________________________________________________________________________________________ 
 
DMID/NIAID/NIH 
8 
CONFIDENTIAL 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 15, 2018 
7.2.2.3 
Specimen Preparation, Handling, and Shipping ...............................66 
7.2.2.1 
Instructions for Specimen Preparation, Handling, and Storage ........66 
7.2.2.2 
Laboratory Specimen Shipping ........................................................66 
 
ASSESSMENT OF SAFETY ...............................................................................................67 
 
Assessing and Recording Safety Parameters ..............................................................67 
8.1.1 Adverse Events (AEs) ....................................................................................67 
8.1.1.1 
Adverse Events Grading ...................................................................67 
8.1.2 Serious Adverse Events .................................................................................68 
 
Specification of Safety Parameters .............................................................................69 
 
Reporting Procedures ..................................................................................................69 
8.3.1 Reporting Serious Adverse Events ................................................................69 
8.3.2 Regulatory Reporting for Studies Conducted Under DMID-Sponsored IND
 ........................................................................................................................70 
8.3.3 Reporting of Pregnancy .................................................................................71 
 
Type and Duration of Follow-up of Subjects after Adverse Events ...........................71 
 
Procedures to be Followed in the Event of Abnormal Laboratory Test Values or 
Abnormal Clinical Findings......................................................................................72 
 
Halting Rules ..............................................................................................................72 
 
Safety Oversight (ISM plus SMC) .............................................................................72 
8.7.1 Independent Safety Monitor (ISM) ................................................................72 
8.7.2 Safety Monitoring Committee (SMC) ...........................................................73 
 
HUMAN SUBJECTS PROTECTION .................................................................................74 
 
Ethical Standard ..........................................................................................................74 
 
Institutional Review Board .........................................................................................74 
 
Informed Consent Process ..........................................................................................75 
9.3.1 Exclusion of Special Populations ...................................................................76 
 
Future Use of Stored Specimens .................................................................................76 
 
Subject Confidentiality ...............................................................................................76 


DMID Protocol 13-0053  
Version 7.0 
Pretomanid in Adults with Hepatic Impairment 
19 October 2022 
________________________________________________________________________________________________________ 
 
DMID/NIAID/NIH 
9 
CONFIDENTIAL 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 15, 2018 
 
Study Discontinuation ................................................................................................77 
 
STATISTICAL CONSIDERATIONS .................................................................................78 
 Responsibility for Analysis .........................................................................................78 
 Study Hypotheses .......................................................................................................78 
10.2.1 Primary Hypothesis ........................................................................................78 
10.2.2 Secondary Hypotheses ...................................................................................78 
 Sample Size Considerations .......................................................................................78 
 Treatment Assignment Procedures .............................................................................78 
10.4.1 Randomization Procedures ............................................................................78 
10.4.2 Masking Procedures .......................................................................................79 
 Planned Interim Analyses ...........................................................................................79 
10.5.1 SMC Safety Review .......................................................................................79 
 Analysis Plan ..............................................................................................................80 
10.6.1 Analysis Sets ..................................................................................................80 
10.6.2 Safety Analysis Set ........................................................................................80 
10.6.3 PK Analysis Set .............................................................................................80 
10.6.4 Primary PK Analysis ......................................................................................80 
10.6.5 Secondary Safety Analyses ............................................................................81 
10.6.5.1 Adverse Events .................................................................................81 
10.6.5.2 Laboratory Parameters ......................................................................82 
10.6.5.3 Vital Signs.........................................................................................82 
10.6.5.4 ECG Data ..........................................................................................82 
10.6.6 Demographics and Screening Summaries .....................................................83 
 
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS ..............84 
 
QUALITY CONTROL AND QUALITY ASSURANCE ...................................................85 
 
DATA HANDLING AND RECORD KEEPING ................................................................86 
 Data Management Responsibilities ............................................................................86 
 Data Coordinating Center/Biostatistician Responsibilities ........................................86 


DMID Protocol 13-0053  
Version 7.0 
Pretomanid in Adults with Hepatic Impairment 
19 October 2022 
________________________________________________________________________________________________________ 
 
DMID/NIAID/NIH 
10 
CONFIDENTIAL 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 15, 2018 
 Data Capture Methods ................................................................................................87 
 Types of Data ..............................................................................................................87 
 Timing/Reports ...........................................................................................................87 
 Study Records Retention ............................................................................................87 
 
CLINICAL MONITORING .................................................................................................88 
 Site Monitoring Plan ...................................................................................................88 
 
PUBLICATION POLICY ....................................................................................................89 
 
LITERATURE REFERENCES ............................................................................................91 
 
APPENDICES ......................................................................................................................95 
 
Schedule of Events............................................................................96 
 
Child-Pugh System ...........................................................................99 
 
Toxicity Tables ...............................................................................100 
 
 


DMID Protocol 13-0053  
Version 7.0 
Pretomanid in Adults with Hepatic Impairment 
19 October 2022 
________________________________________________________________________________________________________ 
 
DMID/NIAID/NIH 
11 
CONFIDENTIAL 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 15, 2018 
LIST OF TABLES 
Table 1: Study Groups ...................................................................................................................20 
Table 2: Summary of 4 Pretomanid Phase 2 studies ......................................................................27 
Table 3: Mean log CFU for Pretomanid in the 5th Phase 2 multidrug trial (NC-003) ..................29 
Table 4: Study Groups ...................................................................................................................39 
Table 5: Pretomanid Formulation ..................................................................................................42 
Table 6: Prohibited CYP450 Enzyme Altering Medications/Substances per Subject 
Exclusion Criteria .......................................................................................................46 
 
 


DMID Protocol 13-0053  
Version 7.0 
Pretomanid in Adults with Hepatic Impairment 
19 October 2022 
________________________________________________________________________________________________________ 
 
DMID/NIAID/NIH 
12 
CONFIDENTIAL 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 15, 2018 
LIST OF FIGURES 
Figure 1: Schematic of Study Design ............................................................................................20 
Figure 2: Structure of Pretomanid (C14H12F3N3O5) ..................................................................23 
 
 


DMID Protocol 13-0053  
Version 7.0 
Pretomanid in Adults with Hepatic Impairment 
19 October 2022 
________________________________________________________________________________________________________ 
 
DMID/NIAID/NIH 
13 
CONFIDENTIAL 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 15, 2018 
LIST OF ABBREVIATIONS 
AE 
Adverse Event/Adverse Experience 
ALT 
Alanine Aminotransferase 
ANOVA 
Analysis of Variance 
AST 
Aspartate Aminotransferase 
AUC 
Area Under the Curve 
AUC0-t 
AUC from time zero to the last observable concentration 
AUC0-∞ 
AUC extrapolated to infinity 
BDQ 
Bedaquiline 
BPM 
Beats Per Minute 
BUN 
Blood Urea Nitrogen 
CBC 
Complete Blood Count 
CFR 
Code of Federal Regulations 
CFU 
Colony-Forming Unit 
CFZ 
Clofazimine 
CL/F 
Apparent Clearance 
Cmax 
Maximum plasma concentration 
CMS 
Clinical Materials Services 
CNS 
Central Nervous System 
CROMS 
Clinical Research Operations and Management Support 
CSR 
Clinical Study Report 
CT 
Computed Tomography 
CV 
Coefficients of Variation 


DMID Protocol 13-0053  
Version 7.0 
Pretomanid in Adults with Hepatic Impairment 
19 October 2022 
________________________________________________________________________________________________________ 
 
DMID/NIAID/NIH 
14 
CONFIDENTIAL 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 15, 2018 
DHHS 
Department of Health and Human Services 
DMID 
Division of Microbiology and Infectious Diseases, NIAID, NIH, 
DHHS 
EBA 
Early Bactericidal Activity 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EEG 
Electroencephalogram 
EFV 
Efavirenz 
FDA 
Food and Drug Administration 
FWA 
Federal Wide Assurance 
GCP 
Good Clinical Practice 
HDPE 
High-density polyethylene 
HBsAg 
Hepatitis B surface antigen 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human Immunodeficiency Virus 
HR 
Heart Rate 
ICH 
International Conference on Harmonisation 
ICMJE 
International Committee of Medical Journal Editors 
IDE 
Investigational Device Exemption 
IDS 
Investigational Drug Service 
IEC 
Independent or Institutional Ethics Committee 
IND 
Investigational New Drug Application 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 


DMID Protocol 13-0053  
Version 7.0 
Pretomanid in Adults with Hepatic Impairment 
19 October 2022 
________________________________________________________________________________________________________ 
 
DMID/NIAID/NIH 
15 
CONFIDENTIAL 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 15, 2018 
ISM 
Independent Safety Monitor 
LPV/r 
Ritonavir-Boosted Lopinavir 
MDR-TB 
Multi-drug resistant Tuberculosis 
MedDRA 
Medical Dictionary for Regulatory Activities 
MIC 
Minimum Inhibitory Concentration 
MOP 
Manual of Procedures 
MOX 
Moxifloxacin 
MRI 
Magnetic Resonance Imaging 
MTB 
Mycobacterium tuberculosis 
N 
Number (typically refers to subjects) 
NIAID 
National Institute of Allergy and Infectious Diseases, NIH, DHHS 
NIH 
National Institutes of Health 
OCRA 
Office of Clinical Research Affairs, DMID, NIAID, NIH, DHHS 
OHRP 
Office for Human Research Protections 
OTC 
Over the Counter 
PCP 
Phencyclidine 
PI 
Principal Investigator 
PK 
Pharmacokinetics 
PR 
P-R Interval on an ECG 
PT 
Prothrombin Time 
PZA 
Pyrazinamide 
QA 
Quality Assurance 
QC 
Quality Control 


DMID Protocol 13-0053  
Version 7.0 
Pretomanid in Adults with Hepatic Impairment 
19 October 2022 
________________________________________________________________________________________________________ 
 
DMID/NIAID/NIH 
16 
CONFIDENTIAL 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 15, 2018 
QRS 
Q-R-S Complex on an ECG 
QT/QTc 
QT Interval of an ECG/Corrected QT Interval of an ECG 
QTcB 
Heart Rate-Corrected QT Interval (Bazett’s Formula) 
QTcF 
Heart Rate-Corrected QT Interval (Fridericia’s Formula) 
RH 
Relative Humidity 
RIF 
Rifampin 
RR 
R-R Interval on an ECG 
SAE 
Serious Adverse Event/Serious Adverse Experience 
SD 
Standard Deviation 
SDCC 
Statistical and Data Coordinating Center 
SMC 
Safety Monitoring Committee 
t1/2 
Terminal elimination half life 
TB 
Tuberculosis 
TEAE 
Treatment Emergent Adverse Event 
Tmax 
Time to maximum plasma concentration  
ULN 
Upper Limit of Normal 
US 
United States 
Vd/F 
Apparent Volume of distribution 
VTEU 
Vaccine and Treatment Evaluation Unit 
WHO 
World Health Organization 
XDR-TB 
Extensively drug resistant Tuberculosis 
 
 
 


DMID Protocol 13-0053  
Version 7.0 
Pretomanid in Adults with Hepatic Impairment 
19 October 2022 
________________________________________________________________________________________________________ 
 
DMID/NIAID/NIH 
17 
CONFIDENTIAL 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 15, 2018 
PROTOCOL SUMMARY 
Title: 
A Phase 1, Single Dose, Open-label Study Comparing the 
Pharmacokinetics and Safety of Pretomanid in Subjects with 
Mild, Moderate, and Severe Hepatic Impairment to Matched, 
Non-hepatically Impaired Subjects 
Design of the Study: 
 
 
This is a Phase 1, single dose, open-label study comparing the 
pharmacokinetics and safety of Pretomanid in subjects with 
mild, moderate, and severe hepatic impairment to matched non-
hepatically impaired subjects. 
Mild hepatic impairment: Child-Pugh A = 5 to 6 points 
Moderate hepatic impairment: Child-Pugh B = 7 to 9 points 
Severe hepatic impairment: Child-Pugh C = 10 to 15 points 
This study will enroll approximately 6 subjects with mild hepatic 
impairment (Child-Pugh A), approximately 6 subjects with 
moderate hepatic impairment (Child-Pugh B), approximately 6 
subjects with severe hepatic impairment (Child-Pugh C), and 
approximately 18 matched non-hepatically impaired subjects. 
Non-hepatically impaired subjects in the control group will be 
matched to subjects with hepatic impairment based on age (± 10 
years) and body weight (± 20%) as measured at screening (Visit 
00A). A control subject may be matched to more than one case 
subject with hepatic impairment if warranted and if the subjects 
to which they are matched are not in the same disease severity 
group. Control subjects may be matched to hepatically impaired 
subjects at any site. In this case the control subject would 
participate in the study one time but be matched to more than 
one subject with hepatic impairment. If subjects in either the 
hepatic impaired or control subject groups withdraw from the 


DMID Protocol 13-0053  
Version 7.0 
Pretomanid in Adults with Hepatic Impairment 
19 October 2022 
________________________________________________________________________________________________________ 
 
DMID/NIAID/NIH 
18 
CONFIDENTIAL 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 15, 2018 
study prior to completion of Day 5 (Visit 04) when the last PK 
samples are obtained, the subject may be replaced. 
The screening visit (00A) will occur up to 21 days prior to 
subject admission to the confinement/hospital unit. Subjects who 
meet study inclusion/exclusion criteria will then have one 
inpatient visit and four outpatient visits for a total of five study 
visits (not including the screening visit). Subjects will be 
admitted to the confinement/hospital unit the day before they 
begin the confinement/hospitalization period (Visit 00B). The 
subject will receive a single oral dose of 200 mg Pretomanid on 
the morning of Visit 01 (Day 1). Serial PK measurements will be 
obtained on Days 1-5 and will follow the schedule in Appendix 
A. Subjects will remain in the confinement/hospital unit for 
Visits 00B (pre-dose Admission Day) through Visit 01J (post-
dose Days 1 and 2) sites may wish to keep subjects confined 
through Visit 2 (post-dose Day 3). Subjects may be discharged 
after assessments on Day 2 are complete (the 36-hour PK 
sampling time point) and then return for a follow-up visit on Day 
3 or they may be discharged after the Day 3 (Visit 2) follow-up 
visit is completed depending on site preference. Subjects will 
return for follow-up visits on Days 4, and 5 with a final visit on 
Day 12 (Visits 03, 04, and 05, respectively). 
Study Phase: 
1 
Study Population: 
Approximately 18 adult males and females, 18 to 70 years of 
age, inclusive, with mild, moderate, or severe hepatic 
impairment who meet all eligibility criteria 
Approximately 18 matched non-hepatically impaired adult males 
and females, 18 to 70 years of age, inclusive, who meet all 
eligibility criteria 
Number of Sites: 
Two Sites  


DMID Protocol 13-0053  
Version 7.0 
Pretomanid in Adults with Hepatic Impairment 
19 October 2022 
________________________________________________________________________________________________________ 
 
DMID/NIAID/NIH 
19 
CONFIDENTIAL 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 15, 2018 
Description of Study 
Product or Intervention: 
Single oral dose of 200 mg Pretomanid tablets manufactured by 
a contractor for the Global Alliance for TB Drug Development. 
Study Objectives: 
 
  
Primary: 
• 
To evaluate the pharmacokinetics of a single oral dose of 
Pretomanid in subjects with mild, moderate, and severe 
hepatic impairment (as assessed by Child-Pugh score), 
relative to matched non-hepatically impaired subjects. 
Secondary: 
• 
To evaluate the safety of a single oral dose of Pretomanid in 
subjects with mild, moderate, and severe hepatic impairment 
(as assessed by Child-Pugh score), relative to matched non-
hepatically impaired subjects. 
 
Subject Participation 
Duration: 
Approximately 5 weeks (including screening) 
Study Duration: 
Approximately 24 months 
 
 


DMID Protocol 13-0053  
Version 7.0 
Pretomanid in Adults with Hepatic Impairment 
19 October 2022 
________________________________________________________________________________________________________ 
 
DMID/NIAID/NIH 
20 
CONFIDENTIAL 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 15, 2018 
Table 1: Study Groups 
Study Group 
Severity* 
N 
Group 1 
Child-Pugh A = 5 to 6 points (Mild) 
6 
Group 2 
Child-Pugh B = 7 to 9 points (Moderate) 
6 
Group 3 
Child-Pugh C = 10 to 15 points (Severe) 
6 
Group 4 
Non-hepatically impaired controls 
18 
* The subjects are categorized, into one of the 4 groups at screening. 
Figure 1: Schematic of Study Design  
 
 
1Group 4a is referring to the non-hepatically impaired controls matched with Group 1 
2Group 4b is referring to the non-hepatically impaired controls matched with Group 2 
3Group 4c is referring to the non-hepatically impaired controls matched with Group 3 


DMID Protocol 13-0053  
Version 7.0 
Pretomanid in Adults with Hepatic Impairment 
19 October 2022 
________________________________________________________________________________________________________ 
 
DMID/NIAID/NIH 
21 
CONFIDENTIAL 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 15, 2018 
 
KEY ROLES 
Lead Principal 
Investigator: 
 
Principal Investigator:  
 
 
Principle Investigator:  
 
 
DMID Clinical Project 
Manager: 
 
Julius Wilder, MD, PhD 
Duke University  
Department of Medicine 
  
Emmanuel Walter, MD, MPH 
Duke University  
Duke Clinical Vaccine Unit 
 
Getahun Abate, MD, PhD, MSc 
Saint Louis University School of Medicine 
 
 
Erica Sondergaard, RN, BSN  
Respiratory Diseases Branch 
DMID/NIAID/NIH/DHHS  
 
 
Statistical and Data 
Coordinating Center: 
 
Institutions:  
 
The Emmes Company, LLC 
 
 
 
Duke University  
Saint Louis University  
 


DMID Protocol 13-0053  
Version 7.0 
Pretomanid in Adults with Hepatic Impairment 
19 October 2022 
________________________________________________________________________________________________________ 
 
DMID/NIAID/NIH 
22 
CONFIDENTIAL 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 15, 2018 
 
BACKGROUND AND SCIENTIFIC RATIONALE 
 
Background  
2.1.1 
Tuberculosis 
Tuberculosis (TB) causes a significant global health burden with an estimated annual worldwide 
incidence in 2015 of approximately 10.4 million new cases (1). Approximately 1.8 million 
people died from TB in 2015 (1, 2) making TB the leading infectious killer of adults worldwide. 
TB is also the leading infectious cause of death among people with HIV or acquired 
immunodeficiency syndrome (3). 
TB is an infectious disease caused by the bacterium Mycobacterium tuberculosis (MTB). This 
infection primarily affects the lungs (pulmonary TB) but can affect other organs such as the 
kidneys, bones, and brain (4). TB is transmitted by inhalation of infective droplets containing 
MTB and expelled into the air by a person with active TB (4). 
The mainstays of therapy against TB are antibiotic combination regimens. The recommended 
treatment includes a combination of rifampin, isoniazid, pyrazinamide, ethambutol or 
streptomycin (5-7).  A 4-drug regimen of directly observed therapy is administered for 2 months 
(intensive phase), and is then followed by rifampin and isoniazid for an additional 4-7 months 
(6). The goal of the prolonged regimen is to ensure sterilization of tuberculosis lesions and to 
prevent development of drug resistance (7). If administered correctly, cure rates as high as 95% 
can be achieved (8).  
Unfortunately, the prolonged and complicated treatment course of TB affects patient compliance 
(9), which has led to development of multi-drug resistant TB (MDR-TB) (6, 9) and extensively 
drug resistant strains (XDR-TB)(10). The WHO estimates that ~4% of new TB cases, and 20% 
of previously treated cases of TB have MDR-TB(3). Of those new MDR-TB cases 9% are XDR-
TB (3). Therefore, there is a need to develop novel drugs, such as Pretomanid (previously known 
as PA-824) to be used in combination, for the treatment of TB. 


DMID Protocol 13-0053  
Version 7.0 
Pretomanid in Adults with Hepatic Impairment 
19 October 2022 
________________________________________________________________________________________________________ 
 
DMID/NIAID/NIH 
23 
CONFIDENTIAL 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 15, 2018 
Figure 2: Structure of Pretomanid (C14H12F3N3O5) 
 
2.1.1.1 
Mechanism of action 
Pretomanid is a nitroimidazooxazine and its mechanism of action involves inhibition of the 
synthesis of mycobacterial cell wall proteins and lipids. A second potential source of bactericidal 
activity may involve generation of reactive nitrogen species including nitric oxide (11). 
2.1.1.2 
In Vitro Microbiological Activity 
The minimum inhibitory concentration (MIC) of Pretomanid against drug-sensitive MTB isolates 
was similar to the MIC of isoniazid (Pretomanid MIC ≤0.015 to 0.25 µg/mL). Pretomanid also 
has activity against drug-resistant clinical isolates of MTB (MIC of 0.03 to 0.25 µg/mL) (7). 
2.1.1.3 
Pharmacology and toxicology 
Numerous non-clinical single-dose studies on the PK and toxicity profile of Pretomanid have 
been performed. 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 (see Investigator Brochure, Section 4.4.1.1). The apparent elimination t½ of 
Pretomanid following a single oral dose was approximately 3 to 7 hours in rats, monkeys, and 
rabbits.  In rats, the time to peak plasma concentration (Tmax) ranged from 3 to 8 hours. 
Subsequent slow elimination of Pretomanid metabolites occurs with an average of 88.1% and 
67.5% of the metabolites recovered in the urine and feces for rats and monkeys, respectively. 


DMID Protocol 13-0053  
Version 7.0 
Pretomanid in Adults with Hepatic Impairment 
19 October 2022 
________________________________________________________________________________________________________ 
 
DMID/NIAID/NIH 
24 
CONFIDENTIAL 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 15, 2018 
Non-clinical studies relevant to the absorption and PK profile of Pretomanid following repeated 
dose administration were also performed. With repeated dosing, the exposure to Pretomanid 
increased as the dose level increased in the rat, rabbit, and monkey. But the increase in exposure 
was less than dose proportional at higher doses (see Investigator Brochure Section 4.4.1.2). 
Elimination kinetics were comparable to values observed after single doses, suggesting sustained 
Pretomanid exposure in these animal species does not result in increased clearance due to auto-
induction of metabolism or other means of eliminating the drug from the body. In both pregnant 
rats and rabbits, maternal and fetal exposures are similar, indicating that Pretomanid readily 
crosses the placenta (see Investigator Brochure Section 4.4.1.2). 
2.1.1.4 
Clinical Pharmacology and Biopharmaceutics 
2.1.1.4.1 In vitro 
Human plasma protein binding for Pretomanid was evaluated and was 86.4%. The effect of 
Pretomanid on p-glycoprotein was determined in a screening study in MDCK II cells transfected 
with a vector expressing the p-glycoprotein transporter (see Investigator Brochure Section 
4.4.2.1). Pretomanid did not have a significant effect on the p-glycoprotein transporter. 
The potential induction and inhibition of human CYP isoforms was evaluated. In vitro studies 
showed that Pretomanid does not induce cytochrome CYP 3A4, 2C9, or 2E1. Pretomanid is a 
weak competitive inhibitor for CYP3A4/5, CYP2C8, 2C9 and 2C19 (see Investigator Brochure 
Section 4.4.3.1). An in vitro reaction phenotyping experiment indicated that Pretomanid is not a 
substrate of CYP2C9, 2C19, or 2D6. The primary pathway for Pretomanid metabolism is 
CYP3A4. 
2.1.1.4.2 In vivo 
A phase 1, open-label, single ascending dose study in healthy volunteers (N=53) of Pretomanid 
(50, 250, 500, 750, 1000, 1250, or 1500 mg) showed that Pretomanid was absorbed with a 
median Tmax of 4 to 5 hours across all treatment groups (11). Pretomanid exposure, based on 
Cmax or AUC values, increased in a less than dose-proportional manner with increasing doses 
up to 1000 mg. Dose levels above 1000 mg achieved minimal additional Pretomanid exposure 
for both Cmax and AUC. The overall mean apparent t½ of Pretomanid ranged from 14 to 20 
hours across dose groups and elimination kinetics after single-dose administration did not exhibit 


DMID Protocol 13-0053  
Version 7.0 
Pretomanid in Adults with Hepatic Impairment 
19 October 2022 
________________________________________________________________________________________________________ 
 
DMID/NIAID/NIH 
25 
CONFIDENTIAL 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 15, 2018 
any apparent dose dependency. The mean CL/F values increased with increasing Pretomanid 
doses (11). 
The PK of Pretomanid was further evaluated in a multiple-dose ascending study in healthy 
volunteers. Pretomanid (200, 600, 1,000 or 1,400 mg) was administered once daily for 7 days to 
healthy subjects (N=24) (11). Similar to the single ascending dose study, mean Tmax was 4-5 
hours in each dose group (11). The apparent elimination half-life did not significantly change 
with multiple doses or dose increases (11). Pretomanid achieved steady state plasma 
concentrations after 5 to 6 days, and daily dosing for 5 to 7 days was associated with a mean 
accumulation ratio of 2 for both Cmax and AUC in the 200 mg and 600 mg groups (11). Similar 
to the single ascending dose study, the mean apparent t½ after 7 days of dosing was 
approximately 16 hours in the 200- and 600-mg dose groups. Dose levels above 600 mg 
achieved minimal additional Pretomanid absorption with respect to both Cmax and AUC (11). 
The potential for metabolic-based drug-drug interactions mediated via CYP3A was evaluated 
using midazolam. Healthy subjects (N=14) received a single oral dose of midazolam 2 mg, 
followed by a 2-day washout interval. All subjects then received 400 mg Pretomanid, 
administered orally after an overnight fast once daily for 14 days. The Cmax and AUC values for 
midazolam after co-administration with Pretomanid were approximately 85% of those observed 
after treatment with midazolam alone. Furthermore, the Tmax and t½ values for midazolam and 
its metabolite 1-hydroxy-midazolam were not different in the presence or absence of Pretomanid. 
Hence, dosing with Pretomanid at 400 mg/day for 14 days (to steady state) had minimal effect on 
the PK of midazolam. These results suggest a low risk for drug-drug interactions with 
Pretomanid in vivo. 
A Phase 1 PK study to evaluate drug-drug interactions between Pretomanid (200 mg daily) and 
efavirenz (EFV), ritonavir-boosted lopinavir (LPV/r), and rifampin (RIF), showed no changes in 
EFV exposures and PK parameters and moderate changes in LPV/r exposure (<20%). Co-
administration with RIF showed a >50% decrease in Pretomanid exposure (see investigator 
brochure). 
2.1.1.5 
Efficacy studies 
Pretomanid has been evaluated in 5 (single and multi-dose) Phase-2 studies. The Phase-2 studies 
characterized the bactericidal activity, safety, and PK in subjects with newly diagnosed 
pulmonary TB. Phase 3 efficacy and safety trials are planned or underway for Pretomanid given 
orally at a dose of 100 or 200 mg/day in combination with other anti-TB drugs. 


DMID Protocol 13-0053  
Version 7.0 
Pretomanid in Adults with Hepatic Impairment 
19 October 2022 
________________________________________________________________________________________________________ 
 
DMID/NIAID/NIH 
26 
CONFIDENTIAL 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 15, 2018 
The early bacterial activity (EBACFU (0-14)) of Pretomanid over 14 days in adult subjects with 
newly diagnosed, smear-positive, pulmonary TB was evaluated in three Phase 2, randomized, 
blinded, parallel-group studies. The EBACFU (0-14) is the rate of decline of the log CFU count 
over 14 days, i.e., – (log (CFUDay14) – log (CFUDay0)/14 (note the negative sign; a higher positive 
number means a greater rate of decline).  In each of the Phase 2 studies, treatment was 
administered once daily for 14 days either alone or in combination with other anti-TB drugs. 
Each study included a group of subjects who were randomly assigned to receive Rifafour e-275 
(single combination pill of rifampicin, isoniazid, pyrazinamide, and ethambutol) as a control. 
The subjects were hospitalized throughout the 2-week treatment period and sputum collections 
were done at specified time points for assessment of CFU count. 
The first study evaluated oral doses of 200, 600, 1000, and 1200 mg/day in 60 subjects (15 per 
dose category) (7). The primary endpoint was the mean rate of change in log CFU of MTB in 
sputum. The mean EBACFU (0-14) of TB for Pretomanid was equivalent at all four dosages 
(0.098 +/- SD 0.072) (Table 2). Since maximum efficacy was unexpectedly achieved at the 
lowest dosage tested, the activity of lower dosages was explored. 
The second phase 2 single dose study evaluated lower oral dosages of Pretomanid at 50, 100, 
150, and 200 mg/day in 60 subjects (12).  The primary efficacy endpoint was the mean rate of 
decline in log CFU of TB in sputum. The mean EBACFU (0-14) was 50 mg (0.063 ± 0.058), 100 
mg (0.091 ± 0.073), (150 mg 0.078 ± 0.074), and 200 mg (0.112 ± 0.070) (12) (Table 2). The 
study was not powered for testing the difference between arms, but there was a trend toward 
significance, indicating a lower early bacterial activity at the 50 mg dose (12). 
A third phase 2 clinical trial was designed to select multi-drug combination therapies involving 
Pretomanid (200 mg) and included the following combination regimens (Pretomanid + 
bedaquiline, Pretomanid + pyrazinamide, and Pretomanid + pyrazinamide + moxifloxacin) (13). 
Other regimens in the study included bedaquiline alone, bedaquiline + pyrazinamide, and 
Rifafour e-275. The primary endpoint was the mean rate of decline in log CFU of TB in sputum. 
The combination of Pretomanid + moxifloxacin + pyrazinamide (0.233, SD 0.128) had a 
significantly higher EBACFU (0-14) than bedaquiline (0.07, SD.0068), bedaquiline + 
pyrazinamide (0.131, SD 0.102), bedaquiline + Pretomanid (0.114, SD 0.050) (13), Pretomanid 
+ pyrazinamide (0.154, SD 0.040), and  the standard TB treatment regimen (0.140, SD 0.094) 
(13) (Table 2). 
A fourth Phase 2 study evaluated the efficacy of Pretomanid (100 and 200 mg) as add-on therapy 
to multi-drug regimens with moxifloxacin and pyrazinamide to treat patients with MTB and 
MDR-TB (NC-002, see investigator brochure). The primary end point was the rate of decline of 


DMID Protocol 13-0053  
Version 7.0 
Pretomanid in Adults with Hepatic Impairment 
19 October 2022 
________________________________________________________________________________________________________ 
 
DMID/NIAID/NIH 
27 
CONFIDENTIAL 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 15, 2018 
log CFU over the course of 56 days, BACFU (0-56), defined analogously to EBACFU (0-14). The 
MOX + Pretomanid 200 mg + PZA group had the highest mean BACFU (0-56) relative to control 
(Rifafour). The second highest BACFU (0-56) was found in the MOX + Pretomanid 100mg + 
PZA group (Table 2). There were 9 patients with MDR-TB who were treated with MOX + 
Pretomanid 200 mg + PZA and the mean log CFU reduction in this group compared favorably 
with the Rifafour control group. 
The fifth Phase 2 study (NC-003, see investigator brochure) evaluated the efficacy of Pretomanid 
as part of a drug regimen including bedaquiline (BDQ), pyrazinamide (PZA), and clofazimine 
(CFZ) (Table 3). The primary efficacy variable was the EBACFU (0-14). There were 7 treatment 
groups in this study (Table 3). Treatment group BDQ + PA + PZA had the highest mean EBA 
over 14 days of treatment. 
Table 2: Summary of 4 Pretomanid Phase 2 studies 
Year 
N 
Pretomanid 
Regimen 
Dosage 
Primary 
Outcome 
Mean daily fall in CFU 
2010 
60 
Once Daily 
200, 600, 1000, and 
1200 mg/day 
Mean rate of 
decline in log 
CFU of TB 
over 14 days 
0.098 (+/-0.072) was equivalent 
for all four dosages 
2012 
60 
Once Daily 
50, 100, 150, and 
200 mg/day 
Mean rate of 
decline in log 
CFU of TB 
over 14 days 
50mg 0.063 ± 0.058 
100mg 0.091 ± 0.073 
150mg 0.078 ± 0.074 
200mg 0.112 ± 0.070 
2012 
81 
Once Daily 
1. Pretomanid + 
bedaquiline 
2. Pretomanid + 
pyrazinamide 
3. Pretomanid + 
pyrazinamide + 
moxifloxacin 
(all Pretomanid doses 
were 200 mg/day) 
Mean rate of 
decline in log 
CFU of TB 
over 56 days 
Pretomanid + moxifloxacin + 
pyrazinamide (0.233) was 
significantly higher than 
bedaquiline (0.061), bedaquiline + 
pyrazinamide (0.131), and 
comparable with that of standard 
treatment 


DMID Protocol 13-0053  
Version 7.0 
Pretomanid in Adults with Hepatic Impairment 
19 October 2022 
________________________________________________________________________________________________________ 
 
DMID/NIAID/NIH 
28 
CONFIDENTIAL 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 15, 2018 
Year 
N 
Pretomanid 
Regimen 
Dosage 
Primary 
Outcome 
Mean daily fall in CFU 
2014 
207 
Once Daily 
1. Pretomanid 200 mg 
+ pyrazinamide + 
moxifloxacin 
2. Pretomanid 100 mg 
+ pyrazinamide + 
moxifloxacin 
3. Pretomanid 200 mg 
+ pyrazinamide + 
moxifloxacin (Tx 
MDR-TB) 
Mean rate of 
decline in log 
CFU of TB 
over 14 days 
1. Pretomanid 200 mg + 
pyrazinamide + 
moxifloxacin (0.155) 
2. Pretomanid 100 mg + 
pyrazinamide + 
moxifloxacin (0.133) 
3. Pretomanid 200 mg + 
pyrazinamide + 
moxifloxacin  
(Tx MDR-TB) (0.117) 
 
 
 


DMID Protocol 13-0053  
Version 7.0 
Pretomanid in Adults with Hepatic Impairment 
19 October 2022 
________________________________________________________________________________________________________ 
 
DMID/NIAID/NIH 
29 
CONFIDENTIAL 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 15, 2018 
Table 3: Mean log CFU for Pretomanid in the 5th Phase 2 multidrug trial (NC-003) 
Treatment Group 
Mean rate of decline in log CFU of TB over 
14 Days [CI] 
BDQ + PA + PZA + CFZ (N=14) 
0.111 [0.037-0.184] 
BDQ + PA + PZA (N=12) 
0.167 [0.078-0.256] 
BDQ + PA + CFZ (N=15) 
0.076 [0.007-0.147] 
BDQ + PZA + CFZ (N=14) 
0.119 [0.031-0.211] 
PZA (N=15) 
0.037 [-0.025-0.100] 
CFZ (N=15) 
-0.017 [-0.086-0.055] 
Rifafour e-275 (N=15) 
0.151 [0.070-0.231] 
 
2.1.2 
Summary of safety 
Approximately 1000 subjects across 15 clinical trials (Phase-1 and Phase-2) have been exposed 
to Pretomanid. These studies indicate the drug is well tolerated. The most common side effect 
noted in Phase-1 clinical studies was headache (11). The most common side effects in Phase-2 
studies were gastrointestinal (GI) including stomach discomfort, nausea, vomiting, flatulence, 
and diarrhea (11). 
Phase-1 and Phase-2 studies have shown Pretomanid to have a minimal impact on the liver. 
Three subjects exposed to Pretomanid in one study (NC-001, see investigator brochure) 
developed elevation of ALT in the setting of taking a Pretomanid (200 mg daily) containing 
regimen (Pretomanid + bedaquiline, Pretomanid + pyrazinamide, and Pretomanid + 
pyrazinamide + moxifloxacin groups).  These subjects were withdrawn from treatment due to 
this elevation in ALT levels. Of note, the rate of discontinuation for this adverse event in this 
study was similar to that for bedaquiline-containing regimens in other studies (13).  Furthermore, 
none of the subjects had associated symptoms and the elevated transaminases resolved upon 
discontinuation of treatment (13). Among the other completed Phase 1 and 2 studies, there were 
only two treatment emergent adverse events (TEAEs) of changes in hepatic enzymes. One TEAE 
of hepatic enzymes involved increased AST/ALT for a subject taking 200 mg/day. The other 
involved a subject in the 1200 mg/day group. Neither TEAE was assessed as severe, and neither 


DMID Protocol 13-0053  
Version 7.0 
Pretomanid in Adults with Hepatic Impairment 
19 October 2022 
________________________________________________________________________________________________________ 
 
DMID/NIAID/NIH 
30 
CONFIDENTIAL 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 15, 2018 
resulted in discontinuation of treatment (11). New information concerning reported fulminant 
hepatic failure and resulting deaths in persons taking Pretomanid are described in Section 2.3.1 
below. 
 
Scientific Rationale 
Pretomanid is metabolized extensively in the liver (CYP3A4) and has a low extraction ratio. In 
the setting of advanced liver disease both hepatic blood flow and hepatic function can be 
compromised. Therefore, the pharmacokinetics of Pretomanid are likely to be altered in subjects 
with hepatic impairment compared to matched healthy subjects. We hypothesize that the 
metabolism of Pretomanid will be impacted by the presence of advanced liver disease. The 
purpose of this protocol is to evaluate the safety and pharmacokinetics of Pretomanid in the 
setting of underlying liver disease defined as a Child-Pugh score of A, B, or C. The severity of 
liver disease is based on five clinical features: 1) total bilirubin level, 2) serum albumin, 3) 
prothrombin time (measured as the INR), 4) the degree of ascites, and 5) the grade of hepatic 
encephalopathy. The total point score is then used to determine the subject’s Child-Pugh class. 
The route of administration of Pretomanid for this study will be oral and the dose will be 200 
mg. A single oral dose of Pretomanid will be taken once. The PK profile for Pretomanid 
following oral dosing was consistent for healthy subjects and subjects with pulmonary TB. 
Pretomanid was readily absorbed after oral administration and slowly eliminated in plasma. 
Pretomanid plasma concentrations increased in a dose-related manner after single-dose 
administration of up to 1000 mg in healthy subjects and subjects with TB, but the increase was 
less than dose proportional, particularly at doses above 200 mg/day. There is a trend towards 
increased side effects with increasing dosages (7). Furthermore, efficacy studies have shown 
equivalent early bacterial activity at dosages ranging from 200 mg to 1200 mg. The doses of 
Pretomanid that will be evaluated in regimens in Phase 3 are 100 mg and 200 mg. Hence, the 
dosage of Pretomanid for this study will be 200 mg daily. 
2.2.1 
Purpose of Study 
For the primary objective, the hypothesis is that Pretomanid PK parameters following drug 
exposure will differ between patients with hepatic impairment and non-hepatically impaired 
controls.   
2.2.2 
Study Population 
The study population will be representative of subjects with varying degrees of liver disease as 
defined by Child-Pugh scores. The Child-Pugh scores used for eligibility in the study will be 


DMID Protocol 13-0053  
Version 7.0 
Pretomanid in Adults with Hepatic Impairment 
19 October 2022 
________________________________________________________________________________________________________ 
 
DMID/NIAID/NIH 
31 
CONFIDENTIAL 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 15, 2018 
calculated at screening only. The Child-Pugh score is based on five clinical measures of liver 
function: total bilirubin, serum albumin, prothrombin, ascites, and hepatic encephalopathy.  
Based on their score patients are defined as mild (5-6 points), moderate (7-9 points), or severe 
(10-15 points). Approximately 36 subjects between the ages of 18 and 70 years will be enrolled 
over an estimated 9-month period. A subject is considered enrolled in this study once they have 
signed a study consent form, met all eligibility criteria, and have been admitted to the 
confinement/hospital unit on Admission Visit (Day -1). 
Subjects with hepatic impairment for this study will be mainly identified at Duke University 
Health System Hospitals and Clinics and the Durham Veterans Administration Hospital as well 
as St Louis University. Non-hepatically impaired controls will be identified from the site-specific 
recruitment registries and the community. Subjects for this study may also be identified through 
advertisement, letters, and other forms of communication. 
 
Potential Risks and Benefits 
2.3.1 
Potential Risks 
The potential risks of this study are those associated with having blood drawn, adverse reactions 
to the Pretomanid medication, and breach of confidentiality. Drawing blood may cause transient 
discomfort and fainting. Fainting is usually brief and managed by having the subject lie down. 
Bruising at the blood draw site may occur but can be prevented or lessened by applying pressure 
to the draw site for several minutes. Drawing blood may also cause infection. The use of sterile 
technique will make infection at the site where blood will be drawn extremely unlikely. 
Among 10 completed Phase 1 clinical trials, there were no reported deaths or serious TEAEs. 
One subject was withdrawn from study due to a TEAE. The subject who required withdrawal 
was assigned to a Pretomanid 1000 mg group and developed a severe generalized rash on day 9 
of therapy. She was treated with diphenhydramine, prednisone, and hydroxyzine and the rash 
resolved within 11 days. A second subject who likely had a pre-existing condition developed a 
significant TEAE characterized by proteinuria. She never developed symptoms and her 
proteinuria resolved following her completion of the study. A renal biopsy later revealed the 
diagnosis of focal segmental glomerulosclerosis (11). 
In the single-dose, dose range-finding study in healthy subjects, the overall percentage of 
subjects reporting TEAEs was similar for Pretomanid and placebo, and there was no apparent 
increase in frequency of TEAEs across the Pretomanid dose range of 50 to 1500 mg/day. In the 
repeated-dose, dose ranging study the overall percentage of subjects with TEAEs was higher for 
Pretomanid (50%) than for placebo (33%) and appeared to increase with increasing dose (17% 


DMID Protocol 13-0053  
Version 7.0 
Pretomanid in Adults with Hepatic Impairment 
19 October 2022 
________________________________________________________________________________________________________ 
 
DMID/NIAID/NIH 
32 
CONFIDENTIAL 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 15, 2018 
for 200 mg/day, 50% for 600 mg/day, and 83% for 1000 mg/day). In the renal safety study, the 
frequency of AEs was higher for Pretomanid 1000 mg (90%) than Pretomanid 800 mg (52%) 
and placebo (38%). Higher dosages appeared to be associated with increased frequency of 
TEAEs. 
Headache was the most common TEAE reported in healthy subjects. Across the completed Phase 
1 studies, a total of 42 healthy subjects were treated with the 200-mg dose of Pretomanid (the 
highest dose proposed for future clinical development). Of these 42 subjects, 24% (10/42) 
reported headache. The most common side effects reported in Phase 2 studies (13/167 subjects, 
7.8%) were gastrointestinal, including abdominal discomfort, nausea, vomiting, flatulence and 
diarrhea. 
The possible effect of Pretomanid on the QT interval was examined in a “thorough QT/QTc 
study,” (DMID 10-0058, see investigators brochure). In that study, the upper limit of the 90% 
confidence limit showed a decrease in heart rate as well as increases in the QT interval corrected 
for heart rate (using Bazett [QTcB] or Fridericia [QTcF] formulas), PR interval, and QRS 
interval. The increases in the PR and QRS interval were small and not considered clinically 
significant. The mean decrease in ECG-recorded heart rate averaged approximately 6 bpm for 
the 200 mg Pretomanid dose given as a single agent. 
Adverse events in subjects with pulmonary TB were evaluated in Phase 2 studies and one death 
was reported. Across these Phase 2 studies, serious TEAEs were reported in 3.6% (13/360) of 
subjects exposed to Pretomanid and 9.2% (33/360) of subjects exposed to Pretomanid were 
withdrawn from treatment due to a TEAE (see Investigator Brochure Section 5.3.1.2). None of 
the nine serious TEAEs were related to study drug. Four of the subjects with serious TEAEs 
were treated with Pretomanid 200 mg, either alone or as part of a multi-drug combination 
regimen. For two subjects, the serious TEAE occurred more than 30 days after the last dose of 
Pretomanid (pneumonia and worsening pulmonary TB). The remaining serious TEAEs occurred 
while the subjects were receiving study treatment and included hemoptysis, pneumothorax, and 
neurocysticercosis. These three serious TEAEs led to discontinuation of study drug. The death 
that occurred was in Study NC-002. This study evaluated Pretomanid (at 100 mg and 200 mg 
dosages) as part of a multidrug regimen with moxifloxacin and pyrazinamide to treat patients 
with MTB and MDR-TB (NC-002, see investigator brochure). A 37-year-old female received the 
Moxifloxacin 400 mg + Pretomanid 100 mg + Pyrazinamide 1500 mg regimen for only 1 day 
and was withdrawn from the study because of elevated liver enzymes found present before 
dosing. Thirty-four days after administration of study drug she developed chest pain and 
difficulty breathing, cough, fever, weakness, vomiting, loss of appetite, and syncope and died. 
Death was not believed to be related to study drug (NC002, see investigator brochure). 


DMID Protocol 13-0053  
Version 7.0 
Pretomanid in Adults with Hepatic Impairment 
19 October 2022 
________________________________________________________________________________________________________ 
 
DMID/NIAID/NIH 
33 
CONFIDENTIAL 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 15, 2018 
Adverse events leading to discontinuation of treatment included elevation of ALT and 
electrocardiogram (ECG) changes. For three subjects, all from the same study, the TEAE leading 
to discontinuation was increased ALT. The elevated transaminases were detected at a scheduled 
laboratory evaluation and in all three subjects the increased ALT was asymptomatic and ALT 
value returned towards baseline levels upon discontinuation of study treatment. The maximum 
increase ranged from 4.0 to 5.5 x the Upper Limit of Normal (ULN). There were no reported 
significant changes in bilirubin or alkaline phosphatase. Elevation of ALT requiring withdrawal 
was also seen among two additional subjects in this study (one in bedaquiline alone group and 
one in bedaquiline + pyrazinamide group) (13). Data thus far suggests that Pretomanid is not 
associated with significant hepatic toxicity when given as a single agent for up to 14 days. 
However, when administered within a regimen with other drugs (for example MOX and PZA) 
known to be associated with hepatic toxicity, increases in aminotransferase levels have been 
observed in a few subjects requiring withdrawal from clinical trials. 
There were three deaths within an ongoing Phase 3 study evaluating the safety and efficacy of 
bedaquiline plus linezolid plus Pretomanid in subjects with pulmonary infection of either XDR-
TB or treatment intolerant/non-responsive MDR-TB (The Nix-TB Study). Approximately half of 
the subjects were HIV co-infected, and all had documented XDR-TB. The causes of death have 
varied based on autopsies and clinical data. Two deaths were related to severe pulmonary 
tuberculosis, disseminated tuberculosis, acute severe worsening of pulmonary tuberculosis and 
multi-organ TB. These deaths were both considered by the investigator and sponsor as not 
related to the study drug regimen. A third death occurred as a result of gastrointestinal bleeding. 
This was reported by the investigator as possibly related to the investigational drug regimen, 
although the sponsor considered the event unlikely to be related to the study drug regimen.  
In a separate Phase 3 study evaluating the efficacy, safety, and tolerability of the combination of 
Pretomanid combined with moxifloxacin and pyrazinamide (STAND trial), there were three 
deaths. All subjects died with associated liver injury. Review of the deaths by an independent 
safety board concluded that these deaths were related to Drug Induced Liver Injury (DILI). In all 
3 cases the onset of DILI symptoms was early during the course of TB treatment (22, 24 and 21 
days respectively) suggesting that the etiology was likely an immuno-allergic pattern of DILI. In 
all 3 cases there was rapid clinical deterioration and 2 had coagulopathy (in the other case, INR 
was not tested). Two cases were HIV-infected, and one was HIV negative. In all 3 cases there 
was a delay to stopping study medication after DILI symptom onset. This incidence of fatal DILI 
(1.4%) among participants receiving study drug in combination with moxifloxacin and 
pyrazinamide is considerably higher than observed with conventional TB treatment. The risk of 
DILI with traditional TB drugs is approximately 1% and fulminant hepatitis approximately 0.1%. 
Although a direct causal relationship between Pretomanid and the deaths in this study could not 


DMID Protocol 13-0053  
Version 7.0 
Pretomanid in Adults with Hepatic Impairment 
19 October 2022 
________________________________________________________________________________________________________ 
 
DMID/NIAID/NIH 
34 
CONFIDENTIAL 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 15, 2018 
be definitively established or ruled out, these events raised the possibility that subjects taking 
Pretomanid for at least three weeks duration might be at risk for liver injury and should be 
monitored for evidence of hepatotoxicity, including routine monitoring of serum transaminase 
levels. The risk of liver injury appears raised when Pretomanid is combined with other agents 
known for hepatic toxicity.  
Given the deaths that occurred on the STAND trial, the Food and Drug Administration (FDA) 
performed a review of the study findings and safety of Pretomanid. Following its own internal 
review, the FDA authorized continuation of clinical trials evaluating Pretomanid’s safety and 
efficacy and suggested recommendations for the Pretomanid clinical development program. 
These included 1) close monitoring of liver enzymes; 2) study personnel education regarding 
signs/symptoms of liver toxicity; 3) close medical monitoring of liver related laboratory tests; 4) 
study drug holding rules in the event that liver toxicity is observed; and 5) close AE/laboratory 
data monitoring. The design of this protocol meets FDA recommendations. In addition, this 
study is designed as a single dose study which should reduce the risk of liver toxicity 
substantially. 
The increases in the QTc interval seen with Pretomanid were relatively small at doses of <200 
mg and there was a suggestion that with higher doses, this effect was saturated. The prolongation 
of the QTc interval was rarely clinically significant. No Pretomanid-treated subject across the 
Phase 2 studies had a QTcF interval of 500 msec or greater, and few subjects had an increase 
from baseline in the QTcF interval of >60 msec. Cardiac-related TEAEs were reported for 19 of 
the 360 subjects (5%) exposed to Pretomanid across the completed Phase 2 studies, and for none 
of the 289 subjects treated with Pretomanid in the Phase 1 studies. One of these events was 
considered to be serious. 
Two subjects exposed to Pretomanid in Phase 2 studies were discontinued due to cardiac-related 
TEAEs (Wolff-Parkinson-White syndrome and prolonged ECG QTc). The subject withdrawn 
due to QTc prolongation was asymptomatic and the event resolved upon discontinuation of 
treatment. The subject with Wolff-Parkinson-White syndrome was lost to follow-up. Results of 
ECG evaluations in the completed Phase 2 studies in subjects with pulmonary TB suggest that 
once-daily oral administration of Pretomanid is associated with increases in the QTc (at dosages 
of 50, 100, 150, 200, 600, 1000, and 1200 mg), PR (at dosages of 50, 200, 600, and 1000 mg), 
and QRS intervals (at dosages of 50, 100, 600, and 1200 mg/day), as well as with a decrease in 
heart rate. One subject in one of the comparator groups also had ECG findings. Rifafour e-275 
was associated with mean decreases in the QTcF interval, QRS interval and PR interval with a 
mean increase in heart rate. There were no reported TEAEs of bradycardia across the Phase 1 or 
Phase 2 studies with Pretomanid. 


DMID Protocol 13-0053  
Version 7.0 
Pretomanid in Adults with Hepatic Impairment 
19 October 2022 
________________________________________________________________________________________________________ 
 
DMID/NIAID/NIH 
35 
CONFIDENTIAL 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 15, 2018 
Skin and subcutaneous disorder TEAEs were among the most common events reported following 
Pretomanid dosing in the completed Phase 1 and 2 studies. Among Phase 1 studies, 12.2% of 
subjects reported a skin or subcutaneous disorder. Among the Phase 2 studies, 12.6% reported a 
skin/subcutaneous disorder. The most common skin related TEAEs reported following 
Pretomanid exposure were pruritus and rash. The overall percentage of subjects in Phase 1 and 
Phase 2 studies with rash was 1.3% and 2.4% respectively. The percentage of subjects exposed 
to Pretomanid who had pruritus in Phase 1 and Phase 2 studies was 2.5% and 2.4% respectively. 
Across all completed clinical studies, most of the skin related TEAEs were assessed as mild in 
intensity, and only one was assessed as severe. A severe generalized rash occurred in a subject 
following 8 days of dosing 1000 mg/day Pretomanid and resulted in the discontinuation of the 
subject from the study.  Although treatment with Pretomanid does appear to be associated with 
skin related TEAEs, such as pruritus or rash, these events tend to be mild in intensity and resolve 
without sequelae. 
In the single and multiple ascending dose studies, Pretomanid had a dose dependent effect on 
serum creatinine. In the single ascending dose study, 11 subjects (28%) treated with Pretomanid 
experienced a shift in serum creatinine from within the normal range at baseline to above the 
normal range at 36 hours; no placebo subjects exhibited this shift (11). Abnormal serum 
creatinine values in these subjects ranged from 1.22 to 1.45 mg/dL (normal range: 
0.69 -1.20 mg/dL) (11). By the end of the washout period (Day 7), serum creatinine levels had 
returned to baseline values (11). In the multiple ascending dose study, the maximum absolute 
postdose serum creatinine value was 1.60 mg/dL and the maximum change from baseline was 
0.38 mg/dL, both observed on Day 5 at supra-therapeutic doses (1000 mg/day). Serum creatinine 
values did not exceed 1.3 mg/dL in the 200-mg group or 1.4 mg/dL in the 600-mg group (11). 
Serum creatinine levels returned to normal levels during the 7-day washout period in all subjects 
(11). Given the findings in these studies, a Phase 1 renal safety study was performed. This 
randomized, double-blind, placebo-controlled, ascending multiple-dose study (800 or 1000 
mg/day) showed a dose dependent increase in serum creatinine. There was also one renal related 
TEAE. This involved a subject who developed proteinuria in association with hypoalbuminuria 
who was eventually diagnosed with focal segmental glomerulosclerosis believed to have been 
present prior to exposure to Pretomanid (11). Pharmacokinetic data from the renal safety study 
suggests that serum creatinine changes occurred due to inhibition of renal tubular creatinine 
secretion. This is considered a benign effect that has been described for several marketed drugs 
(14). 
The initial 3-month nonclinical toxicology studies in rats and monkeys reported the development 
of cataracts during both treatment and recovery in rats dosed with Pretomanid 300 mg/kg/day 
and during the 3-month recovery period in monkeys in the Pretomanid 450/300-mg/kg/day 


DMID Protocol 13-0053  
Version 7.0 
Pretomanid in Adults with Hepatic Impairment 
19 October 2022 
________________________________________________________________________________________________________ 
 
DMID/NIAID/NIH 
36 
CONFIDENTIAL 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 15, 2018 
group. Four clinical studies have been conducted, each of which included prospectively planned 
ophthalmologic evaluations (slit-lamp examinations, visual acuity testing) pre-dose and at 3- or 
6-months after the final dose of study treatment (Studies CL-010, CL-006, CL-009, and 
NC-001). Mild lenticular opacities were noted upon visual acuity testing in 2 of the 152 subjects 
exposed to Pretomanid across these four studies; both subjects were asymptomatic. The 
ophthalmological data accumulated thus far indicates that Pretomanid does not appear to pose a 
cataractogenic potential in humans. There may be other risks that are currently unforeseeable. 
Although rat and rabbit embryonic development studies indicate no effects of Pretomanid on 
fetal development, testicular atrophy in rats was observed in 3-month and 6-month repeat-dose 
toxicology studies and a Segment I fertility study. In this fertility study, testicular atrophy was 
associated with infertility; an approximate 30% reduction in fertility was also observed at a lower 
dose not associated with testicular atrophy. A detailed study in sexually mature male monkeys 
demonstrated no effects on testicular histology or function in adult cynomolgus monkeys after 
3 months’ dosing. Male subjects in the 8-week study of NC-002 had evaluations of the male 
hormones testosterone, LH and FSH at baseline and at the end of the eight weeks of treatment.  
No median changes were noted that raised concern that the regimen caused any testicular 
toxicity. 
An analysis of male reproductive tract hormones to assess testicular function and the 
hypothalamic-pituitary-gonadal axis has been completed using data from two Phase 2 trials (NC-
002 and NC-005) with 8 weeks of Pretomanid dosing and one ongoing Phase 3 trial (NC-006) 
with 17-26 weeks of Pretomanid dosing. This interim analysis for NC-006 included 
approximately 20-50/time point/group for the drug sensitive (DS) groups and 5-13/time 
point/group for the multidrug resistant group. 
An independent expert in reproductive toxicology reported that at baseline the male trial subjects 
had reproductive tract hormones levels consistent with primary hypogonadism associated with 
their illness, and that this improved with the treatments administered over the course of the trials. 
The expert concluded that based on the hormone evaluations to date, there is no evidence that 
Pretomanid is a testicular toxicant in men at the doses and exposure times evaluated. If 
Pretomanid were a testicular toxicant, the subject’s hormones would be expected to change to 
reflect damage to the testis. Such toxicity-related changes would include a decline in inhibin B 
levels, a hormone produced by Sertoli cells, the sustentacular cells of the seminiferous 
epithelium, and an associated compensatory increase in follicle stimulating hormone (FSH) 
levels. These toxicity-related hormone changes would be expected to be associated with 
Pretomanid treatment, to occur in a dose dependent manner, and to be exacerbated by increasing 
time of exposure. This pattern of response was not observed. In addition, if Pretomanid were 


DMID Protocol 13-0053  
Version 7.0 
Pretomanid in Adults with Hepatic Impairment 
19 October 2022 
________________________________________________________________________________________________________ 
 
DMID/NIAID/NIH 
37 
CONFIDENTIAL 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 15, 2018 
causing testicular injury, testosterone levels might be expected to fall slightly with a 
compensatory increase in luteinizing hormone (LH) levels in a dose- and time-dependent 
manner. In fact, testosterone levels increased in all groups receiving Pretomanid, and LH levels 
remain unchanged (NC-002 and NC-006). 
The potential for Pretomanid to have an effect on the testes will remain under evaluation. 
2.3.2 
Known Potential Benefits 
There is no known benefit to subjects in this study who will receive Pretomanid besides the 
potential to treat future TB patients. This novel medication may provide a less complicated 
regimen for treating TB that has activity against drug resistant strains. Furthermore, the 
substantial low potential for metabolic based drug-drug interactions makes this a viable 
candidate for treating TB in subjects infected with HIV as well without adjusting the dose of 
either anti-retroviral therapy or Pretomanid. 


DMID Protocol 13-0053  
Version 7.0 
Pretomanid in Adults with Hepatic Impairment 
19 October 2022 
________________________________________________________________________________________________________ 
 
DMID/NIAID/NIH 
38 
CONFIDENTIAL 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 15, 2018 
 
STUDY DESIGN, OBJECTIVES AND ENDPOINTS OR 
OUTCOME MEASURES 
 
Study Design Description 
This is a Phase 1, single dose (200 mg), open-label, study comparing the pharmacokinetics and 
safety of Pretomanid in subjects with mild, moderate, and severe hepatic impairment relative to 
matched non-hepatically impaired subjects.  
This study will enroll approximately 6 subjects with mild hepatic impairment (Child-Pugh A), 
approximately 6 subjects with moderate hepatic impairment (Child-Pugh B), approximately 6 
subjects with severe hepatic impairment (Child-Pugh C), and approximately 18 matched non-
hepatically impaired subjects. Subjects with moderate hepatic (Child-Pugh B) and severe hepatic 
impairment (Child-Pugh C) will be enrolled simultaneously following enrollment of  subjects 
with mild impairment. An interim safety analysis of data for the first 3 hepatic impairment 
subjects’ data will be performed in between the mild hepatic impairment group and the moderate 
and severe hepatic groups (Child-Pugh B and Child-Pugh C).  A second interim safety analysis 
will be performed after the first 3 subjects are enrolled in the moderate or severe hepatic groups.  
If enrollment into the severe hepatic impairment group (Child-Pugh C) is completed before that 
of the moderate hepatic impairment group (Child-Pugh B), results from the Child-Pugh C cohort 
will be analyzed to determine the impact of severe hepatic impairment on the PK of Pretomanid 
and the need to continue enrollment of persons with moderate hepatic impairment (Child-Pugh 
B) will be reevaluated to determine whether the objectives of the study have been met.   
Non-hepatically impaired subjects in the control group will be matched to hepatically impaired 
subjects by age (± 10 years) and screening body weight (± 20%) consistent with previous studies 
on hepatic impairment with matched controls (15-17). A control subject may be matched to more 
than one hepatic impairment subject if warranted (e.g., lack of sufficient enrollment of non-
hepatically impaired subjects) and if the subjects to which they are matched are not in the same 
disease severity group. In this case the control subject would participate in the study one time but 
be matched to more than one subject with hepatic impairment. If subjects in either the hepatically 
impaired or non-hepatically impaired control groups withdraw from the study prior to 
completion of Day 5 (Visit 04) when the last PK samples are obtained, the subject may be 
replaced. At screening, the subjects will be categorized, into one of the following 4 groups as 
described in Table 4.   
 


DMID Protocol 13-0053  
Version 7.0 
Pretomanid in Adults with Hepatic Impairment 
19 October 2022 
________________________________________________________________________________________________________ 
 
DMID/NIAID/NIH 
39 
CONFIDENTIAL 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 15, 2018 
Table 4: Study Groups 
Study Group 
Severity 
N 
Group 1 
Child-Pugh A = 5 to 6 points (Mild) 
6 
Group 2 
Child-Pugh B = 7 to 9 points (Moderate) 
6 
Group 3 
Child-Pugh C = 10 to 15 points (Severe) 
6 
Group 4 
Non-hepatically impaired controls 
18 
 
A detailed schedule of assessments is shown in Appendix A. The study will consist of the 
following: 
• 
Screening period (Day -22 to Day -2) will occur between 1 and 21 days before admission to 
the confinement/hospital unit clinic (Day -1).  
• 
Study product will be administered on Study Day 1. 
• 
An approximately 36-hour – 60 hour confinement/hospitalization period that includes 
intensive PK sampling from Study Day 1 through Study Day 2 (36-hour sample) or Day 3 
depending on site preference. 
• 
Visits on Study Days (3), 4, and 5 for medical/surgical history and concomitant medications 
review, safety laboratory testing (Study Day 5), assessment of vital signs, PK sampling, and 
SAE/AE assessment, and on Study Day 12 for final study procedures (review of 
medical/surgical history and concomitant medications, assessment of vital signs, testing for 
coagulation and pregnancy, urinalysis, physical exam, ECG, safety laboratory testing and 
SAE/AE assessment). 
 


DMID Protocol 13-0053  
Version 7.0 
Pretomanid in Adults with Hepatic Impairment 
19 October 2022 
________________________________________________________________________________________________________ 
 
DMID/NIAID/NIH 
40 
CONFIDENTIAL 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 15, 2018 
 
Study Objectives 
3.2.1 
Primary  
• To evaluate the pharmacokinetics of a single oral dose of Pretomanid in subjects with mild, 
moderate, and severe hepatic impairment (as assessed by Child-Pugh score), relative to 
matched non-hepatically impaired subjects.  
3.2.2 
Secondary 
• To evaluate the safety of a single oral dose of Pretomanid in subjects with mild, moderate, and 
severe hepatic impairment (as assessed by Child-Pugh score), relative to matched non-
hepatically impaired subjects. 
 
Study Endpoints or Outcome Measures 
3.3.1 
Primary  
• The pharmacokinetics of a single dose of Pretomanid will be assessed from serial blood 
samples collected prior to dosing (Day 1) and at multiple time points post dosing: 1h, 
2h, 4h, 5h, 6h, 8h, 12h, 16h, 24h, 36h, 48h, 72h, and 96h. The primary outcome measure 
will be total plasma concentration of Pretomanid. The following will be determined: 
o AUC(0-∞): Area under the concentration time-curve extrapolated to infinity 
o AUC(0-last): Area under the concentration time-curve to the last concentration 
above the lower limit of quantitation 
o Cmax: Maximum Pretomanid concentration 
o Tmax: Time of maximum Pretomanid concentration 
o t(1/2): Apparent terminal elimination half-life 
o CL/F: Apparent oral clearance calculated from Dose/AUC(0-∞) 
o Vd/F: Apparent Volume of Distribution  
 
 


DMID Protocol 13-0053  
Version 7.0 
Pretomanid in Adults with Hepatic Impairment 
19 October 2022 
________________________________________________________________________________________________________ 
 
DMID/NIAID/NIH 
41 
CONFIDENTIAL 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 15, 2018 
3.3.2 
Secondary  
• The secondary outcome measures will be: 
o Incidence and severity of serious adverse events reported at any time from 
the time of study treatment through the end of the study. 
o Incidence and severity of related adverse events at any time from the time 
of study treatment through Day 12.   
o Summary of physical examination findings (height at baseline, and weight 
at serial time points from Day of Admission until Day 12), vital signs (serial 
time points from Day of Admission until Day 12), safety laboratory 
parameters (Day of Admission, as well as Days 2, 5, and 12), and ECG data 
(Day of Admission and Day 12).  
  
 
 


DMID Protocol 13-0053  
Version 7.0 
Pretomanid in Adults with Hepatic Impairment 
19 October 2022 
________________________________________________________________________________________________________ 
 
DMID/NIAID/NIH 
42 
CONFIDENTIAL 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 15, 2018 
 
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 Mycobacterium tuberculosis cell wall biosynthesis, as well as by 
generating reactive nitrogen species. 
4.1.1 
Acquisition 
Pretomanid will be provided by the Global Alliance for TB Drug Development according to the 
terms of the Clinical Trials Agreement between the TB Alliance and NIAID. 
 
Formulation, Packaging, and Labeling 
For this study, Pretomanid 200 mg tablets are white to off-white, odorless and oval in 
appearance. The formulation of Pretomanid tablets is summarized in Table 5. Study drug will be 
packaged in high-density polyethylene (HDPE) bottles, each containing 50 tablets, and in blister-
strips comprised of a thermoformable-film and a lidding foil configuration, each strip containing 
7 individual tablets. Sites will receive study product in either packaging depending on supply. 
Study product in either form of packaging should be stored at 15-30°C (59-86°F). 
Table 5: 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 


DMID Protocol 13-0053  
Version 7.0 
Pretomanid in Adults with Hepatic Impairment 
19 October 2022 
________________________________________________________________________________________________________ 
 
DMID/NIAID/NIH 
43 
CONFIDENTIAL 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 15, 2018 
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 
*Water is removed during drug product manufacture. 
DMID or its designee will package the study drug. Study drug will be labeled and supplied 
according to applicable regulatory requirements. 
4.2.1 
Product Storage and Stability 
The investigator or an approved representative (e.g., pharmacist) will ensure that the study drug 
is stored in a locked, secured area (with access limited to authorized study personnel) only under 
recommended storage conditions and in accordance with applicable regulatory requirements. The 
Pretomanid tablets will be stored at 15-30°C (59-86°F). 
The drug is stable at 25°C at 60% relative humidity (RH) for at least two years and for 6 months 
at 40°C and 75% RH. 
 
Acquisition/Distribution 
Pretomanid will be provided by the Global Alliance for TB Drug Development according to the 
terms of the Clinical Trials Agreement between the TB Alliance and NIAID. 
 
Dosage/Regimen, Preparation, Dispensing and Administration of 
Study Intervention/Investigational Product 
A single 200 mg tablet will be administered orally on the morning of Visit 01, Day 1 with 240 
mL of water following an overnight fast. All participants will receive the same study product. 
 


DMID Protocol 13-0053  
Version 7.0 
Pretomanid in Adults with Hepatic Impairment 
19 October 2022 
________________________________________________________________________________________________________ 
 
DMID/NIAID/NIH 
44 
CONFIDENTIAL 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 15, 2018 
 
Pre-determined Modification of Study Intervention/Investigational 
Product for an Individual Subject 
There will be no dose modifications.  
 
Accountability Procedures for the Study Intervention/Investigational 
Product(s) 
The Pretomanid will be sent to the DMID Clinical Materials Services (CMS), Fisher Bioservices, 
and then will be supplied to the participating VTEU site prior to the start of the study. Should the 
site principal investigator require additional doses of Pretomanid during the trial, further 
instructions are provided in the protocol-specific MOP. 
After receipt of the Pretomanid, the site principal investigator is responsible for its distribution 
and disposition and has ultimate responsibility for drug accountability. The site principal 
investigator may delegate to the site research pharmacist responsibility for study product 
accountability. The participating VTEU site’s 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 the research 
pharmacy.  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 VTEU site’s study product accountability records and 
dispensing logs per the site monitoring plan. The research pharmacists at each site will maintain 
an up-to-date inventory of study product. Prior to administration, the research pharmacist will 
transfer a single dose of study product for a subject to confinement/hospital unit staff using the 
MOP-specific timeframe, and a record of the transfer will be made. Any unused product will be 
returned to Any unused tablets at the research site’s pharmacy should be retained within the 
container in which they were supplied from the CMS. Unused Pretomanid tablets will be 
retained until 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 VTEU 
sites by the DMID Clinical Project Manager. 


DMID Protocol 13-0053  
Version 7.0 
Pretomanid in Adults with Hepatic Impairment 
19 October 2022 
________________________________________________________________________________________________________ 
 
DMID/NIAID/NIH 
45 
CONFIDENTIAL 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 15, 2018 
 
Assessment of Subject Compliance with Study 
Intervention/Investigational Product   
Subject compliance is not anticipated to be an issue. Direct observation of study drug 
administration will be performed by confinement/hospital unit personnel per their standard 
procedures. If a subject vomits within two hours of dosing, they will not be redosed, they will not 
have further study samples taken for PK analysis, and they will be discontinued from the study. 
This subject could either be replaced or be reconsidered for the study after two weeks following 
completion of re-screening activities specified in the protocol. If a subject vomits >2 hours of 
dosing, they will not be redosed, but will continue with study assessments including collection of 
PK samples. 
 
Concomitant Medications/Treatments 
Administration of any medications, therapies, or vaccines will be recorded on the appropriate 
data collection form. Concomitant medications recorded will include all current medications and 
medications taken within 30 days prior to signing the informed consent and during the study 
period. Medications reported in the electronic case report form (eCRF) are limited to those taken 
within 30 days prior to the study drug administration through day 12 of the study. Prescription 
and over-the-counter drugs will be included as well as herbals, vitamins, and supplements. 
Systemic medications that might interfere with the evaluation of the investigational product 
should not be used unless absolutely necessary. A subject will be withdrawn for use of excluded 
medications. Medications in this category include the prohibited medications per the Subject 
Exclusion Criteria (see Section 5.2) and are summarized in Table 6. 


DMID Protocol 13-0053  
Version 7.0 
Pretomanid in Adults with Hepatic Impairment 
19 October 2022 
________________________________________________________________________________________________________ 
 
DMID/NIAID/NIH 
46 
CONFIDENTIAL 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 15, 2018 
Table 6: Prohibited CYP450 Enzyme Altering Medications/Substances per Subject 
Exclusion Criteria 
CYP450 Inducers 
CYP450 Inhibitors 
Carbemazepines 
Rifampicin 
Alcohol (chronic)* 
Phenytoin 
Griseofulvin 
Phenobarbital 
Sulphonylureas 
Sodium valproate 
Isoniazid 
Ketoconazole 
Fluconazole 
Chloramphenicol 
Erythromycin 
Sulfonamides 
Ciprofloxacin 
Metronidazole 
Grapefruit juice 
*Chronic alcohol use for this study is the consistent consumption of greater than one drink per 
day or seven drinks per week. 
 
 


DMID Protocol 13-0053  
Version 7.0 
Pretomanid in Adults with Hepatic Impairment 
19 October 2022 
________________________________________________________________________________________________________ 
 
DMID/NIAID/NIH 
47 
CONFIDENTIAL 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 15, 2018 
 
STUDY ENROLLMENT AND WITHDRAWAL 
The study population will be representative of subjects with varying degrees of liver disease as 
defined by Child-Pugh scores. The Child-Pugh scores used for eligibility in the study will be 
calculated at screening only. The Child-Pugh score is based on five clinical measures of liver 
function: total bilirubin, serum albumin, prothrombin, ascites and hepatic encephalopathy.  
Based on their score patients are defined as mild (5-6 points), moderate (7-9 points), or severe 
(10-15 points). Approximately 36 subjects between the ages of 18 and 70 years will be enrolled 
over an estimated 9-month period. A subject is considered enrolled in this study once they have 
signed a study consent form, met all eligibility criteria, and have been admitted to the 
confinement/hospital unit on Admission Visit (Day -1). 
Subjects with hepatic impairment for this study will be mainly identified at Duke University 
Health System Hospitals and Clinics and the Durham Veterans Administration Hospital as well 
as St Louis University. Non-hepatically impaired controls will be identified from the site-specific 
recruitment registries and the community. Subjects for this study may also be identified through 
advertisement, letters, and other forms of communication. 
Subject Inclusion and Exclusion Criteria must be confirmed by a study clinician licensed to make 
medical diagnoses. 
No exemptions are granted on Subject Inclusion/Exclusion Criteria in DMID-sponsored studies. 
Questions about eligibility will be directed toward the DMID Medical Officer. 
 
Eligibility Criteria 
5.1.1 
Subject Inclusion Criteria 
Subjects must meet all of the following inclusion criteria in order to participate in the study: 
Inclusion Criteria for Patients with Hepatic Impairment (Groups 1-3) 
1) Subject is able to give voluntary written informed consent before any study related 
procedure is performed. 
2) 18-70 years of age, inclusive. 
3) Acceptable laboratory values* obtained at screening (within 21 days prior to admission to 
the confinement/hospital unit) and either at or within 72 hours of admission to the 
confinement/hospital unit. 


DMID Protocol 13-0053  
Version 7.0 
Pretomanid in Adults with Hepatic Impairment 
19 October 2022 
________________________________________________________________________________________________________ 
 
DMID/NIAID/NIH 
48 
CONFIDENTIAL 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 15, 2018 
*Chemistry, complete blood count, AST, ALT, total bilirubin, alkaline phosphatase, albumin, and urinalysis 
deemed not clinically significant by the investigator. 
4) Hepatic impairment classified as Child-Pugh class A (mild), B (moderate), or C (severe) 
criteria at screening for Groups 1, 2, or 3, respectively, and documented evidence of hepatic 
cirrhosis*. 
*by biopsy, nuclear scan, CT, MRI, ultrasound, or other clinically acceptable methods 
5) If female, not of childbearing potential* or agrees to avoid becoming pregnant by using 
acceptable contraception** during the duration of the study. 
*Non-childbearing potential is defined as being post-menopausal for at least 2 years, status after bilateral 
oophorectomy or status after hysterectomy. 
**Females of childbearing potential must agree to use two acceptable methods of contraceptives: bilateral 
tubal ligation; barrier method (condom) by the male partner (even if vasectomized); hormonal 
contraceptives; intrauterine contraceptive devices; diaphragm in combination with contraceptive jelly, 
cream, foam, or spermicide; and abstinence from sexual intercourse with men. 
6) If subject is male and capable of reproduction, agrees to avoid fathering a child for three 
months after dosing by using an acceptable method of birth control*. 
*In addition to the use of a barrier method (condom) even if 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 #5, and abstinence from sexual intercourse with women. 
7) If the subject is female, a negative serum pregnancy test at screening and a negative urine 
pregnancy test at admission to the confinement/hospital unit. 
 
8) Willingness to comply with all protocol requirements. 
Inclusion Criteria for Non-Hepatically Impaired Controls (Group 4) 
1) Subject is able to give voluntary written informed consent before any study related 
procedure is performed. 
2) 18-70 years of age, inclusive. 


DMID Protocol 13-0053  
Version 7.0 
Pretomanid in Adults with Hepatic Impairment 
19 October 2022 
________________________________________________________________________________________________________ 
 
DMID/NIAID/NIH 
49 
CONFIDENTIAL 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 15, 2018 
3) Subject is a healthy volunteer as determined by no clinically significant findings from 
medical history, physical examination, vital signs, and 12-lead ECG as determined by the 
Site Investigator. 
4) Acceptable laboratory values* obtained at screening (within 21 days prior to admission to 
the confinement/hospital unit) and either at or within 72 hours of admission to the 
confinement/hospital unit. 
*Chemistry, complete blood count, AST, ALT, total bilirubin, alkaline phosphatase, albumin, and urinalysis 
within the reference range for the test laboratory, unless deemed not clinically significant by the 
investigator. 
5) If female, not of childbearing potential* or agrees to avoid becoming pregnant by using 
acceptable contraception** during the duration of the study. 
*Non-childbearing potential is defined as being post-menopausal for at least 2 years, status after bilateral 
oophorectomy or status after hysterectomy. 
**Females of childbearing potential must agree to use two acceptable methods of contraceptives: bilateral 
tubal ligation; barrier method (condom) by the male partner (even if vasectomized); hormonal 
contraceptives; intrauterine contraceptive devices; diaphragm in combination with contraceptive jelly, 
cream, foam, or spermicide; and abstinence from sexual intercourse with men. 
6) If subject is male and capable of reproduction, agrees to avoid fathering a child for three 
months after dosing by using an acceptable method of birth control*. 
*In addition to the use of a barrier method (condom) even if 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 #5, and abstinence from sexual intercourse with women. 
7) If the subject is female, a negative serum pregnancy test at screening and a negative urine 
pregnancy test at admission to the confinement/hospital unit. 
8) Willingness to comply with all protocol requirements. 
5.1.2 
Subject Exclusion Criteria 
Subjects meeting any of these exclusion criteria during screening (Visit 00A) will be excluded 
from study participation:  
 


DMID Protocol 13-0053  
Version 7.0 
Pretomanid in Adults with Hepatic Impairment 
19 October 2022 
________________________________________________________________________________________________________ 
 
DMID/NIAID/NIH 
50 
CONFIDENTIAL 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 15, 2018 
Exclusion Criteria for Patients with Hepatic Impairment (Groups 1-3) 
1) Hypokalemia (< 3.5mEq/L), severe hypomagnesemia (< 1.1 mg/dL) or severe 
hypocalcemia (< 7.5 mg/dL). 
2) AST or ALT > 10 times the upper limit of normal. 
3) Creatinine clearance <60 ml/min. 
4) Inability to swallow tablets. 
5) Presence of any condition or finding* which would jeopardize subject safety, impact study 
result validity, or diminish the subject’s ability to undergo all study procedures and 
assessments**.  
*in the opinion of the site investigator 
**e.g., inability to draw PK samples 
6) History of fever or documented fever (oral temperature ≥100.4° F or ≥ 38.0° C) in the 48 
hours prior to admission to the confinement/hospital unit. 
7) Currently breastfeeding. 
8) History of chronic tobacco/nicotine use (>10 cigarettes per day for 3 months minimum 
prior to admission). 
9) History of clinically significant allergy or severe side effects with nitroimidazoles (e.g., 
Metronidazole and related substances and azole antifungals or aromatase inhibitors). 
10) Receipt of an investigational drug, vaccine or biologic in a clinical trial within 30 days 
prior to screening. 
11) Use of any over the counter (OTC) medication* within 7 days prior to admission to the 
confinement/hospital unit, unless** the substance would not likely impact the validity of 
the study results. 
*including vitamins and herbal supplements, cough and cold medications. 
**in the opinion of the site investigator 
12) Treatment with CYP450 enzyme altering drugs* within 7 days prior to admission to the 
confinement/hospital unit, unless** the substance would not likely impact the validity of 
the study results. 
*except hormonal contraceptives 
**in the opinion of the site investigator 
 
NOTE: See list of CYP450 enzyme altering drugs under the concomitant medications section Table 6. 


DMID Protocol 13-0053  
Version 7.0 
Pretomanid in Adults with Hepatic Impairment 
19 October 2022 
________________________________________________________________________________________________________ 
 
DMID/NIAID/NIH 
51 
CONFIDENTIAL 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 15, 2018 
13) A positive blood screen for HIV. 
14) A positive alcohol breath test (or other suitable test for alcohol) or a urine screen test for 
drugs of abuse* at screening and at admission to the confinement/hospital unit. 
*Amphetamines, barbiturates, cocaine metabolites, marijuana, opiates, phencyclidine (PCP). 
NOTE: Results of the urine screen test can be ignored if in the opinion of the PI the results can be 
explained by the concomitant medications history. 
15) Unwillingness to abstain from engaging in strenuous physical activity (e.g., running, 
bicycling, weightlifting, competitive sports) during the course of the study. 
16) Consumption of grapefruit juice in the 48 hours before admission to the 
confinement/hospital unit, or the inability to abstain from these until completion of Day 
12. 
17) A QTcF interval >450 msec (males) or >450 msec (females) at screening (Visit 00A) or 
admission to the confinement/hospital unit (Visit 00B) or a history of prolonged QTc 
interval. 
18) A family history* of Long QT Syndrome, premature cardiac death**, or sudden death 
without a preceding diagnosis of a condition*** that could be causative of sudden death. 
*parents 
**due to ischemic heart disease or sudden cardiac death before 55 years of age (men) or 65 years of age 
(women) 
***such as known coronary artery disease, congestive heart failure, or terminal cancer 
19) Any clinically significant ECG abnormality, in the opinion of the site investigator, at 
screening and at admission to the confinement/hospital unit. 
20) Donation of >500 mL blood within the 30 days prior to admission to the 
confinement/hospital unit. 
21) Plans to donate blood during the study or up to 14 days after dosing. 
22) Persons with a transjugular intrahepatic portosystemic shunt  
Exclusion Criteria for Non-Hepatically Impaired Controls (Group 4) 
1) Inability to swallow tablets. 
2) Presence of any condition or finding* which would jeopardize subject safety, impact study 
result validity, or diminish the subject’s ability to undergo all study procedures and 
assessments**. 


DMID Protocol 13-0053  
Version 7.0 
Pretomanid in Adults with Hepatic Impairment 
19 October 2022 
________________________________________________________________________________________________________ 
 
DMID/NIAID/NIH 
52 
CONFIDENTIAL 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 15, 2018 
*in the opinion of the site investigator 
**e.g., inability to collect PK samples 
3) History of fever or documented fever (oral temperature ≥100.4° F or ≥ 38.0° C) in the 48 
hours prior to admission to the confinement/hospital unit. 
4) Currently breastfeeding. 
5) History of chronic tobacco/nicotine use (>10 cigarettes per day for 3 months minimum 
prior to admission to the confinement/hospital unit). 
6) History of seizures (other than febrile seizures during childhood) or known or suspected 
CNS disorders that may predispose to seizures. 
7) History of clinically significant allergy or severe side effects with nitroimidazoles (e.g., 
Metronidazole and related substances and azole antifungals or aromatase inhibitors). 
8) Receipt of an investigational drug, vaccine or biologic in a clinical trial within 30 days 
prior to screening. 
9) Use of any over the counter (OTC) medication* within 7 days prior to admission to the 
confinement/hospital unit, unless** the substance would not likely impact the validity of 
the study results. 
*including vitamins and herbal supplements, antacids, cough and cold medications. 
**in the opinion of the site investigator 
10) Use of prescription medication except hormonal contraceptives within 30 days prior to 
admission to the confinement/hospital unit, unless* the substance would not likely impact 
study result validity. 
*in the opinion of the site investigator 
11) Treatment with CYP450 enzyme altering drugs* within 7 days prior to admission to the 
confinement/hospital unit, unless** the substance would not likely impact the validity of 
the study results. 
*except hormonal contraceptives 
**in the opinion of the site investigator 
NOTE: See list of CYP450 enzyme altering drugs under the concomitant medications section. 
12) A positive blood screen for HIV. 
13) A positive blood screen for hepatitis B surface antigen (HBsAg), or hepatitis C antibody. 


DMID Protocol 13-0053  
Version 7.0 
Pretomanid in Adults with Hepatic Impairment 
19 October 2022 
________________________________________________________________________________________________________ 
 
DMID/NIAID/NIH 
53 
CONFIDENTIAL 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 15, 2018 
14) A positive alcohol breath test (or other suitable test for alcohol) or a urine screen test for 
drugs of abuse* at screening and at admission to the confinement/hospital unit. 
*Amphetamines, barbiturates, benzodiazepines, cocaine metabolites, marijuana, opiates, phencyclidine 
(PCP). 
15) A history of alcohol abuse or dependence within the past 1 month prior to admission to the 
confinement/hospital unit. 
16) Unwillingness to abstain from engaging in strenuous physical activity (e.g., running, 
bicycling, weightlifting, competitive sports) during the course of the study. 
17) Consumption of grapefruit juice in the 48 hours before admission to the 
confinement/hospital unit, or the inability to abstain from these until completion of Day 
12.  
18) A QTcF interval >450 msec (males) or >450 msec (females) at screening (Visit 00A) or 
admission to the confinement/hospital unit (Visit 00B) or a history of prolonged QTc 
interval. 
19) A family history* of Long QT Syndrome, premature cardiac death**, or sudden death 
without a preceding diagnosis of a condition*** that could be causative of sudden death. 
*parents 
**due to ischemic heart disease or sudden cardiac death before 55 years of age (men) or 65 years of age 
(women) 
***such as known coronary artery disease, congestive heart failure, or terminal cancer 
20) Any clinically significant ECG abnormality, in the opinion of the site investigator, at 
screening and at admission to the confinement/hospital unit. 
21) Donation of >500 mL of blood within the 30 days prior to admission to the 
confinement/hospital unit. 
22) Plans to donate blood during the study or up to 14 days after dosing. 
23) Persons with a transjugular intrahepatic portosystemic shunt. 
 
Withdrawal from the Study, Discontinuation of Study Product, or 
Study Termination  
5.2.1 
Reasons for Withdrawal   
Subjects may voluntarily withdraw their consent at any time and for any reason, without penalty. 


DMID Protocol 13-0053  
Version 7.0 
Pretomanid in Adults with Hepatic Impairment 
19 October 2022 
________________________________________________________________________________________________________ 
 
DMID/NIAID/NIH 
54 
CONFIDENTIAL 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 15, 2018 
A subject may withdraw or may be withdrawn from the study for any of the following reasons: 
• 
Medical disease or condition, or any new clinical findings for which continued participation, 
in the opinion of the site principal investigator or appropriate sub-investigator, would 
compromise the safety of the subject, or would interfere with the subject's successful 
completion of the study, or would interfere with the evaluation of responses. 
• 
Subject no longer meets eligibility criteria. 
• 
As deemed necessary by the site principal investigator or appropriate sub-investigator for 
noncompliance or other reasons. 
• 
Subject’s withdrawal of consent. 
• 
Subject lost to follow-up. 
• 
Termination of the study. 
• 
New information becomes available that makes further participation unsafe. 
5.2.2 
Handling of Withdrawals  
The primary reason for withdrawal from the study will be recorded on the Study Status data 
collection form. Subjects will be encouraged to complete the Early Termination Visit. The Early 
Termination Visit procedures are listed in Section 6.3.4. 
Although subjects are free to withdraw at any time or may be withdrawn by the site principal 
investigator or appropriate sub-investigator at any time, subjects who only receive Pretomanid 
will be encouraged to remain in this study for safety follow-up assessments.  
Every attempt will be made to follow all adverse events, including unsolicited non-serious 
adverse events, serious adverse events, and new onset chronic medical conditions, ongoing at the 
time of early withdrawal through resolution as per applicable collection times defined for the 
specific type of adverse event. 
In the case of subjects who fail to appear for a safety follow-up assessment, extensive effort (i.e., 
three documented contact attempts via phone calls, e-mails, etc., made on separate occasions and 
followed by a certified letter if possible) will be made to locate or recall them, or at least to 
determine their health status. These efforts will be documented in the subject’s records. 
Subjects may be replaced if they vomit study drug within two hours of dosing, if they withdraw, 
are withdrawn or terminated from this study or are lost to follow-up prior to completion of Day 5 
(Visit 04) when the last PK samples are obtained. 


DMID Protocol 13-0053  
Version 7.0 
Pretomanid in Adults with Hepatic Impairment 
19 October 2022 
________________________________________________________________________________________________________ 
 
DMID/NIAID/NIH 
55 
CONFIDENTIAL 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 15, 2018 
5.2.3 
Study Termination  
Although the Sponsor intends to complete the study, the Sponsor reserves the right to 
discontinue the study at any time for clinical or administrative reasons, or if required by the IRB 
or regulatory agencies. 


DMID Protocol 13-0053  
Version 7.0 
Pretomanid in Adults with Hepatic Impairment 
19 October 2022 
________________________________________________________________________________________________________ 
 
DMID/NIAID/NIH 
56 
CONFIDENTIAL 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 15, 2018 
 
STUDY SCHEDULE 
 
Screening (Visit 00A) (Day -22 to Day -2)  
The screening visit (00A) will occur up to 21 days prior to subject enrollment to assess eligibility 
of study subjects. A subject is considered enrolled in this study once they have signed a study 
consent form, met all eligibility criteria and have been admitted to the confinement/hospital unit 
on Admission Visit (Day -1).  The investigator or designees must provide the subject with the 
written informed consent form, allowing the subject to review and understand the informed 
consent, ask questions, and receive answers prior to signing the consent form. Screening 
procedures are not required to be performed on a single visit. However, all procedures should be 
completed within the 21-day window. 
The following procedures are to occur within the screening period: 
• 
Obtain signed and dated written informed consent. Informed consent must be obtained before 
any other procedures are performed. 
• 
Review inclusion and exclusion criteria. 
• 
Review complete medical and surgical history. All medical and surgical history occurring 
within the past 5 years must be noted, including drug, alcohol and tobacco use. 
• 
Collect demographic data and current disease characteristics including age, gender, race, 
ethnicity, Child-Pugh class. 
• 
Complete physical examination. 
• 
Record medication history including the name and total daily dose of medication over the 
past 30 days, including vitamins, over the counter, and prescription drugs. Per exclusion 
criteria, determine if concomitant medications could exclude subject from study. 
• 
Record a resting (5-minute rest period) 12-lead ECG. 
• 
Record vital sign measurements (sitting blood pressure, sitting heart rate, height/weight, and 
oral body temperature). 
• 
Draw a fasting (2 hours) blood sample for clinical chemistry tests. 
• 
Draw blood samples for the following:  
• 
Serum pregnancy test for females of childbearing potential. 
• 
Hematology tests. 
• 
Coagulation Parameter: INR. 
• 
HIV antibodies.   
• 
Hepatitis B surface antigen and hepatitis C antibody. 


DMID Protocol 13-0053  
Version 7.0 
Pretomanid in Adults with Hepatic Impairment 
19 October 2022 
________________________________________________________________________________________________________ 
 
DMID/NIAID/NIH 
57 
CONFIDENTIAL 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 15, 2018 
• 
Alcohol breath test or other suitable test for alcohol (e.g., blood alcohol test). 
• 
Calculate Child-Pugh score (Appendix B) using historical information.  
• 
Collect urine samples for urinalysis and drugs of abuse (amphetamines, barbiturates, 
benzodiazepines, cocaine metabolites, opiates, cannabinoids, and phencyclidine (PCP)). 
• 
The investigator must review all laboratory results and screening criteria before a subject 
initiates the Study Day 1 Visit. 
• 
Subjects who do not qualify for the study based on the results of the screening procedures do 
not need to return for any subsequent visit. 
Documentation of the subject’s fulfillment of the entry criteria, for all subjects considered for the 
study and subsequently included or excluded, is to be completed. Documentation of screening 
failure details may be recorded using eligibility screening forms or a subject screen failure log. 
A subject may be re-screened if there is a transient disease status (e.g., subject complained of a 
“cold or fever” and met a temporary delaying enrollment criterion of acute illness or fever). No 
subject may be screened more than twice due to a screening failure result as defined above. 
Please contact the DMID Medical Officer for clarification or questions regarding screening 
failures. 
 
Admission (Visit 00B) (Day -1)  
Subjects will be admitted to the confinement/hospital unit on Day -1 (Visit 00B). The following 
procedures are to occur on the Admission Day: 
• 
Review inclusion and exclusion criteria. 
• 
Obtain interim medical/surgical history, including an assessment for new medical conditions 
and symptoms by interview of subjects and note any changes since the previous clinic visit. 
• 
Complete physical examination. 
• 
Record concomitant medications including name and total daily dose of all prescription 
drugs, herbal products, vitamins, minerals, and over-the-counter medications. Per exclusion 
criteria, determine if concomitant medications could exclude subject from study. 
• 
Record a resting (5-minute rest period) 12-lead ECG. May be performed within 72 hours of 
admission to the confinement unit.  
• 
Record vital sign measurements (sitting blood pressure, sitting heart rate, weight, and oral 
body temperature). 
• 
Urine pregnancy test for females of childbearing potential. 


DMID Protocol 13-0053  
Version 7.0 
Pretomanid in Adults with Hepatic Impairment 
19 October 2022 
________________________________________________________________________________________________________ 
 
DMID/NIAID/NIH 
58 
CONFIDENTIAL 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 15, 2018 
• 
Draw a fasting (2 hour) blood sample for clinical chemistry tests. May be performed within 
72 hours of admission to the confinement unit. 
• 
Draw blood samples for the following (these can be drawn with fasting draw for chemistry 
tests) May be performed within 72 hours of admission to the confinement unit. 
• 
Hematology tests. 
• 
Coagulation parameter: INR. 
• 
Alcohol breath test or other suitable test for alcohol (e.g., blood alcohol test). 
• 
Collect urine sample for urinalysis and drugs of abuse (amphetamines, barbiturates, 
benzodiazepines, cocaine metabolites, opiates, cannabinoids, and phencyclidine (PCP). 
If screening laboratory tests are performed within 72 hours of admission to the 
confinement/hospital unit, the tests do not have to be repeated with the exception of the urine 
pregnancy test for females of childbearing potential and the urine drug screen for all subjects, 
which will be repeated. If a subject meets eligibility criteria and is admitted, but is not dosed, the 
subject could be re-evaluated for participation in the study. If subject is re-evaluated within 3 
months of serologic testing, serology testing (HIV, HCV, HBsAg) will not be repeated. The 
subject’s history will be reviewed to ensure they do not have any new risk factors since the last 
serological testing that would predispose them to hepatitis or HIV.  
 
Planned Study Visits 
6.3.1 
Dosing (Visit 01) (Day 1) and Confinement/Hospitalization (Visit 01A to Visit 
01J) (Day 1 and Day 2)   
Prior to dosing on Day 1, subjects will have pharmacokinetic samples collected (10 minutes pre-
dose) and vital signs (sitting blood pressure, sitting heart rate, weight, and oral body temperature) 
obtained (30 minutes pre-dose).  Subjects will then be administered a single oral 200 mg tablet of 
Pretomanid the morning of Visit Day 1 with 240 mL of water following an overnight fast, and 
the AE and SAE assessment period will begin. Vital signs (sitting blood pressure, sitting heart 
rate, and oral body temperature) will also be obtained 30 minutes after dose administration. 
Events that occur between the time of consent and administration of study drug will be recorded 
in the medical history. Subjects will be confined in the confinement/hospital unit overnight. 
Subjects will be discharged after assessments on Day 2 are completed (the 36-hour PK sampling 
time point). 
After dosing, subjects will be assessed at 1, 2, 4, 5, 6, 8, 12-, 16-, 24- and 36-hours post-dose. 
For each assessment, the PK sample will be collected, AEs and SAEs will be assessed, and vital 


DMID Protocol 13-0053  
Version 7.0 
Pretomanid in Adults with Hepatic Impairment 
19 October 2022 
________________________________________________________________________________________________________ 
 
DMID/NIAID/NIH 
59 
CONFIDENTIAL 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 15, 2018 
signs (sitting blood pressure, sitting heart rate, and oral body temperature) will be recorded. A 
supine blood pressure will be obtained if the sitting blood pressure is abnormal. Weight will be 
collected at the 36-hour sampling time point. Instruct the subjects to volunteer any information 
regarding AEs/SAEs at any time during the study or query the subjects with an open question 
regarding any AEs/SAEs they may be experiencing (for example, “How do you feel?”), and 
document the findings. 
Approximately 36 to 48 hours after the dose, depending on site preference, subjects will be 
discharged. 
At 36 hours:  
• Draw a fasting (2 hours) blood sample for clinical chemistry tests. This laboratory can be 
performed prior to the 36-hour post-dose draw to ensure fasting. 
• Draw blood samples for the following (these can be drawn with fasting draw for chemistry 
tests): 
o Hematology tests 
o Coagulation parameter: INR 
o Collect urine samples for urinalysis.  
Depending on site preference, participants may be discharged from the confinement/hospital 
unit.  
6.3.2 
Follow-up (Visits 02, 03, and 04) (Day 3, Day 4, and Day 5)  
Subjects discharged at Day 2 will return for a follow-up visit on Day 3 (Visit 02).  Subjects 
remaining in the confinement/hospital unit at Day 2 will complete all Day 3 (Visit 02) 
procedures as outlined for all subjects. After completion of Day 3 procedures those participants 
may be discharged from the hospital/confinement unit.  
All subjects will return for follow-up visits on Days 4 (Visit 03) and 5 (Visit 04).  
The following procedures are to occur on Days 3 (Visit 02), 4 (Visit 03) and 5 (Visit 04): 
• 
Obtain interim medical/surgical history, including an assessment for new medical conditions 
and symptoms by interview of subjects and note any changes since the previous clinic visit. 
• 
A targeted review of body systems will be obtained at these visits focused on liver disease 
and will include questions pertaining to development of ascites, jaundice, pruritis, 


DMID Protocol 13-0053  
Version 7.0 
Pretomanid in Adults with Hepatic Impairment 
19 October 2022 
________________________________________________________________________________________________________ 
 
DMID/NIAID/NIH 
60 
CONFIDENTIAL 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 15, 2018 
gastrointestinal bleeding, and encephalopathy. If the subject answers yes to any of these 
questions, a targeted physical exam will be performed.  
• 
Record concomitant medications including name and total daily dose of all prescription 
drugs, herbal products, vitamins, minerals, and over-the-counter medications. Per exclusion 
criteria, determine if concomitant medications could exclude subject from study. 
• 
Record vital sign measurements (sitting blood pressure, sitting heart rate, weight, and oral 
body temperature). 
• 
Obtain blood sample for PK analysis. 
• 
Information regarding AEs/SAEs will be assessed and recorded on the appropriate data 
collection form.  
• 
Day 5 (in addition to the assessments listed above): 
o Draw a fasting (2 hours) blood sample for clinical chemistry tests  
o Draw blood samples for the following (these can be drawn with fasting draw for 
chemistry tests): 
 Hematology tests.  
 Coagulation parameter: INR.  
o Collect urine samples for urinalysis. 
6.3.3 
Final Study Visit (Visit 05) (Day 12)  
The final study visit will occur 11 days after Pretomanid administration. The following 
procedures are to occur on Day 12: 
• 
Complete physical examination. 
• 
Obtain interim medical/surgical history, including an assessment for new medical conditions 
and symptoms by interview of subjects and note any changes since the previous clinic visit.  
• 
 A targeted review of systems will be obtained at these visits focused on liver disease and 
will include questions pertaining to development of ascites, jaundice, pruritus, 
gastrointestinal bleeding, and encephalopathy.  
• 
Record concomitant medications including name and total daily dose of all prescription 
drugs, herbal products, vitamins, minerals, and over-the-counter medications. Per exclusion 
criteria, determine if concomitant medications could exclude subject from study 
• 
Record a resting (5-minute rest period) 12-lead ECG. 


DMID Protocol 13-0053  
Version 7.0 
Pretomanid in Adults with Hepatic Impairment 
19 October 2022 
________________________________________________________________________________________________________ 
 
DMID/NIAID/NIH 
61 
CONFIDENTIAL 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 15, 2018 
• 
Record vital sign measurements (sitting blood pressure, sitting heart rate, weight and oral 
body temperature).  
• 
Draw a fasting (2 hours) blood sample for clinical chemistry tests. 
• 
Draw blood samples for the following:  
o Serum pregnancy test for females of childbearing potential. 
o Hematology tests. 
o  Coagulation Parameter: INR. 
• 
Collect urine samples for urinalysis. 
• 
Information regarding AEs/SAEs will be assessed and recorded on the appropriate data 
collection form.  
6.3.4 
Early Termination Visit  
The following assessments will be performed at the early termination visit for subjects who 
withdraw, or are withdrawn or terminated from this study: 
• 
Obtain interim medical/surgical history, including an assessment for new medical conditions 
and symptoms by interview of subjects and note any changes since the previous clinic visit.   
• 
Complete physical examination  
• 
A targeted review of systems will be obtained at these visits focused on liver disease and will 
include questions pertaining to development of ascites, jaundice, pruritis, gastrointestinal 
bleeding, and encephalopathy.  
• 
All concomitant medications will be recorded on the appropriate data collection form.  
• 
Information regarding AEs/SAEs will be assessed and recorded on the appropriate data 
collection form.  
• 
Urine or serum pregnancy test. 
 
Unscheduled Study Visits  
Unscheduled visits are allowed for the following reasons: 
• 
Management of an AE or SAE. 
• 
Performance of additional laboratory tests for clinically abnormal test values (e.g., 
confirming elevated levels of liver enzymes). 


DMID Protocol 13-0053  
Version 7.0 
Pretomanid in Adults with Hepatic Impairment 
19 October 2022 
________________________________________________________________________________________________________ 
 
DMID/NIAID/NIH 
62 
CONFIDENTIAL 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 15, 2018 
• 
Any time the investigator feels that it is clinically appropriate for subject safety. 
• 
Urine or serum pregnancy test. 
• 
PK sampling. 
Unscheduled visits will be labeled and documented by the number of the visit the subject just 
completed, followed by the letter “S” to denote the first unscheduled visit (e.g., 01AS, 02S), the 
letter “T” to denote second unscheduled visit, etc. 
 
Protocol Deviations 
A protocol deviation is any non-compliance with the clinical trial protocol, GCP, or protocol-
specific MOP requirements. The noncompliance may be either on the part of the subject, the site 
principal investigator, or other study personnel. As a result of deviations, corrective actions are 
to be developed by the site and implemented promptly. 
These practices are consistent with ICH E6: 
4.5 Compliance with Protocol, Sections 4.5.1, 4.5.2, and 4.5.3 
5.1 Quality Assurance and Quality Control, Section 5.1.1 
5.20 Non-compliance, Sections 5.20.1, and 5.20.2. 
It is the responsibility of the site principal investigator and other study personnel to use 
continuous vigilance to identify and report deviations within 5 working days of identification of 
the protocol deviation, or within 5 working days of the scheduled protocol-required activity. All 
deviations must be promptly reported to DMID, via the SDCC’s IDES. 
All protocol deviations, as defined above, must be addressed in study subject or non-subject 
specific data collection forms. A completed copy of the DMID Protocol Deviation Form must be 
maintained in the Regulatory File, as well as in the subject's chart. Protocol deviations must be 
sent to the local IRB/IEC per their guidelines. The site principal investigator and other study 
personnel are responsible for knowing and adhering to their IRB requirements. 


DMID Protocol 13-0053  
Version 7.0 
Pretomanid in Adults with Hepatic Impairment 
19 October 2022 
________________________________________________________________________________________________________ 
 
DMID/NIAID/NIH 
63 
CONFIDENTIAL 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 15, 2018 
 
DESCRIPTION OF CLINICAL AND LABORATORY 
EVALUATIONS 
 
Clinical Evaluations 
Complete medical history will be obtained by interview of subjects during the screening visit. 
Subjects 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, 
kidney, urologic system, nervous system, blood, lymph glands, 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. 
Medication history (concomitant medications) will include a review of all current medications 
and medications as specified in Section 4.8. 
A physical examination will be performed by a licensed clinician listed on the Form FDA 1572, 
to include MD, NP and PA. The comprehensive physical examination must include the following 
organ or body system assessments: skin; head, eyes, ears, nose, and throat; thyroid; neurological; 
chest and lungs; cardiovascular; abdomen (liver and spleen); lymph nodes; musculoskeletal, and 
extremities. Assessments of any specific signs or symptoms reported by the subject must also be 
performed and documented along with any other findings of note. Findings from the screening 
must be characterized as either normal or abnormal, and if abnormal, a description of the 
abnormality must be provided. Following the screening visit physical examination, changes must 
be classified as new, worsened, or improved from those at screening.  
Vital sign measurements must include the subject’s sitting heart rate, sitting blood pressure (mm 
Hg), height (at screening only), weight (at screening, admission day, prior to dosing, 36-hour, 
48-hour, 72-hour, 96-hour and Day 12 time points) and oral body temperature (ºC). If a 
physiologic parameter, e.g., vital signs, is outside of the protocol-specified range, then the 
measurement may be repeated once if, in the judgment of the investigator, the abnormality is the 
result of an acute, short-term, rapidly reversible condition (e.g., stress, anxiety, or “white coat 
syndrome”).  A physiologic parameter may also be repeated if there is a technical problem with 
the measurement caused by malfunctioning, or an inappropriate measuring device (i.e., 
inappropriate-sized blood pressure cuff). If there is an abnormal blood pressure measurement, the 
subject should lay down for 10 minutes and then the measurement should be repeated while the 
subject is awake and resting supine. 


DMID Protocol 13-0053  
Version 7.0 
Pretomanid in Adults with Hepatic Impairment 
19 October 2022 
________________________________________________________________________________________________________ 
 
DMID/NIAID/NIH 
64 
CONFIDENTIAL 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 15, 2018 
In addition, a resting 12-lead ECG will be performed at screening, admission, and the final visit. 
At subsequent visits, assessment for AEs and SAEs will occur and the subject will be 
interviewed about interim AEs/SAEs and medical history. 
7.1.1 
Assessment of Subject Compliance with Study Intervention/Investigational 
Product   
Subject compliance is not anticipated to be an issue. Direct observation of study drug 
administration will be performed by confinement/hospital unit personnel per their standard 
procedures. If a subject vomits within two hours of dosing, they will not be redosed, they will not 
have further study samples taken for PK analysis, and they will be discontinued from the study. 
This subject could either be replaced or be reconsidered for the study after two weeks following 
completion of re-screening activities specified in the protocol. If a subject vomits >2 hours of 
dosing, they will not be redosed, but will continue with study assessments including collection of 
PK samples. 
 
Laboratory Evaluations 
7.2.1 
Clinical Laboratory Evaluations 
Clinical laboratory evaluations will include the following safety and screening labs: 
• 
Blood Screen of hepatitis B surface antigen 
• 
Hepatitis C antibody 
• 
HIV antibodies 
• 
Urine screen test for drugs of abuse, including amphetamines, barbiturates, benzodiazepines, 
cocaine metabolites, opiates, cannabinoids, and phencyclidine (PCP) 
• 
Chemistry parameters (2 hour fasting): total bilirubin, serum albumin, potassium, 
magnesium, calcium, serum creatinine, BUN, alkaline phosphatase, alanine aminotransferase 
(ALT), aspartate aminotransferase (AST) and CBC with differential.  For patients with 
severe hepatic impairment (Child-Pugh C) an ammonia level will be drawn at screening and 
will be used as a baseline reading for safety purposes, not as a study entry criterion.  
• 
Hematology parameters: hematocrit, hemoglobin, red blood cell count, white blood cell 
count, automated differential (neutrophils, eosinophils, basophils, lymphocytes, monocytes), 
and platelet count. 
• 
Coagulation parameter: INR 


DMID Protocol 13-0053  
Version 7.0 
Pretomanid in Adults with Hepatic Impairment 
19 October 2022 
________________________________________________________________________________________________________ 
 
DMID/NIAID/NIH 
65 
CONFIDENTIAL 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 15, 2018 
• 
Urinalysis: A macroscopic urine test (dip) will be performed at the confinement/hospital unit. 
If the macroscopic urine test is abnormal, a microscopic Urinalysis including color, specific 
gravity, pH, protein, glucose, ketones, bilirubin, urobilinogen, blood, nitrites, and leukocyte 
esterase will be performed.  
• 
Women of childbearing potential must complete a serum pregnancy test in the screening 
period and on Day 12.  A urine pregnancy test will be performed on the day of admission. A 
negative result is required for continued participation in the study. 
• 
Alcohol breath test or other suitable test for alcohol (e.g., blood alcohol test) 
The total blood volume collected for this study will be approximately 160.5 mL including: 
• 
Visit 00A (Screening): Chemistry, hematology, serology (HIV, HCV, and HBsAg), 
coagulation, and pregnancy tests for a total of approximately 27.5 mL. 
• 
Visit 00B (Admission or within 72 hours of Admission): Chemistry, hematology, and 
coagulation for a total of approximately 11.5 mL. 
• 
Visits 01-01I (Day 1): PK samples - 6 mL blood/sample x 10 samples for a total of 
approximately 60 mL. 
• 
Visit 01J (36 hours after dosing): Chemistry, hematology, PK sample, and coagulation tests 
for a total of approximately 17.5 mL. 
• 
Visit 02 (Day 3) and Visit 03 (Day 4): PK samples - 6 mL blood/sample x 2 samples for a 
total of approximately 12 mL.  
• 
Visit 04 (Day 5 Visit): Chemistry, hematology, PK sample, and coagulation tests for a total 
of approximately 17.5 mL. 
• 
Visit 05 (Day 12 Visit): Chemistry, hematology, coagulation, and pregnancy tests for a total 
of approximately 14.5 mL. 
• 
To avoid multiple needle sticks (venipunctures), after the first blood draw, a venous catheter 
will remain in place until discharge from the confinement/hospital unit. 
7.2.2 
Special Assays or Procedures   
7.2.2.1 
ECG 
A standard 12-lead ECG must be recorded in the screening period, on the day of admission, and 
Study Day 12 after the subject has been resting for at least five minutes. The heart rate from the 
ECG machine should not be used as part of the vital sign measurements. 


DMID Protocol 13-0053  
Version 7.0 
Pretomanid in Adults with Hepatic Impairment 
19 October 2022 
________________________________________________________________________________________________________ 
 
DMID/NIAID/NIH 
66 
CONFIDENTIAL 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 15, 2018 
7.2.2.2 
PK Samples 
Blood samples will be collected (K2 EDTA tubes) in this study to characterize the 
pharmacokinetics of Pretomanid in non-hepatically impaired controls and subjects with hepatic 
impairment (see PK sampling points in Appendix A, Schedule of Events). 
The exact date and time of all pharmacokinetic blood samples should be recorded.  The pre-dose 
blood sample should be collected within 10 minutes 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 collections at 24 and 36 hours after dosing, collection times must be 
+/- 1 hour, and at 48, 72, and 96 hours after dosing, they must be +/-4 hours.  
Dates should be recorded in an unambiguous format (e.g., DD MMM YYYY), and time should 
be recorded to the nearest minute (e.g., HH:MM using the 24-hour clock). Blood samples not 
drawn or drawn out of the defined window should be recorded and reported as protocol 
deviations.  
7.2.2.3 
Specimen Preparation, Handling, and Shipping 
7.2.2.1 
Instructions for Specimen Preparation, Handling, and Storage 
Instructions related to handling of safety laboratory samples and pharmacokinetic samples are 
provided in study documents (e.g., laboratory manual, MOP). 
7.2.2.2 
Laboratory Specimen Shipping 
Clinical laboratory assessments will be performed at Duke and SLU. PK samples will be shipped 
on dry ice to Fisher BioServices prior to sending to the bioanalytical laboratory.  
Fisher BioServices 
20439 Seneca Meadows Parkway 
Germantown, MD 20876 
Telephone: 240-477-1350 
Email: DMID.CMS@ThermoFisher.com 
Fax: 240-477-1360 
The frequency and conditions of shipment will be described in the MOP. 


DMID Protocol 13-0053  
Version 7.0 
Pretomanid in Adults with Hepatic Impairment 
19 October 2022 
________________________________________________________________________________________________________ 
 
DMID/NIAID/NIH 
67 
CONFIDENTIAL 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 15, 2018 
 
ASSESSMENT OF SAFETY 
 
Assessing and Recording Safety Parameters 
8.1.1 
Adverse Events (AEs) 
An adverse event is defined as any untoward medical occurrence in a subject regardless of its 
causal relationship to study treatment. An adverse event can be any unfavorable and unintended 
sign (including any clinically significant abnormal laboratory test result), symptom, or disease 
temporally associated with the use of the study drug, whether or not it is considered to be study-
drug related. Included in this definition are any newly occurring events or previous condition that 
has increased in severity or frequency since the administration of study drug. 
All adverse events that are observed or reported by the subject during the study (from the time of 
the first dose of study drug until the Study Day 12 Visit) must be reported, regardless of their 
relationship to study drug or their clinical significance. 
8.1.1.1 
Adverse Events Grading 
Severity of Event:   
AEs will be assessed by the investigator using a protocol-defined grading system (toxicity table 
included as an appendix).  For events not included in the protocol-defined grading system, the 
following guidelines will be used to quantify severity: 
• 
Mild (Grade 1):  Events that are usually transient and may require only minimal or no 
treatment or therapeutic intervention and generally do not interfere with the subject’s usual 
activities of daily living. 
• 
Moderate (Grade 2):  Events that are usually alleviated with additional specific therapeutic 
intervention.  The event interferes with usual activities of daily living, causing discomfort but 
poses no significant or permanent risk of harm to the research participant. 
• 
Severe (Grade 3):  Events interrupt usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention.  Severe events are usually 
incapacitating. 
Relationship to Study Product: The assessment of the AE’s relationship to study product will 
be done by the licensed study physician indicated on the Form FDA 1572 and the assessment 
will be part of the documentation process.  Whether the AE is related or not, is not a factor in 


DMID Protocol 13-0053  
Version 7.0 
Pretomanid in Adults with Hepatic Impairment 
19 October 2022 
________________________________________________________________________________________________________ 
 
DMID/NIAID/NIH 
68 
CONFIDENTIAL 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 15, 2018 
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.  The relationship to study product 
will be assessed for AEs using the terms related or not related: 
• 
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. 
8.1.2 
Serious Adverse Events 
A serious adverse event (SAE) is any adverse event occurring at any dose and regardless of 
causality that: 
• 
Results in death. 
• 
Is life-threatening. 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization. 
• 
Results in persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions. 
• 
Is a congenital anomaly or birth defect in an offspring of a subject taking study drug 
• 
Is an important medical event. 
The term “life-threatening” refers to an event in which the subject was at immediate risk of death 
at the time of the event. It does not refer to an event that hypothetically might have caused death 
if it were more severe. 
Important medical events are those that may not meet any of the criteria defined above, however, 
they may be considered serious when, based upon appropriate medical judgment, they may 
jeopardize the subject and may require medical or surgical intervention to prevent one of the 
other outcomes listed in the SAE definition. 
Pregnancy is not considered an adverse event; however, for females, information will be 
collected for any pregnancies which occur during study drug administration until the Study Day 
12 Visit. Male subjects should notify the study team if a pregnancy occurs in a partner within 3 
months after study drug administration.  If the male subject reports a pregnancy, information 
about complications during pregnancy, labor and delivery, or congenital birth defects will be 


DMID Protocol 13-0053  
Version 7.0 
Pretomanid in Adults with Hepatic Impairment 
19 October 2022 
________________________________________________________________________________________________________ 
 
DMID/NIAID/NIH 
69 
CONFIDENTIAL 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 15, 2018 
collected from the male subject’s female partner using a site-specific Pregnant Partner 
Information and Authorization form. Certain pregnancy outcomes (congenital anomaly or birth 
defect in an offspring of a subject taking study drug) will require submission as an SAE. (See 
Section 8.3.1) 
The investigator is responsible for reporting to the Sponsor or designee all adverse events and 
SAEs that are observed or reported by the subject during the study (from Day 1 until the Study 
Day 12 Visit), regardless of their relationship to study drug or their clinical significance. All 
SAEs reported or observed during the study must be followed until return to pretreatment status 
or stabilization of the condition with the expectation that it will remain chronic. The Sponsor or 
designee may contact the investigator to obtain additional information on any SAE which has not 
resolved at the time the subject completes the study. 
 
Specification of Safety Parameters 
There are no solicited events to be captured for this study. 
 
Reporting Procedures 
AE and SAE reporting is to occur at Visits 01 through 05. 
Any medical condition that is present at screening or admission will be considered as pre-
existing reported on the Medical History form and will not be reported as an AE. If the severity 
or frequency of any pre-existing medical condition increases during the study period, then it will 
be recorded as an AE. 
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. 
8.3.1 
Reporting Serious Adverse Events 
Any AE that meets a protocol-defined serious criterion must be submitted immediately (within 
24 hours of site awareness) on an SAE form to the DMID Pharmacovigilance Group at the 
following address: 
 
 


DMID Protocol 13-0053  
Version 7.0 
Pretomanid in Adults with Hepatic Impairment 
19 October 2022 
________________________________________________________________________________________________________ 
 
DMID/NIAID/NIH 
70 
CONFIDENTIAL 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 15, 2018 
DMID Pharmacovigilance Group 
Clinical Research Operations and Management Support (CROMS) 
6500 Rock Spring Drive, Suite 650 
Bethesda, MD 20817, USA 
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: PVG@dmidcroms.com 
 
In addition to the SAE form, selected SAE data fields must also be entered into AdvantageEDC. 
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 Independent Safety Monitor (ISM) when 
they are provided 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 subject safety and protocol conduct. 
At any time after completion of the study, if the site principal investigator or appropriate sub 
investigator becomes aware of an SAE that is suspected to be related to study product, the site 
principal investigator or appropriate sub-investigator will report the event to the DMID 
Pharmacovigilance Group. 
8.3.2 
Regulatory Reporting for Studies Conducted Under DMID-Sponsored IND 
Following notification from the site principal investigator or appropriate sub-investigator, 
DMID, the Investigational New Drug (IND) sponsor, will report any suspected adverse reaction 
that is both serious and unexpected. DMID will report an adverse event as a suspected adverse 
reaction only if there is evidence to suggest a causal relationship between the drug and the 
adverse event. DMID will notify FDA and all participating site principal investigators (i.e., all 
principal investigators to whom the Sponsor is providing drug under its IND(s) or under any 
principal investigator’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 


DMID Protocol 13-0053  
Version 7.0 
Pretomanid in Adults with Hepatic Impairment 
19 October 2022 
________________________________________________________________________________________________________ 
 
DMID/NIAID/NIH 
71 
CONFIDENTIAL 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 15, 2018 
Sponsor determines that the information qualifies for reporting as specified in 21 CFR Part 
312.32. DMID will also notify 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 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 the FDA at 
least annually in a summary format. 
8.3.3 
Reporting of Pregnancy 
Pregnancies occurring in study subjects will be reported via AdvantageEDC on the Pregnancy 
Report form. Efforts will be made to follow all pregnancies reported during the course of the 
study to pregnancy outcome pending the subject’s permission. For females, pregnancies will be 
reported from the time of study drug administration until after the study is completed (Study Day 
12). Male subjects should contact the study team to report a pregnancy in a partner up to 3 
months after study drug administration. If the male subject reports a pregnancy, information 
about complications during pregnancy, labor and delivery, or congenital birth defects will be 
collected from the male subject’s female partner using a site-specific Pregnant Partner 
Information and Authorization form. 
 
Type and Duration of Follow-up of Subjects after Adverse Events 
AEs will be collected, assessed, and followed through the resolution from the time of receipt of 
study drug through study Day 12. 
SAEs will be followed from the time of the time of receipt of study drug through resolution even 
if this extends beyond the study-reporting period (approximately 12 days after study drug 
administration). 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 data 
collection form. 
 


DMID Protocol 13-0053  
Version 7.0 
Pretomanid in Adults with Hepatic Impairment 
19 October 2022 
________________________________________________________________________________________________________ 
 
DMID/NIAID/NIH 
72 
CONFIDENTIAL 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 15, 2018 
 
Procedures to be Followed in the Event of Abnormal Laboratory 
Test Values or Abnormal Clinical Findings 
The site principal investigator or appropriate sub-investigator is responsible for reporting all 
AE/SAEs that are observed or reported during the study, regardless of the relationship to study 
product. AE/SAEs, abnormal clinical laboratory test values, or abnormal clinical findings will be 
documented, reported, and followed appropriately. 
 
Halting Rules 
The study will be immediately suspended, and no additional doses administered if any of the 
following occurs: 
 
1. Any death occurring during the study that was not the result of trauma or accident. 
2. 2 or more hepatically impaired subjects experience a serious adverse event (other than 
death), related to study product.  
3. 2 or more non-hepatically impaired subjects experience a serious adverse event (other 
than death), related to study product. 
4. 3 or more subjects develop a severe (Grade 3) abnormality in the same laboratory 
parameter, regardless of relatedness to study product. Exception to this would be: 
a. Grade 3 CK elevation without systemic complaints 
b. 
 If there are obvious and acceptable physiological explanations for a Grade 3 
abnormality (e.g., Grade 3 hematuria in a menstruating female). 
In this case, the study will be suspended pending review and discussion of all appropriate study 
data by the Investigator, Sponsor or DMID Medical Monitor, the Independent Safety Monitor, 
and the Safety Monitoring Committee. The study will not be re-started until all parties have 
agreed to the course of action to be taken, the IRB and Food and Drug Administration (FDA) 
have been notified, and IRB approval is obtained. 
 
Safety Oversight (ISM plus SMC) 
8.7.1 Independent Safety Monitor (ISM)  
The ISM is a physician with relevant expertise whose primary responsibility is to provide 
independent safety monitoring in a timely fashion. The ISM will review SAEs in real time and 


DMID Protocol 13-0053  
Version 7.0 
Pretomanid in Adults with Hepatic Impairment 
19 October 2022 
________________________________________________________________________________________________________ 
 
DMID/NIAID/NIH 
73 
CONFIDENTIAL 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 15, 2018 
other AEs as needed and provide an independent assessment to DMID. Each participating VTEU 
site will have an ISM with experience in infectious diseases or internal medicine, in close 
proximity to the VTEU site, and have the authority to readily access study participant records. 
8.7.2 Safety Monitoring Committee (SMC) 
The SMC will meet at several time points during the study (see Section 10.5.1) to monitor 
subject safety. The SMC will consist of independent evaluators who will have no relationship 
with the conduct of the trial. The SMC will operate under the rules of a DMID-approved charter 
that will be approved at the organizational meeting of the SMC.  Within the Charter each data 
element that the SMC needs to assess will be clearly defined and may include safety and ECG 
outcomes. The SMC will provide recommendation regarding  enrollment following enrollment 
of the mild hepatic impairment group (Child-Pugh A) and after enrollment of the first three 
subjects in the moderate or severe hepatic impairment groups (Child-Pugh B or Child-Pugh C). 
The study unblinded statistician may provide independent analyses to the SMC as needed. The 
SMC will advise DMID of its findings. In the event of study halt, the SMC will be consulted to 
review the data and provide a recommendation related to the continued dosing of the subjects. 


DMID Protocol 13-0053  
Version 7.0 
Pretomanid in Adults with Hepatic Impairment 
19 October 2022 
________________________________________________________________________________________________________ 
 
DMID/NIAID/NIH 
74 
CONFIDENTIAL 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 15, 2018 
 
HUMAN SUBJECTS PROTECTION 
 
Ethical Standard 
The site principal investigator will ensure that this trial is conducted in full conformity with 
principles of the Belmont Report: Ethical Principles and Guidelines for the Protection of Human 
Subjects of Research of the National Commission for the Protection of Human Subjects of 
Biomedical and Behavioral Research (April 18, 1979) and codified in 45 CFR 46, 21 CFR 50 
and 56, and ICH E6; 62 Federal Regulations 25691 (1997), if applicable. The site principal 
investigator’s Institution will hold a current Federal Wide Assurance (FWA) issued by the Office 
of Human Research Protection (OHRP) for federally funded research. 
 
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 subjects.  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 GCP, and as applicable, 21 CFR 56 
(Institutional Review Boards) and 21 CFR 50 (Protection of Human Subjects), other federal, 
state, and local regulations.  The IRB must be registered with the Office of Human Research 
Protection (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 subjects, prior to 
recruitment and enrollment of subjects. 
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 subjects 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 subject.  


DMID Protocol 13-0053  
Version 7.0 
Pretomanid in Adults with Hepatic Impairment 
19 October 2022 
________________________________________________________________________________________________________ 
 
DMID/NIAID/NIH 
75 
CONFIDENTIAL 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 15, 2018 
 
Informed Consent Process 
The site principal investigator will choose subjects in accordance with the eligibility criteria 
detailed in Section 5. Before any study procedures are performed, subjects must sign an informed 
consent form and subjects must provide consent as appropriate for age that complies with the 
requirements of 21 CFR Part 50 and 45 CFR 46 and the local IRB. 
Informed consent is a process that is initiated prior to the individuals agreeing to participate in a 
trial and continuing throughout the individual’s trial participation. Before any study procedures 
are performed, including pre-screening of subjects for eligibility, subjects will receive a 
comprehensive explanation of the proposed study procedures and study interventions/products, 
including the nature and risks of this trial, alternate therapies, any known AEs, the 
investigational status of the components, and the other elements that are part of obtaining proper 
informed consent. Subjects will also receive a detailed explanation of the proposed use and 
disclosure of their protected health information, including specifically their serum samples. 
Subjects will be allowed sufficient time to consider participation in the trial, after having the 
nature and risks of the trial explained to them and have the opportunity to discuss the trial with 
their family, friends or legally authorized representative or think about it prior to agreeing to 
participate. 
Informed consent forms describing in detail the study interventions/products, study procedures, 
risks and possible benefits are given to the subjects. The informed consent form must not include 
any exculpatory statements. Informed consent forms will be IRB-approved, and the subject will 
be asked to read and review the appropriate document. Upon reviewing the appropriate 
document, the site principal investigator (or designee) will explain the research study to the 
subject and answer any questions that may arise. Subjects must sign the informed consent form, 
and written documentation of the informed consent process is required prior to starting any study 
procedures/interventions being done specifically for the trial, including administering study 
product. 
DMID will provide the site principal investigator, in writing, any new information that 
significantly impacts the subjects' risk of receiving the investigational product. This new 
information will be communicated by the site principal investigator to subjects who consent to 
participate in the trial in accordance with IRB requirements. The informed consent document 
will be updated and subjects will be re-consented, if necessary. 
Study personnel may employ IRB-approved recruitment efforts prior to obtaining the subject’s 
consent; however, before any study procedures are performed to determine protocol eligibility an 


DMID Protocol 13-0053  
Version 7.0 
Pretomanid in Adults with Hepatic Impairment 
19 October 2022 
________________________________________________________________________________________________________ 
 
DMID/NIAID/NIH 
76 
CONFIDENTIAL 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 15, 2018 
informed consent form must be signed. Subjects will be given a copy of all informed consent 
forms that they sign. 
By signing the informed consent form, the subject agrees to complete all evaluations required by 
the trial, unless the subject withdraws voluntarily, or is withdrawn or terminated from the trial 
for any reason. 
The rights and welfare of the subjects will be protected by emphasizing to the subject that the 
quality of their medical care will not be adversely affected if they decline to participate in or 
withdraw from this trial. 
New information will be communicated by the site principal investigator to subjects who consent 
to participate in this trial in accordance with IRB requirements.  The informed consent document 
will be updated and subjects will be re-consented per IRB requirements, if necessary.  Subjects 
will be given a copy of all informed consent forms that they sign. 
9.3.1 
Exclusion of Special Populations  
This trial will be inclusive of all adult persons who meet the Subject Inclusion/Exclusion 
Criteria, regardless of religion, sex, or ethnic background. No persons under the age of 18 will be 
enrolled in this study. 
 
Future Use of Stored Specimens 
Samples will not be banked for future use. 
 
Subject Confidentiality 
Subjects will have code numbers and will not be identified by name. Subject confidentiality is 
strictly held in trust by the participating site principal investigators, their study personnel, the 
Sponsor(s), and their agents. This confidentiality is extended to cover testing of biological 
samples, in addition to the clinical information relating to participating subjects. 
The study protocol, documentation, data, and all other information generated will be held in 
strict confidence. No information concerning the trial, or the data will be released to any 
unauthorized third party without prior written approval of the Sponsor. 
All information provided by the Sponsor and all data and information generated by the 
participating VTEU site as part of the trial (other than a subject’s medical records) will be kept 
confidential by the site principal investigator and other study personnel to the extent permitted by 


DMID Protocol 13-0053  
Version 7.0 
Pretomanid in Adults with Hepatic Impairment 
19 October 2022 
________________________________________________________________________________________________________ 
 
DMID/NIAID/NIH 
77 
CONFIDENTIAL 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 15, 2018 
law. This information and data will not be used by the site principal investigator or other study 
personnel for any purpose other than conducting the trial. These restrictions do not apply to: (1) 
information which becomes publicly available through no fault of the site principal investigator 
or other study personnel; (2) information which is necessary to disclose in confidence to an IRB 
solely for the evaluation of the trial; (3) information which is necessary to disclose in order to 
provide appropriate medical care to a study subject; or (4) study results which may be published 
as described in Section 15. If a written contract for the conduct of the study which includes 
confidentiality provisions inconsistent with this statement is executed, that contract’s 
confidentiality provisions shall apply rather than this statement. 
The study monitor, applicable regulatory authorities, such as the FDA, or other authorized 
representatives of the Sponsor may inspect all documents and records required to be maintained 
by the site principal investigator. This includes, but is not limited to, medical records (office, 
clinic, or hospital) and pharmacy records for the subjects in this trial. The participating VTEU 
site will permit access to such records. 
 
Study Discontinuation  
If the study is discontinued, enrolled subjects will continue to be followed for safety assessments. 
No further doses of Pretomanid will be administered. 
 
 


DMID Protocol 13-0053  
Version 7.0 
Pretomanid in Adults with Hepatic Impairment 
19 October 2022 
________________________________________________________________________________________________________ 
 
DMID/NIAID/NIH 
78 
CONFIDENTIAL 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 15, 2018 
 
STATISTICAL CONSIDERATIONS 
 
Responsibility for Analysis 
The statistical analysis of the data obtained from this study will be the responsibility of the 
SDCC. A separate statistical analysis plan will be written and finalized prior to the clinical 
database lock.  
 
Study Hypotheses 
10.2.1 
Primary Hypothesis 
For the primary objective, the hypothesis is that Pretomanid PK parameters following drug 
exposure will differ between patients with hepatic impairment and non-hepatically impaired 
controls.   
10.2.2 
Secondary Hypotheses 
No formal hypothesis will be tested for the secondary safety analyses.  
 
Sample Size Considerations 
The sample size was determined based on feasibility and FDA guidance (18). Following FDA 
guidance, enrollment is anticipated to include at least 6 subjects in each arm. This sample size is 
expected to estimate the group differences with adequate precision. Previous studies of 
Pretomanid have estimated coefficients of variation (CV) of <21% after 250 mg dosing (N=8) 
and <33% after 200 mg dosing (N=6) for single dose AUC(0-∞) and Cmax in healthy adult 
subjects (10). Assuming an observed two-fold difference between the group with severe hepatic 
impairment and matched controls with no correlation between matched pairs and a coefficient of 
variation of 25%, a 90% confidence interval for the fold difference between severely impaired 
and non-hepatically impaired group is (1.55, 2.59). 
 
Treatment Assignment Procedures 
10.4.1 
Randomization Procedures 
There is no randomization performed for this study. Subjects are assigned to the 4 study groups 
based on the Child-Pugh score, with approximately 6 subjects in each of the hepatic impairment 


DMID Protocol 13-0053  
Version 7.0 
Pretomanid in Adults with Hepatic Impairment 
19 October 2022 
________________________________________________________________________________________________________ 
 
DMID/NIAID/NIH 
79 
CONFIDENTIAL 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 15, 2018 
groups (Groups 1, 2, and 3) and approximately 18 non-hepatically impaired subjects in Group 4. 
The group designations are: 
Group 1: Child-Pugh A (Mild) 
Group 2: Child-Pugh B (Moderate) 
Group 3: Child-Pugh C (Severe) 
Group 4: Non-hepatically impaired controls  
Subjects with hepatic impairment will be enrolled starting with subjects who have mild disease. 
Subjects with moderate and severe hepatic disease will be enrolled simultaneously.  If enrollment 
into the severe hepatic impairment group (Child-Pugh C) is completed before that of the 
moderate hepatic impairment group (Child-Pugh B), results from the Child-Pugh C cohort will 
be analyzed to determine the impact of severe hepatic impairment on the PK of Pretomanid and 
the need to continue enrollment of persons with moderate hepatic impairment (Child-Pugh B) 
will be reevaluated to determine whether the objectives of the study have been met.  Non-
hepatically impaired subject matches will be dosed only after the corresponding subject with 
hepatic impairment has completed the 36-hour blood sampling procedure. The group of up to 18 
subjects with normal hepatic function will be matched to the 18 subjects with hepatic impairment 
based on age (± 10 years) and body weight at screening (± 20% body weight). A control subject 
may be matched to more than one hepatic impairment subject if warranted, and if the subjects to 
which they are matched are not in the same disease severity group. Therefore, there may be less 
than 18 subjects with normal hepatic function.  
10.4.2 
Masking Procedures 
Not applicable; this is an open-label study. 
 
Planned Interim Analyses 
10.5.1 
SMC Safety Review  
Two SMC interim safety reviews are planned. 
1. After 3 subjects in Group 1 (Child-Pugh A (Mild)) are enrolled and complete follow-up 
through Day 12 (Visit 05). This review will be completed prior to opening enrollment for 
Group 2 (Child-Pugh B (Moderate) and Group 3 (Child-Pugh C (Severe)). Enrollment in 
Group 1 and Group 4 may continue during the safety review. 


DMID Protocol 13-0053  
Version 7.0 
Pretomanid in Adults with Hepatic Impairment 
19 October 2022 
________________________________________________________________________________________________________ 
 
DMID/NIAID/NIH 
80 
CONFIDENTIAL 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 15, 2018 
2. After 3 subjects in Group 2 (Child-Pugh B (Moderate)) or Group 3 (Child-Pugh C (Severe)) 
are enrolled and complete follow-up through Day 12 (Visit 05). Enrollment of Group 2, 
Group 3, and Group 4 may continue during the safety review. 
Each interim safety review will present data by cohort, including AEs, SAEs, clinical laboratory 
tests, vital signs, PK analysis and 12-lead ECG. Cumulative data for all subjects enrolled will be 
included in the safety reviews. 
Interim safety reviews will not include any statistical hypothesis testing. 
 
Analysis Plan 
10.6.1 
Analysis Sets 
The following analysis sets are defined for the analysis and reporting of data. 
10.6.2 
Safety Analysis Set 
The safety analysis set will include all participants who receive study product. 
10.6.3 
PK Analysis Set 
The PK analysis set will consist of participants in the safety population who have evaluable 
plasma PK samples for the estimation of Cmax or AUC (0-∞). This set will be used to assess the 
PK endpoints. Any subjects or data values excluded from this analysis set will be identified, 
along with their reason for exclusion, in the CSR. 
10.6.4 
Primary PK Analysis 
All PK parameters will be estimated through a non-compartmental analysis using a validated 
installation of WinNonlin version 6.3 or later. The recorded true time points will be used for PK 
calculation. Estimated total plasma PK parameters will include the following:  
• AUC(0-∞): Area under the concentration time-curve extrapolated to infinity 
• AUC(0-last): Area under the concentration time-curve to the last concentration above the 
lower limit of quantitation 
• Cmax: Maximum concentration 
• Tmax: Time of maximum concentration 
• t(1/2): Apparent terminal elimination half-life 
• CL/F: Apparent oral clearance calculated from Dose/AUC(0-∞) 


DMID Protocol 13-0053  
Version 7.0 
Pretomanid in Adults with Hepatic Impairment 
19 October 2022 
________________________________________________________________________________________________________ 
 
DMID/NIAID/NIH 
81 
CONFIDENTIAL 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 15, 2018 
• Vd/F: Apparent Volume of Distribution  
Details of the statistical analysis will be included in the statistical analysis plan and may not be 
limited to the following: Hepatic impairment group means of drug exposure will be estimated 
through analysis of variance (ANOVA) models with impairment group as a fixed effected for the 
log-transformed estimated parameters. If the PK analysis set contains a matched control for each 
participant in all impairment groups, correlation between these matched pairs will be 
incorporated into the ANOVA model. Pairwise fold differences in drug exposure will be 
calculated to compare each of the mild, moderate, and severe impairment groups with non-
hepatically impaired controls. Fold differences will be estimated using 90% confidence intervals. 
Tmax will be summarized in each group using the median and range, and group differences will 
be assessed using nonparametric confidence intervals. 
Linear and semilogarithmic concentration-time profiles will also be plotted by impairment and 
non-hepatically impaired groups. Calculated PK parameters will be summarized using standard 
summary statistics (such as mean, median, standard deviation, coefficient of variation, or range) 
by impairment and non-hepatically impaired groups. 
10.6.5 
Secondary Safety Analyses 
The safety analysis will be presented using the safety analysis set. No formal hypothesis testing 
will be conducted.  
10.6.5.1 
Adverse Events 
Adverse events will be coded using Medical Dictionary for Regulatory Activities® (MedDRA). 
All AEs that occur after the receipt of study product will be summarized using frequency counts 
and percentages. Summaries will be presented by hepatic impairment and non-hepatically 
impaired groups MedDRA level hierarchy (system organ class and preferred term) as follows:  
• Overall (i.e., regardless of severity or relationship to treatment) 
• By severity grade (mild, moderate, or severe) 
• By relationship to study product 
Unless otherwise specified, at each level of subject summarization in reporting the incidence of 
the AEs, a subject will be counted once if the subject 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. 


DMID Protocol 13-0053  
Version 7.0 
Pretomanid in Adults with Hepatic Impairment 
19 October 2022 
________________________________________________________________________________________________________ 
 
DMID/NIAID/NIH 
82 
CONFIDENTIAL 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 15, 2018 
Serious AEs (SAEs) will also be summarized by hepatic impairment group and non-hepatically 
impaired group and relationship.  
10.6.5.2 
Laboratory Parameters 
Descriptive summary statistics for laboratory data at admission, Day 2, Day 5, Day 12, and 
change from admission for each post-treatment day will be presented by hepatic impairment and 
non-hepatically impaired groups. For change from admission summaries, subjects with an 
undefined change from admission, because of missing data, will be excluded. Shift tables, 
showing individual subject changes from admission to Days 2, 5, and 12 will be presented for 
each laboratory parameter, by hepatic impairment and non-hepatically impaired groups, using 
the normal ranges from the central laboratory. Subjects with clinically significant outliers will be 
identified in listings. Of note, if screening laboratory tests are performed within 72 hours of 
admission to the confinement/hospital unit, the tests do not have to be repeated with the 
exception of the urine pregnancy test for females of childbearing potential and the urine drug 
screen for all subjects, which will be repeated. 
10.6.5.3 
Vital Signs 
Descriptive summary statistics of vital signs at admission (Day -1), at Day 1 pre-dose and each 
post-dose time point (both absolute and change) will be summarized by hepatic impairment 
group and non-hepatically impaired group. For change from pre-dose summaries, subjects with 
an undefined change from pre-dose, because of missing data, will be excluded. 
10.6.5.4 
ECG Data 
ECG intervals (RR, QRS, QT, and PR) will be summarized at the day of admission and Day 12 
using descriptive statistics. 
In addition, the proportion of subjects with bradycardia, tachycardia, conduction system disease 
(e.g., prolongation of the PR Interval, bundle branch block, fascicular block), arrhythmia (e.g., 
atrial fibrillation, atrial flutter, premature atrial/ventricular contractions, ventricular tachycardia), 
and Brugada pattern will be summarized by hepatic impairment group. 


DMID Protocol 13-0053  
Version 7.0 
Pretomanid in Adults with Hepatic Impairment 
19 October 2022 
________________________________________________________________________________________________________ 
 
DMID/NIAID/NIH 
83 
CONFIDENTIAL 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 15, 2018 
10.6.6 
Demographics and Screening Summaries 
Demographic variables (age, gender, race, and ethnicity) and screening characteristics (height, 
weight) will be summarized by hepatic impairment and non-hepatically 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 is measured at specified 
subsequent visits and therefore will be summarized for all available post-dose visits, in addition 
to screening.  


DMID Protocol 13-0053  
Version 7.0 
Pretomanid in Adults with Hepatic Impairment 
19 October 2022 
________________________________________________________________________________________________________ 
 
DMID/NIAID/NIH 
84 
CONFIDENTIAL 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 15, 2018 
 
SOURCE DOCUMENTS AND ACCESS TO SOURCE 
DATA/DOCUMENTS 
The participating VTEU site will maintain appropriate medical and research records for this trial, 
in compliance with ICH E6, Section 4.9, and regulatory and institutional requirements for the 
protection of confidentiality of subjects. The participating VTEU 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 study records for the purposes of quality 
assurance reviews, audits, monitoring and evaluation of the study safety and progress. These 
representatives will be permitted access to all source data, which include, but are not limited to, 
hospital records, clinical and office charts, laboratory notes, memoranda, evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies or transcriptions 
certified after verification as being accurate and complete, microfiches, photographic negatives, 
microfilm or magnetic media, x-rays, and subject files and records kept at the pharmacy, at the 
laboratories, and medico-technical departments involved in the clinical trial. Source data are all 
information, original records of clinical findings, observations, or other activities in a clinical 
trial necessary for the reconstruction and evaluation of the trial. 


DMID Protocol 13-0053  
Version 7.0 
Pretomanid in Adults with Hepatic Impairment 
19 October 2022 
________________________________________________________________________________________________________ 
 
DMID/NIAID/NIH 
85 
CONFIDENTIAL 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 15, 2018 
 
QUALITY CONTROL AND QUALITY ASSURANCE 
Following a written DMID-accepted site quality management plan, the participating VTEU site 
is responsible for conducting routine quality assurance (QA) and quality control (QC) activities 
to internally monitor study progress and protocol compliance. The site principal investigator will 
provide direct access to all trial-related source data/data collection forms, and reports for the 
purpose of monitoring and auditing by the Sponsor, and inspection by local and regulatory 
authorities. The site principal investigator will ensure all study personnel are appropriately 
trained and applicable documentations are maintained on site. 
The SDCC will implement quality control procedures beginning with the data entry system and 
generate data quality control checks that will be run on the database. Any missing data or data 
anomalies will be communicated to the site(s) for clarification and resolution. 
 


DMID Protocol 13-0053  
Version 7.0 
Pretomanid in Adults with Hepatic Impairment 
19 October 2022 
________________________________________________________________________________________________________ 
 
DMID/NIAID/NIH 
86 
CONFIDENTIAL 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 15, 2018 
 
DATA HANDLING AND RECORD KEEPING 
The site principal investigator is responsible to ensure the accuracy, completeness, legibility, and 
timeliness of the data reported. 
The SDCC will provide data collection forms to be used by the site as source documents. All 
data collection forms should be completed in a neat, legible manner to ensure accurate 
interpretation of data. Black or blue ink is required to ensure clarity of reproduced copies. When 
making a change or correction, cross out the original entry with a single line and initial and date 
the change. Do not erase, overwrite, or use correction fluid or tape on the original. 
Data reported in the eCRF derived from the data collection forms should be consistent with the 
data collection forms or the discrepancies should be explained. The Sponsor and/or its designee 
will provide guidance to site principal investigators and other study personnel on making 
corrections to the data collection forms and eCRF. 
 
Data Management Responsibilities 
All data collection forms, and laboratory reports must be reviewed by the clinical team and data 
entry personnel, who will ensure that they are accurate and complete. Adverse events must be 
recorded on the appropriate data collection form, assessed for severity and relationship, and 
reviewed by the site principal investigator or appropriate sub-investigator. 
Data collection is the responsibility of the study personnel at the participating VTEU site under 
the supervision of the respective site principal investigator. During the study, the site principal 
investigator must maintain complete and accurate documentation for the study. 
The SDCC for this study will be responsible for data management, quality review, analysis, and 
reporting of the study data. 
 
Data Coordinating Center/Biostatistician Responsibilities 
Data collection is the responsibility of the study personnel at the participating clinical study site 
under the supervision of the site principal investigator.  During the study, the site principal 
investigator must maintain complete and accurate documentation for the study. 
The data coordinating center for this study will be responsible for data management, quality 
review, analysis, and reporting of the study data. 


DMID Protocol 13-0053  
Version 7.0 
Pretomanid in Adults with Hepatic Impairment 
19 October 2022 
________________________________________________________________________________________________________ 
 
DMID/NIAID/NIH 
87 
CONFIDENTIAL 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 15, 2018 
 
Data Capture Methods 
Clinical data (including, but not limited to, AE/SAEs, concomitant medications, medical history, 
physical assessments, and clinical laboratory values) and PK data will be entered into a 21 CFR 
11-compliant Internet Data Entry System (IDES) 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. Clinical data will be entered 
directly from the data collection forms completed by the study personnel. 
 
Types of Data 
Data for this study will include safety and outcome measures (e.g., clinical and PK data). 
 
Timing/Reports 
A final report will be prepared following the availability of the cumulative safety and PK data at 
the completion of the study. Interim statistical reports may be generated as deemed necessary 
and appropriate by DMID. Safety summary reports may be generated for the SMC. 
 
Study Records Retention 
Study records and reports, including but not limited to eCRFs, source documents, informed 
consent/assent forms), laboratory test results, and medication inventory records, shall be retained 
for at least six years after the study is completed, but no less than 2 years after a marketing 
application is approved for the drug; or, if an application is not approved for the drug, until 
2 years after shipment and delivery of the drug for investigational use is discontinued and FDA 
has been so notified. The site must contact DMID for authorization prior to the destruction of 
any study records. 
 


DMID Protocol 13-0053  
Version 7.0 
Pretomanid in Adults with Hepatic Impairment 
19 October 2022 
________________________________________________________________________________________________________ 
 
DMID/NIAID/NIH 
88 
CONFIDENTIAL 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 15, 2018 
 
CLINICAL MONITORING 
 
Site Monitoring Plan  
Site monitoring is conducted to ensure that the human subject 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 the study 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, informed consent/assent forms, medical and 
laboratory reports, and protocol and GCP compliance. Site monitors will have access to the study 
site, study personnel, and all study documentation according to the DMID-approved monitoring 
plan. Study monitors will meet with site principal investigators to discuss any problems and 
actions to be taken and document visit findings and discussions. 
 
 
 


DMID Protocol 13-0053  
Version 7.0 
Pretomanid in Adults with Hepatic Impairment 
19 October 2022 
________________________________________________________________________________________________________ 
 
DMID/NIAID/NIH 
89 
CONFIDENTIAL 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 15, 2018 
 
PUBLICATION POLICY 
All investigators funded by the NIH must submit or have submitted for them to the National 
Library of Medicine’s PubMed Central (http://www.ncbi.nlm.nih.gov/pmc/) an electronic 
version of their final, peer-reviewed manuscripts upon acceptance for publication, to be made 
publicly available no later than 12 months after the official date of publication. The NIH Public 
Access Policy ensures the public has access to the published results of NIH funded research. It 
requires investigators to submit final peer-reviewed journal manuscripts that arise from NIH 
funds to the digital archive PubMed Central upon acceptance for publication. Further, the policy 
stipulates that these papers must be accessible to the public on PubMed Central no later than 12 
months after publication. 
Refer to: 
• NIH Public Access Policy, http://publicaccess.nih.gov/ 
• NIH OER Grants and Funding, http://grants.nih.gov/grants/oer.htm 
Following completion of the study, the lead principal investigator is expected to publish the 
results of this research in a scientific journal. The International Committee of Medical Journal 
Editors (ICMJE) member journals have adopted a trials-registration policy as a condition for 
publication. This policy requires that all clinical trials be registered in a public trials registry such 
as ClinicalTrials.gov* (http://clinicaltrials.gov/), which is sponsored by the National Library of 
Medicine. Other biomedical journals are considering adopting similar policies. 
The ICMJE defines a clinical trial as any research project that prospectively assigns human 
subjects to intervention or comparison groups to study the cause-and-effect relationship between 
a medical intervention and a health outcome. Studies designed for other purposes, such as to 
study pharmacokinetics or major toxicity (e.g., Phase I trials), would be exempt from this policy. 
As this is a Phase I study, it is exempt from this policy.  
It is the responsibility of DMID to register this trial in an acceptable registry. Any clinical trial 
starting enrollment after 01 July 2005 must be registered on or before subject enrollment. For 
trials that began enrollment prior to this date, the ICMJE member journals will require 
registration, before considering the results of the trial for publication. 
For trials in which DMID is not the IND/IDE Sponsor, or there is no IND/IDE, and DMID does 
not provide data management services, it is the responsibility of the investigator to register the 
trial and post results in compliance with Public Law 110-85, the Food and Drug Administration 


DMID Protocol 13-0053  
Version 7.0 
Pretomanid in Adults with Hepatic Impairment 
19 October 2022 
________________________________________________________________________________________________________ 
 
DMID/NIAID/NIH 
90 
CONFIDENTIAL 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 15, 2018 
Amendments Act of 2007 (FDAAA). However, this is an IND study, and DMID is the IND 
sponsor.  
Refer to: 
• Public Law 110-85, Section 801, Clinical Trial Databases 
*Journal Citation: De Angelis C, Drazen JM, Frizelle FA, Haug C, Hoey J, Horton R, et al. Clinical trial registration: a statement 
from the International Committee of Medical Journal Editors. N Engl J Med. 2004; 351:1250-1 


DMID Protocol 13-0053  
Version 7.0 
Pretomanid in Adults with Hepatic Impairment 
19 October 2022 
________________________________________________________________________________________________________ 
 
DMID/NIAID/NIH 
91 
CONFIDENTIAL 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 15, 2018 
 
LITERATURE REFERENCES 
1. 
Organization WH. Global Tuberculosis Report2016. 
2. 
Murray CJ, Ortblad KF, Guinovart C, Lim SS, Wolock TM, Roberts DA, Dansereau EA, 
Graetz N, Barber RM, Brown JC, Wang H, Duber HC, Naghavi M, Dicker D, Dandona L, 
Salomon JA, Heuton KR, Foreman K, Phillips DE, Fleming TD, Flaxman AD, Phillips BK, 
Johnson EK, Coggeshall MS, Abd-Allah F, Abera SF, Abraham JP, Abubakar I, Abu-Raddad LJ, 
Abu-Rmeileh NM, Achoki T, Adeyemo AO, Adou AK, Adsuar JC, Agardh EE, Akena D, Al 
Kahbouri MJ, Alasfoor D, Albittar MI, Alcala-Cerra G, Alegretti MA, Alemu ZA, Alfonso-
Cristancho R, Alhabib S, Ali R, Alla F, Allen PJ, Alsharif U, Alvarez E, Alvis-Guzman N, 
Amankwaa AA, Amare AT, Amini H, Ammar W, Anderson BO, Antonio CA, Anwari P, Arnlov 
J, Arsenijevic VS, Artaman A, Asghar RJ, Assadi R, Atkins LS, Badawi A, Balakrishnan K, 
Banerjee A, Basu S, Beardsley J, Bekele T, Bell ML, Bernabe E, Beyene TJ, Bhala N, Bhalla A, 
Bhutta ZA, Abdulhak AB, Binagwaho A, Blore JD, Basara BB, Bose D, Brainin M, Breitborde 
N, Castaneda-Orjuela CA, Catala-Lopez F, Chadha VK, Chang JC, Chiang PP, Chuang TW, 
Colomar M, Cooper LT, Cooper C, Courville KJ, Cowie BC, Criqui MH, Dandona R, Dayama 
A, De Leo D, Degenhardt L, Del Pozo-Cruz B, Deribe K, Des Jarlais DC, Dessalegn M, 
Dharmaratne SD, Dilmen U, Ding EL, Driscoll TR, Durrani AM, Ellenbogen RG, Ermakov SP, 
Esteghamati A, Faraon EJ, Farzadfar F, Fereshtehnejad SM, Fijabi DO, Forouzanfar MH, Fra 
Paleo U, Gaffikin L, Gamkrelidze A, Gankpe FG, Geleijnse JM, Gessner BD, Gibney KB, 
Ginawi IA, Glaser EL, Gona P, Goto A, Gouda HN, Gugnani HC, Gupta R, Hafezi-Nejad N, 
Hamadeh RR, Hammami M, Hankey GJ, Harb HL, Haro JM, Havmoeller R, Hay SI, Hedayati 
MT, Pi IB, Hoek HW, Hornberger JC, Hosgood HD, Hotez PJ, Hoy DG, Huang JJ, Iburg KM, 
Idrisov BT, Innos K, Jacobsen KH, Jeemon P, Jensen PN, Jha V, Jiang G, Jonas JB, Juel K, Kan 
H, Kankindi I, Karam NE, Karch A, Karema CK, Kaul A, Kawakami N, Kazi DS, Kemp AH, 
Kengne AP, Keren A, Kereselidze M, Khader YS, Khalifa SE, Khan EA, Khang YH, 
Khonelidze I, Kinfu Y, Kinge JM, Knibbs L, Kokubo Y, Kosen S, Defo BK, Kulkarni VS, 
Kulkarni C, Kumar K, Kumar RB, Kumar GA, Kwan GF, Lai T, Balaji AL, Lam H, Lan Q, 
Lansingh VC, Larson HJ, Larsson A, Lee JT, Leigh J, Leinsalu M, Leung R, Li Y, De Lima GM, 
Lin HH, Lipshultz SE, Liu S, Liu Y, Lloyd BK, Lotufo PA, Machado VM, Maclachlan JH, 
Magis-Rodriguez C, Majdan M, Mapoma CC, Marcenes W, Marzan MB, Masci JR, Mashal MT, 
Mason-Jones AJ, Mayosi BM, Mazorodze TT, McKay AC, Meaney PA, Mehndiratta MM, 
Mejia-Rodriguez F, Melaku YA, Memish ZA, Mendoza W, Miller TR, Mills EJ, Mohammad 
KA, Mokdad AH, Mola GL, Monasta L, Montico M, Moore AR, Mori R, Moturi WN, 
Mukaigawara M, Murthy KS, Naheed A, Naidoo KS, Naldi L, Nangia V, Narayan KM, Nash D, 
Nejjari C, Nelson RG, Neupane SP, Newton CR, Ng M, Nisar MI, Nolte S, Norheim OF, 
Nowaseb V, Nyakarahuka L, Oh IH, Ohkubo T, Olusanya BO, Omer SB, Opio JN, Orisakwe 
OE, Pandian JD, Papachristou C, Caicedo AJ, Patten SB, Paul VK, Pavlin BI, Pearce N, Pereira 


DMID Protocol 13-0053  
Version 7.0 
Pretomanid in Adults with Hepatic Impairment 
19 October 2022 
________________________________________________________________________________________________________ 
 
DMID/NIAID/NIH 
92 
CONFIDENTIAL 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 15, 2018 
DM, Pervaiz A, Pesudovs K, Petzold M, Pourmalek F, Qato D, Quezada AD, Quistberg DA, 
Rafay A, Rahimi K, Rahimi-Movaghar V, Ur Rahman S, Raju M, Rana SM, Razavi H, Reilly 
RQ, Remuzzi G, Richardus JH, Ronfani L, Roy N, Sabin N, Saeedi MY, Sahraian MA, Samonte 
GM, Sawhney M, Schneider IJ, Schwebel DC, Seedat S, Sepanlou SG, Servan-Mori EE, 
Sheikhbahaei S, Shibuya K, Shin HH, Shiue I, Shivakoti R, Sigfusdottir ID, Silberberg DH, 
Silva AP, Simard EP, Singh JA, Skirbekk V, Sliwa K, Soneji S, Soshnikov SS, Sreeramareddy 
CT, Stathopoulou VK, Stroumpoulis K, Swaminathan S, Sykes BL, Tabb KM, Talongwa RT, 
Tenkorang EY, Terkawi AS, Thomson AJ, Thorne-Lyman AL, Towbin JA, Traebert J, Tran BX, 
Dimbuene ZT, Tsilimbaris M, Uchendu US, Ukwaja KN, Uzun SB, Vallely AJ, Vasankari TJ, 
Venketasubramanian N, Violante FS, Vlassov VV, Vollset SE, Waller S, Wallin MT, Wang L, 
Wang X, Wang Y, Weichenthal S, Weiderpass E, Weintraub RG, Westerman R, White RA, 
Wilkinson JD, Williams TN, Woldeyohannes SM, Wong JQ, Xu G, Yang YC, Yano Y, Yentur 
GK, Yip P, Yonemoto N, Yoon SJ, Younis M, Yu C, Jin KY, El Sayed Zaki M, Zhao Y, Zheng 
Y, Zhou M, Zhu J, Zou XN, Lopez AD, Vos T. Global, regional, and national incidence and 
mortality for HIV, tuberculosis, and malaria during 1990-2013: a systematic analysis for the 
Global Burden of Disease Study 2013. Lancet. 2014;384(9947):1005-70. Epub 2014/07/26. doi: 
10.1016/S0140-6736(14)60844-8 
S0140-6736(14)60844-8 [pii]. PubMed PMID: 25059949. 
3. 
Organization WH. Global tuberculosis report (2012). Geneva, Switzerland: 2012. 
4. 
Comstock GW. Epidemiology of tuberculosis. Am Rev Respir Dis. 1982;125(3 Pt 2):8-
15. Epub 1982/03/01. PubMed PMID: 7073104. 
5. 
Maggi N, Pasqualucci CR, Ballotta R, Sensi P. Rifampicin: a new orally active rifamycin. 
Chemotherapy. 1966;11(5):285-92. Epub 1966/01/01. PubMed PMID: 5958716. 
6. 
Organization WH. Treatment of tuberculosis. Guidelines for national programmes, 3rd 
ed. Geneva, Switzerland2003. Available from: 
http://www.who.int/tb/publications/2008/en/index.html. 
7. 
Diacon AH, Dawson R, Hanekom M, Narunsky K, Maritz SJ, Venter A, Donald PR, van 
Niekerk C, Whitney K, Rouse DJ, Laurenzi MW, Ginsberg AM, Spigelman MK. Early 
bactericidal activity and pharmacokinetics of PA-824 in smear-positive tuberculosis patients. 
Antimicrob Agents Chemother. 2010;54(8):3402-7. Epub 2010/05/26. doi: 10.1128/AAC.01354-
09 
AAC.01354-09 [pii]. PubMed PMID: 20498324; PMCID: 2916303. 


DMID Protocol 13-0053  
Version 7.0 
Pretomanid in Adults with Hepatic Impairment 
19 October 2022 
________________________________________________________________________________________________________ 
 
DMID/NIAID/NIH 
93 
CONFIDENTIAL 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 15, 2018 
8. 
Chang KC, Leung CC, Yew WW, Chan SL, Tam CM. Dosing schedules of 6-month 
regimens and relapse for pulmonary tuberculosis. Am J Respir Crit Care Med. 
2006;174(10):1153-8. Epub 2006/08/16. doi: 200605-637OC [pii] 
10.1164/rccm.200605-637OC. PubMed PMID: 16908866. 
9. 
Kruk ME, Schwalbe NR, Aguiar CA. Timing of default from tuberculosis treatment: a 
systematic review. Trop Med Int Health. 2008;13(5):703-12. Epub 2008/02/13. doi: 
10.1111/j.1365-3156.2008.02042.x 
TMI2042 [pii]. PubMed PMID: 18266783. 
10. 
Caminero JA, Sotgiu G, Zumla A, Migliori GB. Best drug treatment for multidrug-
resistant and extensively drug-resistant tuberculosis. Lancet Infect Dis. 2010;10(9):621-9. Epub 
2010/08/28. doi: 10.1016/S1473-3099(10)70139-0 
S1473-3099(10)70139-0 [pii]. PubMed PMID: 20797644. 
11. 
Ginsberg AM, Laurenzi MW, Rouse DJ, Whitney KD, Spigelman MK. Safety, 
tolerability, and pharmacokinetics of PA-824 in healthy subjects. Antimicrob Agents Chemother. 
2009;53(9):3720-5. Epub 2009/06/17. doi: 10.1128/AAC.00106-09 
AAC.00106-09 [pii]. PubMed PMID: 19528280; PMCID: 2737845. 
12. 
Diacon AH, Dawson R, du Bois J, Narunsky K, Venter A, Donald PR, van Niekerk C, 
Erondu N, Ginsberg AM, Becker P, Spigelman MK. Phase II dose-ranging trial of the early 
bactericidal activity of PA-824. Antimicrob Agents Chemother. 2012;56(6):3027-31. Epub 
2012/03/21. doi: 10.1128/AAC.06125-11 
AAC.06125-11 [pii]. PubMed PMID: 22430968; PMCID: 3370777. 
13. 
Diacon AH, Dawson R, von Groote-Bidlingmaier F, Symons G, Venter A, Donald PR, 
van Niekerk C, Everitt D, Winter H, Becker P, Mendel CM, Spigelman MK. 14-day bactericidal 
activity of PA-824, bedaquiline, pyrazinamide, and moxifloxacin combinations: a randomised 
trial. Lancet. 2012;380(9846):986-93. Epub 2012/07/26. doi: 10.1016/S0140-6736(12)61080-0 
S0140-6736(12)61080-0 [pii]. PubMed PMID: 22828481. 


DMID Protocol 13-0053  
Version 7.0 
Pretomanid in Adults with Hepatic Impairment 
19 October 2022 
________________________________________________________________________________________________________ 
 
DMID/NIAID/NIH 
94 
CONFIDENTIAL 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 15, 2018 
14. 
Ginsberg AM, Laurenzi MW, Rouse DJ, Whitney KD, Spigelman MK. Assessment of 
the effects of the nitroimidazo-oxazine PA-824 on renal function in healthy subjects. Antimicrob 
Agents Chemother. 2009;53(9):3726-33. Epub 2009/06/17. doi: 10.1128/AAC.00112-09 
AAC.00112-09 [pii]. PubMed PMID: 19528286; PMCID: 2737878. 
15. 
Song IH, Borland, J., Savina, P.M., Shuguang, C., Parul, P., Toshihiro, W., Peppercorn, 
A.F., Piscitelli, S.C. Pharmacokinetics of Single-Dose Dolutegravir in HIV-Seronegative 
Subjects With Moderate Hepatic Impairment Compared to Healthy Matched Controls. Clinical 
Pharmacology in Drug Development. 2013;2(4):342-8. 
16. 
Kasichayanula S, Liu X, Zhang W, Pfister M, LaCreta FP, Boulton DW. Influence of 
hepatic impairment on the pharmacokinetics and safety profile of dapagliflozin: an open-label, 
parallel-group, single-dose study. Clin Ther. 2011;33(11):1798-808. Epub 2011/10/28. doi: 
10.1016/j.clinthera.2011.09.011 
S0149-2918(11)00619-9 [pii]. PubMed PMID: 22030444. 
17. 
Yin OQ, Gallagher N, Tanaka C, Fisher D, Sethuraman V, Zhou W, Lin TH, Heuman D, 
Schran H. Effects of hepatic impairment on the pharmacokinetics of nilotinib: an open-label, 
single-dose, parallel-group study. Clin Ther. 2009;31 Pt 2:2459-69. Epub 2010/01/30. doi: 
10.1016/j.clinthera.2009.11.015 
S0149-2918(09)00405-6 [pii]. PubMed PMID: 20110053. 
18. 
FDA. Guidance for Industry: Pharmacokinetics in Patients with Impaired Hepatic 
Function: Study Design, Data Analysis, and Impact on Dosing and Labeling. 2003. Available 
from: 
http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm
072123.pdf. 
 


DMID Protocol 13-0053  
Version 7.0 
Pretomanid in Adults with Hepatic Impairment 
19 October 2022 
________________________________________________________________________________________________________ 
 
DMID/NIAID/NIH 
95 
CONFIDENTIAL 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
 
 
APPENDICES 
 
 


DMID Protocol 13-0053  
Version 7.0 
Pretomanid in Adults with Hepatic Impairment 
19 October 2022 
________________________________________________________________________________________________________ 
 
DMID/NIAID/NIH 
96 
CONFIDENTIAL 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
 
  Schedule of Events  
Study Visit  
00A  
00B  
01  
01
A  
01
B  
01
C  
01
D  
01
E  
01
F 
01
G 
01
H 
0
1I  
01J  
0
2  
0
3  
0
4  
0
5  
Early 
Term  
Study Day  
Screen          
-22 to -2 
Admission -1 
 
1  
 
1  
 
1  
 
1  
 
1  
 
1  
 
1 
 
1  
 
1 
 
2  
 
2  
 
3  
 
4  
 
5  
 
1
2  
 
Time (Window)  
 
 
0  
 (-10 min)  
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 hrs (+/-10 
min) 
16 hr (+/-10 min) 
24 hrs (+/-1 hr)  
36 hrs (+/-1 
 hr) 
48 hrs (+/-4 hrs)  
72 hrs (+/-4 hrs) 
96 hrs (+/-4 hrs)  
 
 
Informed 
Consent  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review 
Inclusion/ 
Exclusion 
Criteria  
X  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics
1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/Surgic
al History2  
X  
X 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
Physical 
Examination3  
X  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Targeted 
Review of 
Body 
Systems12 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
Concomitant 
Medication  
X  
X  
 
 
 
 
 
 
 
 
 
 
 
X  
X  
X  
X 
X 
12-Lead ECG 
(Resting) 
X  
X 1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X  
Vital Signs6  
X  
X  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X  
X  
X  
X  
Safety 
Laboratory 
Testing 
(Hematology, 
Chemistry)9,11  
X4  
X 13 
 
 
 
 
 
 
 
 
 
 
X10 
  
  
X  
X  
Coagulation9  
X4 
X 13 
 
 
 
 
 
 
 
 
 
 
X10 
 
 
X 
X  
Urinalysis9  
X4  
X 13 
 
 
 
 
 
 
 
 
 
 
X10 
  
 
X  
X  
Pregnancy 
Test9  
X4  
X 13 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Drug and 
Alcohol Screen 
5,8  
X4  
X   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood for HIV, 
HCV, HBsAg 
testing8 
X4  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood for PK 
Sampling7  
 
 
 
X 
 
X  
 
X  
 
X  
 
X  
 
X  
 
X 
 
X  
 
X 
 
X  
 
X  
 
X  
 
X  
 
X  
 
 
 
1  


DMID Protocol 13-0053  
Version 7.0 
Pretomanid in Adults with Hepatic Impairment 
19 October 2022 
________________________________________________________________________________________________________ 
 
DMID/NIAID/NIH 
97 
CONFIDENTIAL 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
 
Study Visit  
00A  
00B  
01  
01
A  
01
B  
01
C  
01
D  
01
E  
01
F 
01
G 
01
H 
0
1I  
01J  
0
2  
0
3  
0
4  
0
5  
Early 
Term  
Study Day  
Screen          
-22 to -2 
Admission -1 
 
1  
 
1  
 
1  
 
1  
 
1  
 
1  
 
1 
 
1  
 
1 
 
2  
 
2  
 
3  
 
4  
 
5  
 
1
2  
 
Time (Window)  
 
 
0  
 (-10 min)  
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 hrs (+/-10 
min) 
16 hr (+/-10 min) 
24 hrs (+/-1 hr)  
36 hrs (+/-1 
 hr) 
48 hrs (+/-4 hrs)  
72 hrs (+/-4 hrs) 
96 hrs (+/-4 hrs)  
 
 
Discharge 
from the 
confinement/h
ospital unit 14 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
 
 
Study 
Product 
Administratio
n7b  
 
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE 
Assessment  
 
 
X  
X  
X  
X  
X  
X  
X 
X  
X 
X  
X  
X  
X  
X  
X 
X 
SAE 
Assessment  
 
 
 
X  
 
X  
 
X  
 
X  
 
X  
 
X  
 
X 
 
X  
 
X 
 
X  
 
X  
 
X  
 
X  
 
X  
 
X 
 
X 
Total blood 
drawn  
27.5mL 
11.5mL 
6mL 
6mL 
6mL 
6mL 
6mL 
6mL 
6mL 
6mL 
6mL 
6mL 
17.5mL 
6mL 
6mL 
17.5mL 
14.5mL 
0mL 
 
1 
Child-Pugh Score calculated for hepatically-
impaired subjects at screening 
2 
Complete medical/surgical history taken at 
screening and interim medical/surgical history 
as sequent indicated visits.  
3 
Physical examination must include the 
following organ or body system assessments: 
skin; head, eyes, ears, nose, and throat; 
thyroid; neurological; chest and lungs; 
cardiovascular; abdomen (liver and spleen); 
lymph nodes; musculoskeletal, and 
extremities. At early termination visit, a 
physical examination will be performed.  
4 
If screening laboratory tests are performed 
within 72 hours of admission to the 
confinement/hospital unit, the tests do not 
have to be repeated with the exception of the 
urine pregnancy test for females of child 
bearing potential and the urine drug screen for 
all subjects, which will be repeated. 
5 
Alcohol screen includes alcohol breath test or 
other suitable test for alcohol (e.g., blood 
alcohol test). 
7 
Blood samples for pharmacokinetic 
assessments of Pretomanid will be 
obtained on Days 1 to 5 at the following 
time points: pre-dose and 1, 2, 4, 5, 6, 8, 
12, 16, 24, 36, 48, 72, and 96 hours post-
dose. 
a. 
The following collection windows are 
allowed for the PK blood sample time 
points: 
i. 
Pre-dose: -10 minutes 
ii. 
Dosing through 16 hours 
post-dose inclusive: 
 ± 10 minutes 
iii. 
24 and 36 hours post-dose: ± 
1 hour 
iv. 
48, 72, and 96 hours: ± 4 
hours 
b. 
Subjects will receive the single oral 
dose of Pretomanid 200 mg taken 
with 240 mL of water after overnight 
fast. 
c. The following parameters will be used 
for PK assessments: AUC0-inf, 
9 
Safety labs (also performed at screening 
and 2 hour fasting) include: total bilirubin, 
serum albumin, electrolytes including 
potassium, magnesium, and calcium 
levels, serum creatinine, BUN, alkaline 
phosphatase, AST, ALT, INR (PT 
prolongation), CBC w/differential, 
urinalysis, and pregnancy testing. 
Pregnancy testing at screening and Day 
12 will be serum, and testing at 
admission will be a urine test. 
10 Chemistry (2 hour fasting), hematology, 
coagulation and urinalysis to be done 
prior to discharge.  
11   For patients with severe hepatic 
impairment (Child-Pugh C) an ammonia 
level will be drawn at screening and will 
be used as a baseline reading for safety 
purposes, not as a study entry criterion. 
12  A targeted review of body systems will be 
obtained at these visits focused on liver 
disease and will include questions 
pertaining to development of ascites, 
jaundice, pruritis, gastrointestinal 
bleeding, and encephalopathy. If the 


DMID Protocol 13-0053  
Version 7.0 
Pretomanid in Adults with Hepatic Impairment 
19 October 2022 
________________________________________________________________________________________________________ 
 
DMID/NIAID/NIH 
98 
CONFIDENTIAL 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
 
6 
Vital sign measurements must include the 
subject’s sitting heart rate, sitting blood 
pressure (mm Hg), height (screening only), 
and oral body temperature (ºC). Vital signs will 
be obtained at screening, and on Days -1 to 
12 at the following time points:, admission day, 
prior to dosing, and 30 minutes after dosing, 1, 
2, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96 hours 
and Day 12. Weight will be collected at 
screening, admission day, prior to dosing, 36, 
48, 72, 96 hours and Day 12 time points. 
AUC0-t, Cmax, tmax, half-life and 
CL/F. 
8    Screening labs include: blood screen for 
hepatitis B surface    antigen (HBsAg) 
and hepatitis C antibody, alcohol breath 
test or other suitable test for alcohol 
(e.g., blood alcohol test),urine screen 
test for drugs of abuse [amphetamines, 
barbiturates, benzodiazepines, cocaine 
metabolites, opiates, cannabinoids, 
phencyclidine (PCP)] and a blood screen 
for HIV. 
 
subject answers yes to any of these 
questions, a targeted physical exam will 
be performed 
13 Baseline admissions labs and resting 12-
Lead ECG recording may be done within 
72 hours of admission or at the time of 
admission depending on ability to obtain 
lab results at the site.  
14 Discharge from confinement/hospital unit 
either after Visit 01J or Visit 2 depending 
upon site preference 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


DMID Protocol 13-0053  
Version 7.0 
Pretomanid in Adults with Hepatic Impairment 
19 October 2022 
________________________________________________________________________________________________________ 
 
DMID/NIAID/NIH 
99 
CONFIDENTIAL 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
 
 
Child-Pugh System 
Encephalopathy grade*  
None or 0 
1 or 2 
3 or 4 
Ascites  
Absent 
Slight 
Moderate 
Serum bilirubin (mg/dL)  
< 2 
2 - 3 
> 3 
Serum albumin (g/dL)  
> 3.5 
2.8 - 3.5 
< 2.8 
Prothrombin Time Prolongation (seconds over control) 
or [INR]  
< 4  
(INR < 1.7) 
4 - 6 
(INR 1.7 - 2.3) 
> 6 
(INR > 2.3) 
Points scored for observed finding 
1 
2 
3 
*Encephalopathy must be attributable to liver disease and graded according to present or historical data. If a 
subject with hepatic impairment is taking a pharmaceutical agent to control symptoms of liver disease (e.g., 
lactulose to reduce ammonia) the principal investigator may assign a score that is representative of the 
subject’s status without pharmaceutical intervention. This action will be clearly documented in the source 
documents and approved by the Sponsor’s medical monitor.  
Grade 0: normal consciousness, personality, neurological examination, and electroencephalogram (EEG)  
Grade 1: restless, sleep-disturbed, irritable/agitated, tremor, impaired handwriting, 5 cps waves on EEG  
Grade 2: lethargic, time-disoriented, inappropriate, asterixis, ataxia, slow triphasic waves on EEG 
Grade 3: somnolent, stuporous, place-disorientated, hyperactive reflexes, rigidity slower waves on EEG  
Grade 4: unarousable coma, no personality/behavior, decerebrate, slow 2-3 cps delta activity on EEG. 
 
Group 
Cumulative Score 
Child-Pugh Class 
Description 
1 
5-6 points 
A 
Mild hepatic impairment 
2 
7-9 points 
B 
Moderate hepatic impairment 
3 
10-15 points 
C 
Severe hepatic impairment 
References: 
1. Child CG, Turcotte JG. Surgery and portal hypertension. In: The liver and portal hypertension. Edited by CG 
Child. Philadelphia: Saunders 1964:50-64. 
2. Pugh RN, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R. Transection of the oesophagus for bleeding 
oesophageal varices. Br J Surg. 1973 Aug;60(8):646-9. 


DMID Protocol 13-0053  
Version 7.0 
Pretomanid in Adults with Hepatic Impairment 
19 October 2022 
________________________________________________________________________________________________________ 
 
DMID/NIAID/NIH 
100 
CONFIDENTIAL 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
 
 Toxicity Tables  
ABBREVIATIONS: 
Abbreviations utilized in the Table: 
ULN = Upper Limit of Normal 
Req = Required  
ADL = Activities of Daily 
Living 
LLN = Lower Limit of Normal  
Mod = Moderate 
 
Dec = Decreased  
Rx  = Therapy 
IV  = Intravenous  
 
 
ESTIMATING SEVERITY GRADE  
For abnormalities NOT found elsewhere in the Toxicity Tables use the scale below to estimate 
grade of severity:  
• GRADE 1: Mild   
Transient or mild discomfort  (< 48 hours); no medical 
intervention/therapy required  
• GRADE 2: Moderate   Mild to moderate limitation in activity - some assistance may be 
needed; no or minimal medical intervention/therapy required  
• GRADE 3: Severe   
 Marked limitation in activity, some assistance usually required; 
medical intervention/therapy required, hospitalizations possible  
 
 
 


DMID Protocol 13-0053  
Version 7.0 
Pretomanid in Adults with Hepatic Impairment 
19 October 2022 
________________________________________________________________________________________________________ 
 
DMID/NIAID/NIH 
101 
CONFIDENTIAL 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
 
 
Clinical Adverse Events 
 
VITAL SIGNS 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
 
Fever (°C) ** 
38.0 – 38.4 
38.5 – 38.9 
≥ 39.0 
** Oral 
temperature; 
no recent hot 
or cold 
beverages or 
smoking. A 
protocol 
should select 
either °C or 
°F for 
inclusion. 
 
(°F) ** 
100.4 – 101.1 
101.2 – 102.0 
≥ 102.1  
Tachycardia - 
beats per minute 
101 – 115 
116 – 130 
> 130 or 
ventricular 
dysrhythmias 
Bradycardia - 
beats per minute 
50 – 54 or 45-50 
bpm if pre-dose 
visit rate < 60 
bpm 
45 – 49 or 40-
44 if pre-dose 
visit rate < 
60bpm 
< 45 or  <40 bpm 
if pre-dose visit 
rate <60 bpm 
Hypertension 
(systolic)- mm Hg 
141-150 
151-160 
> 160 
Assume 
supine 
position for 
10 min at rest 
in non-
sleeping 
subjects; for 


DMID Protocol 13-0053  
Version 7.0 
Pretomanid in Adults with Hepatic Impairment 
19 October 2022 
________________________________________________________________________________________________________ 
 
DMID/NIAID/NIH 
102 
CONFIDENTIAL 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
 
adverse 
events, need 
three 
measurements 
on the same 
arm with 
concordant 
results. 
Hypertension 
(diastolic) - mm 
Hg 
91-95 
96-100 
> 100 
Hypotension 
(systolic) - mm Hg 
85-89 
80-84 
< 80 
Tachypnea – 
breaths per minute 
23-25 
26-30 
> 30 
 
 
 
 


DMID Protocol 13-0053  
Version 7.0 
Pretomanid in Adults with Hepatic Impairment 
19 October 2022 
________________________________________________________________________________________________________ 
 
DMID/NIAID/NIH 
103 
CONFIDENTIAL 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
 
CARDIOVASCULAR 
Grade 1 
Grade 2 
Grade 3 
Arrhythmia 
Asymptomat
ic, transient 
signs, no Rx 
required  
Recurrent/ 
persistent; 
symptomatic; Rx 
required  
Unstable dysrhythmia; 
hospitalization and treatment 
required 
Hemorrhage, Blood Loss 
Estimated 
blood loss < 
100 mL 
Estimated blood 
loss > 100 mL, 
no transfusion 
required 
Transfusion required  
QT/QTc prolongation 
Male: 
 441-470 
msec 
 
Female: 
451-470 
msec 
Male: 
471-500 msec 
 
Female: 
471-500 msec: 
> 500 msec 
 
OR 
 
> 60 msec change from 
admission visit  
 
RESPIRATORY 
Grade 1 
Grade 2 
Grade 3 
Cough 
Transient- no 
treatment 
Persistent cough; 
Interferes with daily 
activities 
Bronchospasm, Acute Transient; no 
treatment; 71% - 
80% FEV1 of peak 
flow  
Requires treatment; 
normalizes with 
bronchodilator; FEV1 
60% - 70% (of peak 
flow)  
No normalization 
with bronchodilator; 
FEV1 < 60% of 
peak flow 
Dyspnea 
Does not interfere 
with usual and social 
activities 
Interferes with usual 
and social activities, no 
treatment 
Prevents daily and 
usual social activity 
or requires 
treatment 


DMID Protocol 13-0053  
Version 7.0 
Pretomanid in Adults with Hepatic Impairment 
19 October 2022 
________________________________________________________________________________________________________ 
 
DMID/NIAID/NIH 
104 
CONFIDENTIAL 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
 
 
GASTROINTESTINAL Grade 1 
Grade 2 
Grade 3 
Nausea 
No interference with 
activity 
Some interference with 
activity 
Prevents daily 
activities 
Vomiting 
No interference with 
activity or 1 - 2 
episodes/24 hours 
Some interference with 
activity or > 2 
episodes/24 hours 
Prevents daily 
activity or 
requires IV 
hydration 
Diarrhea 
2 - 3 loose or watery 
stools or < 400 gms/24 
hours 
4 - 5 loose or watery 
stools or 400 - 800 
gms/24 hours 
6 or more 
loose or 
watery stools 
or > 
800gms/24 
hours or 
requires IV 
hydration 
 
 
 


DMID Protocol 13-0053  
Version 7.0 
Pretomanid in Adults with Hepatic Impairment 
19 October 2022 
________________________________________________________________________________________________________ 
 
DMID/NIAID/NIH 
105 
CONFIDENTIAL 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
 
Laboratory Adverse Events 
Blood, Serum, or 
Plasma * 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potassium – 
Hypokalemia 
mmol/L 
3.1 – <LLN 
2.7 – 3.0 
<2.7 
Potassium – 
Hyperkalemia 
mmol/L 
>ULN – 5.6 
6. – 6.5 
>6.5 
Glucose – 
Hypoglycemia  
Fasting- mg/dL # 
61 – <LLN 
55 – <61 
<55 
Glucose – 
Hyperglycemia  
Fasting – mg/dL # 
>ULN – 120 
>120 – 130 
>130 
Blood Urea Nitrogen 
mg/dL 
>ULN – 29 
30 – 35 
>35 
Creatinine – mg/dL  
>ULN – 1.7 
1.8 – 2.0 
>2.0 
Calcium – 
hypocalcemia mg/dL  
8.0 – <LLN 
7.5 – 7.9 
<7.5 
Calcium – 
hypercalcemia mg/dL  
>ULN – 11.0 
11.1 – 11.5 
>11.5 
Magnesium – 
hypomagnesemia 
mg/dL 
1.3 – <LLN 
1.0 – <1.2 
<1.0 


DMID Protocol 13-0053  
Version 7.0 
Pretomanid in Adults with Hepatic Impairment 
19 October 2022 
________________________________________________________________________________________________________ 
 
DMID/NIAID/NIH 
106 
CONFIDENTIAL 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
 
Laboratory Adverse Events 
Blood, Serum, or 
Plasma * 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Albumin – 
Hypoalbuminemia 
g/dL  
2.8 – <LLN 
2.5 – 2.7 
<2.5 
Alkaline phosphatase 
– U/L(Age 18 years)  
>ULN – 240 
241 – 360 
>360 
AST U/L 
>ULN – 105 
106 – 175 
>175 
ALT U/L  
>ULN – 105 
106 – 175 
>175 
Bilirubin (serum 
total) mg/dL 
>ULN - 2.0 
2.1 - 2.5 
>2.5 
Hemoglobin - g/dL 
10.5 – <LLN 
9.5 – 10.4 
< 9.5 
Hematocrit %  
32.3 – <LLN 
28.0 – 32.2 
< 28.0 
RBC Decrease 
(Female) X10^12/L 
 
3.61 – <LLN 
 
3.14 – 3.60 
 
< 3.14 
RBC Decrease 
(Male)   
X10E6/uL  
X10^12/L 
 
3.89 – <LLN 
 
3.28 – 3.88 
 
< 3.28 
WBC Increase  
X10^9/L  
>ULN– 15.0 
 
15.1 – 20.0 
 
> 20.0 
WBC Decrease  
X10^9/L  
 
2.5 – <LLN 
 
1.5 – 2.4 
 
< 1.5 


DMID Protocol 13-0053  
Version 7.0 
Pretomanid in Adults with Hepatic Impairment 
19 October 2022 
________________________________________________________________________________________________________ 
 
DMID/NIAID/NIH 
107 
CONFIDENTIAL 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
 
Laboratory Adverse Events 
Blood, Serum, or 
Plasma * 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Lymphocytes 
Decrease - X10^9/L  
 
0.5 – <LLN 
0.3 – 0.4 
<0.3 
Neutrophils Decrease 
- X10^9/L  
 
1.0 – <LLN 
 
0.5 – 1.0 
< 0.5 
Monocytes Increased 
X10^9/L 
>ULN-2.5 
2.6-3.0 
>3.0 
Eosinophils 
Increased 
X10^9/L 
>ULN-0.75 
0.76-1.50 
>1.50 
Basophils Increased 
X10^9/L  
>ULN - 0.40 
0.41-0.80 
>0. 80 
Platelets Decreased - 
X10^9/L  
 
120 – <LLN 
 
100 – 119 
 
<100 
INR 
>ULN – 1.3 
1.4 - 1.6 
>1.6 
 
Urine * 
Mild  
(Grade 1) 
Moderate 
 (Grade 2) 
Severe 
 (Grade 3) 
Protein 
1+ 
2+ 
>2+ 
Glucose 
Trace - 1+ 
2+ 
>2+ 


DMID Protocol 13-0053  
Version 7.0 
Pretomanid in Adults with Hepatic Impairment 
19 October 2022 
________________________________________________________________________________________________________ 
 
DMID/NIAID/NIH 
108 
CONFIDENTIAL 
DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 18, 2018 
 
Blood (microscopic) - red 
blood cells per high power 
field (rbc/hpf) 
3 - 10  
11 - 50   
>50 and/or 
gross blood 
* The laboratory values provided in the tables serve as guidelines and are dependent upon 
institutional normal parameters.  
* Institutional normal reference ranges should be provided to demonstrate that they are 
appropriate. 
# Laboratory Parameter will not be used as halting criteria.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 

SAP_001.pdf: 
CLINICAL RESEARCH IN INFECTIOUS DISEASES 
STATISTICAL ANALYSIS PLAN 
for 
DMID Protocol: 13-0053 
Study Title: 
A Phase I, Single Dose, Open-label, Study Comparing the Pharmacokinetics 
and Safety of Pretomanid in Subjects with Mild, Moderate, and Severe 
Hepatic Impairment to Matched, Non-Hepatically Impaired Subjects 
NCT02422524 
Version 2.0 
DATE: 08 May 2024 
RESTRICTED 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
08 May 2024 
- ii -
RESTRICTED 
STUDY TITLE 
Protocol Number Code: 
DMID Protocol: 13-0053 
Development Phase: 
Phase 1 
Products: 
Pretomanid 
Form/Route: 
Tablet/Oral 
Indication Studied: 
Tuberculosis 
Sponsor: 
Division of Microbiology and Infectious Diseases 
National Institute of Allergy and Infectious Diseases 
National Institutes of Health 
Clinical Trial Initiation Date: 
First subject enrolled 29MAR2018 (screened 19MAR) 
Clinical Trial Completion Date: 
Date of the Analysis Plan: 
08 May 2024 
Version Number: 
2.0 
This study was performed in compliance with Good Clinical Practice. 
Information contained in this publication is the property of Division of Microbiology and Infectious Diseases and is confidential. This 
information may not be disclosed to third parties without written authorization from Division of Microbiology and Infectious Diseases. This 
report may not be reproduced, stored in a retrieval system or transmitted in any form or by any means - electronic, mechanical, recording or 
otherwise - without the prior authorization from Division of Microbiology and Infectious Diseases. This document must be returned to Division 
of Microbiology and Infectious Diseases upon request. 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
 
08 May 2024 
 
- iii - 
RESTRICTED 
VERSION HISTORY 
 
SAP Version 
Change 
Rationale 
1.0 
Not Applicable  
Original version. 
2.0 
Removed "sequential" when describing the order 
of group enrollments based on changes to the 
study design (i.e., simultaneous enrollment 
allowed in the moderate and severe groups). 
"PA-824" replaced with "Pretomanid" throughout 
to align with the protocol. 
Added language to clarify the definition of 
baseline in Section 6.1: "In general, the last 
recorded value prior to study drug administration 
will be considered as baseline." 
Section 6.2 was updated to adjust the planned 
timing of interim analyses to align with protocol 
v7.0. 
Updated Section 6.7, Section 10.3, added 
additional tables, and expanded others to account 
for by-site summaries and analyses following the 
addition of the Saint Louis site. 
Updated eligibility criteria listed throughout to 
align with protocol v7.0. 
Updated Table 3: Schedule of Study Procedures 
and Figure 2: Schematic of Study Design to align 
with protocol v7.0. 
Updated Table 5: Laboratory/Clinical Adverse 
Event Grading Scale to align with the protocol 
v7.0. 
The study protocol was amended after finalization of 
the SAP v1.0. These SAP updates were driven by 
protocol changes, including the addition of a second 
site (Saint Louis). 
 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
 
08 May 2024 
 
- iv - 
RESTRICTED 
TABLE OF CONTENTS 
STUDY TITLE ...................................................................................................................................... II 
VERSION HISTORY ........................................................................................................................... III 
TABLE OF CONTENTS ...................................................................................................................... IV 
LIST OF ABBREVIATIONS ............................................................................................................. VII 
1. 
PREFACE ............................................................................................................................ 1 
2. 
INTRODUCTION ............................................................................................................... 2 
2.1. 
Purpose of the Analyses ....................................................................................................... 2 
3. 
STUDY OBJECTIVES AND ENDPOINTS ....................................................................... 3 
3.1. 
Study Objectives .................................................................................................................. 3 
3.1.1. 
Primary Study Objective ...................................................................................................... 3 
3.1.2. 
Primary Study Objective ...................................................................................................... 3 
3.2. 
Endpoints ............................................................................................................................. 3 
3.2.1. 
Primary Outcome Measures ................................................................................................ 3 
3.2.2. 
Secondary Outcome Measures ............................................................................................ 3 
3.3. 
Study Definitions and Derived Variables ............................................................................ 4 
3.3.1. 
Impairment Group Definitions ............................................................................................ 4 
4. 
INVESTIGATIONAL PLAN .............................................................................................. 5 
4.1. 
Overall Study Design and Plan ............................................................................................ 5 
4.2. 
Discussion of Study Design, Including the Choice of Control Groups ............................... 5 
4.3. 
Selection of Study Population ............................................................................................. 5 
4.3.1. 
Study Inclusion Criteria ....................................................................................................... 5 
Inclusion Criteria for Patients with Hepatic Impairment (Groups 1-3) .................................................. 5 
Inclusion Criteria for Non-Hepatically Impaired Controls (Group 4) .................................................... 6 
4.3.2. 
Study Exclusion Criteria ...................................................................................................... 7 
Exclusion Criteria for Patients with Hepatic Impairment (Groups 1-3) ................................................. 7 
Exclusion Criteria for Non-Hepatically Impaired Controls (Group 4) ................................................... 8 
4.4. 
Treatments ......................................................................................................................... 10 
4.4.1. 
Treatments Administered ................................................................................................... 10 
4.4.2. 
Identity of Investigational Product(s) ................................................................................ 10 
4.4.3. 
Method of Assigning Subjects to Treatment Groups (Randomization) ............................ 10 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
 
08 May 2024 
 
Table of Contents (continued) 
- v - 
RESTRICTED 
4.4.4. 
Selection of Doses in the Study ......................................................................................... 10 
4.4.5. 
Selection and Timing of Dose for Each Subject ................................................................ 11 
4.4.6. 
Blinding ............................................................................................................................. 11 
4.4.7. 
Prior and Concomitant Therapy ......................................................................................... 11 
4.4.8. 
Treatment Compliance ....................................................................................................... 11 
4.5. 
Pharmacokinetics and Safety Variables ............................................................................. 11 
4.5.1. 
Pharmacokinetics Variables ............................................................................................... 11 
4.5.2. 
Safety Variables ................................................................................................................. 12 
5. 
SAMPLE SIZE CONSIDERATIONS .............................................................................. 13 
6. 
GENERAL STATISTICAL CONSIDERATIONS ........................................................... 14 
6.1. 
General Principles .............................................................................................................. 14 
6.2. 
Timing of Analyses ............................................................................................................ 14 
6.3. 
Analysis Populations ......................................................................................................... 14 
6.3.1. 
Safety Population ............................................................................................................... 14 
6.3.2. 
Pharmacokinetics Population............................................................................................. 14 
6.4. 
Covariates and Subgroups ................................................................................................. 15 
6.5. 
Missing Data ...................................................................................................................... 15 
6.6. 
Interim Analyses and Data Monitoring ............................................................................. 15 
6.7. 
Multicenter Studies ............................................................................................................ 15 
6.8. 
Multiple Comparisons/Multiplicity ................................................................................... 15 
7. 
STUDY SUBJECTS .......................................................................................................... 16 
7.1. 
Disposition of Subjects ...................................................................................................... 16 
7.2. 
Protocol Deviations ........................................................................................................... 16 
8. 
EFFICACY EVALUATION ............................................................................................. 17 
9. 
SAFETY EVALUATION ................................................................................................. 18 
9.1. 
Demographic and Other Baseline Characteristics ............................................................. 18 
9.1.1. 
Prior and Concurrent Medical Conditions ......................................................................... 18 
9.1.2. 
Prior and Concomitant Medications .................................................................................. 18 
9.2. 
Measurements of Treatment Compliance .......................................................................... 18 
9.3. 
Adverse Events .................................................................................................................. 19 
9.3.1. 
Unsolicited Adverse Events ............................................................................................... 19 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
 
08 May 2024 
 
Table of Contents (continued) 
- vi - 
RESTRICTED 
9.4. 
Deaths, Serious Adverse Events and other Significant Adverse Events ........................... 19 
9.5. 
Pregnancies ........................................................................................................................ 19 
9.6. 
Clinical Laboratory Evaluations ........................................................................................ 20 
9.7. 
Vital Signs and Physical Evaluations ................................................................................ 20 
9.8. 
Concomitant Medications .................................................................................................. 21 
9.9. 
Other Safety Measures ....................................................................................................... 21 
10. 
PHARMACOKINETICS .................................................................................................. 22 
10.1. 
Summary of Pharmacokinetic Sampling and Sample Properties ...................................... 22 
10.2. 
Pharmacokinetic Analysis ................................................................................................. 22 
10.2.1. 
Concentration Summaries .................................................................................................. 22 
10.2.2. 
Pharmacokinetic Parameters .............................................................................................. 22 
10.3. 
Comparison of Impairment Groups ................................................................................... 23 
11. 
IMMUNOGENICITY ....................................................................................................... 25 
12. 
OTHER ANALYSES ........................................................................................................ 26 
13. 
REPORTING CONVENTIONS ....................................................................................... 27 
14. 
TECHNICAL DETAILS ................................................................................................... 28 
15. 
SUMMARY OF CHANGES IN THE CONDUCT OF THE STUDY OR PLANNED 
ANALYSES ...................................................................................................................... 29 
16. 
REFERENCES .................................................................................................................. 30 
17. 
LISTING OF TABLES, FIGURES, AND LISTINGS ..................................................... 33 
APPENDICES ...................................................................................................................................... 34 
APPENDIX 1. TABLE MOCK-UPS................................................................................................. 35 
APPENDIX 2. FIGURE MOCK-UPS ............................................................................................. 159 
APPENDIX 3. LISTINGS MOCK-UPS .......................................................................................... 181 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
 
08 May 2024 
 
- vii - 
RESTRICTED 
LIST OF ABBREVIATIONS 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
ANOVA 
Analysis of Variance 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Category 
AUC 
Area Under the Concentration-Time Curve 
AUC(0-last) 
AUC to the Last Measurable Concentration 
AUC(0-∞) 
AUC Extrapolated to Infinity 
BUN 
Blood Urea Nitrogen 
C 
Celsius 
CBC 
Complete Blood Count 
CL/F 
Apparent Oral Clearance 
Cmax 
Maximum Concentration 
CI 
Confidence Interval 
CNS 
Central Nervous System 
CRF 
Case Report Form 
CSR 
Clinical Study Report 
CV 
Coefficients of Variation 
DHHS 
Department of Health and Human Services 
DMID 
Division of Microbiology and Infectious Diseases 
DSMB 
Data and Safety Monitoring Board 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
F 
Fahrenheit 
FDA 
Food and Drug Administration 
GM 
Geometric Mean 
HEENT 
Head, Eyes, Ears, Nose and Throat 
HDPE 
High-density polyethylene 
HBsAg 
Hepatitis B surface antigen 
HIV 
Human Immunodeficiency Virus 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
 
08 May 2024 
 
List of Abbreviations (continued) 
- viii - 
RESTRICTED 
ICH 
International Conference on Harmonisation 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
ITT 
Intention to Treat 
λz 
Elimination Rate Constant 
LLOQ 
Lower Limit of Quantitation 
max 
maximum 
MedDRA 
Medical Dictionary for Regulatory Activities  
min 
Minimum 
mITT 
Modified Intention to Treat 
MRI 
Magnetic Resonance Imaging 
N 
Number (typically refers to subjects) 
NCA 
Noncompartmental Analysis 
NIAID 
National Institute of Allergy and Infectious Diseases, NIH, DHHS 
NIH 
National Institutes of Health 
OTC 
Over the Counter 
PI 
Principal Investigator 
PK 
Pharmacokinetics 
PP 
Per Protocol 
PR 
P-R Interval on an ECG 
PT 
Preferred Term 
QT/QTc 
QT Interval of an ECG/Corrected QT Interval of an ECG 
QTcF 
Heart Rate-Corrected QT Interval (Fridericia’s Formula) 
𝑅𝑅𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎
2
 
R-squared Adjusted 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SDCC 
Statistical and Data Coordinating Center 
SMC 
Safety Monitoring Committee 
SOC  
System Organ Class 
SOP 
Standard Operating Procedures 
t(1/2) 
Apparent Terminal Elimination Half-Life 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
 
08 May 2024 
 
List of Abbreviations (continued) 
- ix - 
RESTRICTED 
Tmax 
Time to Obtain Maximum Concentration (Cmax) 
TB 
Tuberculosis 
Vd/F 
Apparent Volume of Distribution During Terminal Phase 
WHO 
World Health Organization 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
 
08 May 2024 
 
- 1 - 
RESTRICTED 
1. 
PREFACE 
The Statistical Analysis Plan (SAP) for “DMID Protocol 13-0053: A Phase 1, Single Dose, Open-label, Study 
Comparing the Pharmacokinetics and Safety of Pretomanid in Subjects with Mild, Moderate, and Severe 
Hepatic Impairment to Matched, Non-hepatically Impaired Subjects” describes and expands upon the 
statistical information presented in the protocol. 
This document describes all planned analyses and provides reasons and justifications for these analyses as 
well as all planned sample tables, listings and figures. Regarding the final analysis and final integrated 
Clinical Study Report (CSR), this SAP follows the International Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH) Guidelines (1), as indicated in 
Topic E3 (Structure and Content of Clinical Study Reports), and more generally is consistent with Topic E8 
(General Considerations for Clinical Trials) and Topic E9 (Statistical Principles for Clinical Trials). 
Any deviation from this statistical plan will be described and justified in the final study report, as appropriate. 
The reader of this SAP is encouraged to also review the clinical protocol for details on conduct of the study 
and the operational aspects of clinical assessments. 
Some minor modifications may be necessary to the planned design of tables, figures, and listings to 
accommodate data collected during the actual study conduct. 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
 
08 May 2024 
 
- 2 - 
RESTRICTED 
2. 
INTRODUCTION 
Tuberculosis (TB) causes a significant global health burden with an estimated annual worldwide incidence in 
2015 of approximately 10.4 million new cases (2). Approximately 1.8 million people died from TB in 2015 
(2, 3)  making TB the leading infectious killer of adults worldwide. TB is also the leading infectious cause of 
death among people with HIV or acquired immunodeficiency syndrome (4). 
TB is an infectious disease caused by the bacterium Mycobacterium tuberculosis (MTB). This infection 
primarily affects the lungs (pulmonary TB) but can affect other organs such as the kidneys, bones, and brain 
(5). TB is transmitted by inhalation of infective droplets containing MTB and expelled into the air by a person 
with active TB (5). 
The mainstays of therapy against TB are antibiotic combination regimens. The recommended treatment 
includes a combination of rifampin, isoniazid, pyrazinamide, ethambutol or streptomycin (6 - 8). A 4-drug 
regimen of directly observed therapy is administered for 2 months (intensive phase) and is then followed by 
rifampin and isoniazid for an additional 4-7 months (7). The goal of the prolonged regimen is to ensure 
sterilization of tuberculosis lesions and to prevent development of drug resistance (8). If administered 
correctly, cure rates as high as 95% can be achieved (9). 
Unfortunately, the prolonged and complicated treatment course of TB affects patient compliance (10), which 
has led to development of multi-drug resistant TB (MDR-TB) (7, 10) and extensively drug resistant strains 
(XDR-TB) (11). The WHO estimates that ~4% of new TB cases, and 20% of previously treated cases of TB 
have MDR-TB (4). Of those new MDR-TB cases 9% are XDR-TB (4). Therefore, there is a need to develop 
novel drugs, such as Pretomanid (previously known as PA-824) to be used in combination, for the treatment 
of TB. 
In previous efficacy studies Pretomanid was shown to have bactericidal activity in a much shorter treatment 
time than the current recommended regimen. Table 2 shows a summary of previous phase 2 studies involving 
Pretomanid. 
2.1. 
Purpose of the Analyses 
Pretomanid is metabolized extensively in the liver (CYP3A4) and has a low extraction ratio. In the setting of 
advanced liver disease both hepatic blood flow and hepatic function can be compromised. Therefore, the 
pharmacokinetics of Pretomanid are likely to be altered in subjects with hepatic impairment compared to 
matched healthy subjects. The purpose of this protocol is to evaluate the safety and pharmacokinetics of 
Pretomanid in the setting of underlying liver disease defined as a Child-Pugh score of A, B, or C. 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
 
08 May 2024 
 
- 3 - 
RESTRICTED 
3. 
STUDY OBJECTIVES AND ENDPOINTS 
3.1. 
Study Objectives 
3.1.1. 
Primary Study Objective 
• To evaluate the pharmacokinetics of a single oral dose of Pretomanid in subjects with mild, 
moderate, and severe hepatic impairment (as assessed by Child-Pugh score), relative to matched 
non-hepatically impaired subjects. 
3.1.2. 
Primary Study Objective 
• To evaluate the safety of a single oral dose of Pretomanid in subjects with mild, moderate, and 
severe hepatic impairment (as assessed by Child-Pugh score), relative to matched non-hepatically 
impaired subjects. 
3.2. 
Endpoints 
3.2.1. 
Primary Outcome Measures 
• The pharmacokinetics of a single-dose of Pretomanid will be assessed from serial blood samples 
collected prior to dosing (Day 1) and at multiple time points post dosing: 1 h, 2 h, 4 h, 5 h, 6 h, 8 h, 
12 h, 16 h, 24 h, 36 h, 48 h, 72 h, and 96 h. The primary outcome measure will be total plasma 
concentration of Pretomanid. The following will be determined: 
− AUC(0-∞): Area under the concentration time-curve extrapolated to infinity 
− AUC(0-last): Area under the concentration time-curve to the last concentration above the lower 
limit of quantitation (LLOQ) 
− Cmax: Maximum Pretomanid concentration 
− Tmax: Time of maximum Pretomanid concentration 
− t(1/2): Apparent terminal elimination half-life 
− CL/F: Apparent oral clearance calculated from Dose/AUC(0-∞) 
− Vd/F: Apparent Volume of Distribution 
3.2.2. 
Secondary Outcome Measures 
• The secondary outcome measures will be: 
− Incidence and severity of serious adverse events reported at any time from the time of study 
treatment through the end of the study. 
− Incidence and severity of related adverse events at any time from the time of study treatment 
through Day 12. 
− Summary of physical examination findings (height at baseline, and weight at serial time points 
from Day of Admission until Day 12), vital signs (serial time points from Day of Admission 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
 
08 May 2024 
 
- 4 - 
RESTRICTED 
until Day 12), safety laboratory parameters (Day of Admission, as well as Days 2, 5, and 12), 
and ECG data (Day of Admission and Day 12). 
3.3. 
Study Definitions and Derived Variables 
Maximum plasma concentration (Cmax) is defined as: the maximum observed drug concentration in blood 
plasma for a particular dose interval. 
Time of maximum plasma concentration (Tmax) is defined as: the time at which the maximum plasma 
concentration occurs. 
Elimination rate constant (λz) is defined as the first-order rate constant describing rate of elimination from 
plasma. 
The apparent terminal elimination half-life (t(1/2)) will be estimated by ln(2) divided by λz. 
AUC(0-last) is defined as the area under the concentration-time curve (AUC) from administration (time 0) to 
the time of the last quantifiable concentration above the LLOQ. 
AUC(0-∞) is defined as the total AUC and will be computed by adding AUC0-t to an extrapolated value equal 
to the last measured concentration greater than limits of quantitation divided by λz and will be calculated 
using 
Z
tf
t
C
AUC
AUC
λ
+
=
−
∞
−
0
0
, 
where Ctf is the last measurable concentration ≥ LLOQ 
Apparent oral clearance (CL/F) will be calculated as the dose divided by the AUC(0-∞). 
Apparent volume of distribution (Vd/F) is defined as: the theoretical volume that the total amount of 
administered drug would occupy to provide the same concentration as it currently is in blood plasma divided 
by the bioavailability. 
∞
−
×
=
0
/
AUC
z
Dose
F
Vd
λ
 
3.3.1. 
Impairment Group Definitions 
Subjects are stratified into 4 groups based on the Child-Pugh score. The Child-Pugh score is based on five 
clinical measures of liver function: total bilirubin, serum albumin, prothrombin, ascites and hepatic 
encephalopathy. Based on their score (as determined by the site) patients are defined as mild hepatic 
impairment (5-6 points), moderate hepatic impairment (7-9 points), or severe hepatic impairment (10-
15 points). The impairment group designations are: 
• Mild Hepatic Impairment: Child-Pugh A (5-6 points) 
• Moderate Hepatic Impairment: Child-Pugh B (7-9 points) 
• Severe Hepatic Impairment: Child-Pugh C (10-15 points) 
• Matched Controls: Non-hepatically impaired controls 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
 
08 May 2024 
 
- 5 - 
RESTRICTED 
4. 
INVESTIGATIONAL PLAN 
4.1. 
Overall Study Design and Plan 
Approximately 6 subjects will be enrolled in each of the hepatic impairment groups (Mild, Moderate and 
Severe), and approximately 18 non-hepatically impaired subjects will be enrolled as matched controls. 
Subjects with hepatic impairment from all three groups will be enrolled starting with subjects who have mild 
hepatic impairment. Subjects with moderate and severe hepatic disease will be enrolled simultaneously. If 
enrollment into the severe hepatic impairment group is completed before that of the moderate hepatic 
impairment group, results from the severe cohort will be analyzed to determine the impact of severe hepatic 
impairment on the PK of Pretomanid and the need to continue enrollment of persons with moderate hepatic 
impairment will be reevaluated to determine whether the objectives of the study have been met. Non-
hepatically impaired subject matches will be dosed only after the corresponding subject with hepatic 
impairment has completed the 36-hour blood sampling procedure. The group of up to 18 matched controls 
will be matched to the 18 subjects with hepatic impairment based on age (± 10 years) and body weight at 
screening (± 20% body weight). A control subject may be matched to more than one hepatic impairment 
subject if warranted, and if the subjects to which they are matched are not in the same disease severity group. 
Control subjects may be matched to hepatically impaired subjects at any site. Therefore, there may be less 
than 18 subjects with normal hepatic function (Table 1; Figure 2). 
Subjects will receive a single oral dose of Pretomanid 200 mg taken with 240 mL of water after overnight 
fast. 
4.2. 
Discussion of Study Design, Including the Choice of Control Groups 
This is a Phase 1, single dose (200 mg), open-label, study comparing the pharmacokinetics and safety of 
Pretomanid in subjects with mild, moderate, and severe hepatic impairment relative to matched non-
hepatically impaired subjects. 
Non-hepatically impaired controls will be identified from the site specific registries and the community. 
Subjects for this study may also be identified through advertisement, letters, and other forms of 
communication. 
4.3. 
Selection of Study Population 
The study population will be representative of subjects with varying degrees of liver disease as defined by 
Child-Pugh scores. The Child-Pugh scores used for eligibility in the study will be calculated by the site at 
screening only. 
4.3.1. 
Study Inclusion Criteria 
Inclusion Criteria for Patients with Hepatic Impairment (Groups 1-3) 
1. Subject is able to give voluntary written informed consent before any study related procedure is 
performed. 
2. 18-70 years of age, inclusive. 
 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
 
08 May 2024 
 
- 6 - 
RESTRICTED 
3. Acceptable laboratory values* obtained at screening (within 21 days prior to admission to the 
confinement/hospital unit) and at admission to the confinement/hospital unit. 
*Chemistry, complete blood count, AST, ALT, total bilirubin, alkaline phosphatase, albumin, and urinalysis deemed not 
clinically significant by the investigator. 
4. Hepatic impairment classified as Child-Pugh class A (mild), B (moderate), or C (severe) criteria at 
screening for Groups 1, 2, or 3, respectively, and documented evidence of hepatic cirrhosis*. 
*by biopsy, nuclear scan, CT, MRI, ultrasound, or other clinically acceptable methods 
5. If female, not of childbearing potential* or agrees to avoid becoming pregnant by using acceptable 
contraception** during the duration of the study. 
*Non-childbearing potential is defined as being post-menopausal for at least 2 years, status after bilateral oophorectomy 
or status after hysterectomy. 
**Females of childbearing potential must agree to use two acceptable methods of contraceptives: bilateral tubal ligation; 
barrier method (condom) by the male partner (even if vasectomized); hormonal contraceptives; intrauterine contraceptive 
devices; diaphragm in combination with contraceptive jelly, cream, foam, or spermicide; and abstinence from sexual 
intercourse with men. 
6. If subject is male and capable of reproduction, agrees to avoid fathering a child for three months after 
dosing by using an acceptable method of birth control*. 
*In addition to the use of a barrier method (condom) even if 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 #5, and abstinence from sexual intercourse with women. 
7. If the subject is female, a negative serum pregnancy test at screening and a negative urine pregnancy 
test at admission to confinement/hospital unit. 
8. Willingness to comply with all protocol requirements. 
Inclusion Criteria for Non-Hepatically Impaired Controls (Group 4) 
1. Subject is able to give voluntary written informed consent before any study related procedure is 
performed. 
2. 18-70 years of age, inclusive. 
3. Subject is a healthy volunteer as determined by no clinically significant findings from medical history, 
physical examination, vital signs, and 12-lead ECG as determined by the Site Investigator. 
4. Acceptable laboratory values* obtained at screening (within 21 days prior to admission to the 
confinement/hospital unit) and either at or within 72 hours of admission to the confinement/hospital 
unit. 
*Chemistry, complete blood count, AST, ALT, total bilirubin, alkaline phosphatase, albumin, and urinalysis within the 
reference range for the test laboratory, unless deemed not clinically significant by the investigator. 
5. If female, not of childbearing potential* or agrees to avoid becoming pregnant by using acceptable 
contraception** during the duration of the study. 
*Non-childbearing potential is defined as being post-menopausal for at least 2 years, status after bilateral oophorectomy 
or status after hysterectomy. 
**Females of childbearing potential must agree to use two acceptable methods of contraceptives: bilateral tubal ligation; 
barrier method (condom) by the male partner (even if vasectomized); hormonal contraceptives; intrauterine contraceptive 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
 
08 May 2024 
 
- 7 - 
RESTRICTED 
devices; diaphragm in combination with contraceptive jelly, cream, foam, or spermicide; and abstinence from sexual 
intercourse with men. 
6. If subject is male and capable of reproduction, agrees to avoid fathering a child for three months after 
dosing by using an acceptable method of birth control*. 
*In addition to the use of a barrier method (condom) even if 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 #5, and abstinence from sexual intercourse with women. 
7. If the subject is female, a negative serum pregnancy test at screening and a negative urine pregnancy 
test at admission to confinement/hospital unit. 
8. Willingness to comply with all protocol requirements. 
4.3.2. 
Study Exclusion Criteria 
Exclusion Criteria for Patients with Hepatic Impairment (Groups 1-3) 
1. Hypokalemia (< 3.5mEq/L), severe hypomagnesemia (< 1.1 mg/dL) or severe hypocalcemia 
(< 7.5 mg/dL). 
2. AST or ALT > 10 times the upper limit of normal. 
3. Creatinine clearance <60 ml/min. 
4. Inability to swallow tablets. 
5. Presence of any condition or finding* which would jeopardize subject safety, impact study result 
validity, or diminish the subject’s ability to undergo all study procedures and assessments**. 
*in the opinion of the site investigator 
**e.g., inability to draw PK samples 
6. History of fever or documented fever (oral temperature ≥100.4° F or ≥ 38.0° C) in the 48 hours prior 
to admission to the confinement/hospital unit. 
7. Currently breastfeeding. 
8. History of chronic tobacco/nicotine use (>10 cigarettes per day for 3 months minimum prior to 
confinement/hospital unit admission). 
9. History of clinically significant allergy or severe side effects with nitroimidazoles (e.g., Metronidazole 
and related substances and azole antifungals or aromatase inhibitors). 
10. Receipt of an investigational drug, vaccine or biologic in a clinical trial within 30 days prior to 
screening. 
11. Use of any over the counter (OTC) medication* within 7 days prior to admission to the 
confinement/hospital unit, unless** the substance would not likely impact the validity of the study 
results. 
*including vitamins and herbal supplements, cough and cold medications. 
**in the opinion of the site investigator 
 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
 
08 May 2024 
 
- 8 - 
RESTRICTED 
12. Treatment with CYP450 enzyme altering drugs* within 7 days prior to admission to the 
confinement/hospital unit, unless** the substance would not likely impact the validity of the study 
results. 
*except hormonal contraceptives 
**in the opinion of the site investigator 
NOTE: See list of CYP450 enzyme altering drugs under the concomitant medications Section 4.4.7. 
13. A positive blood screen for HIV. 
14. A positive alcohol breath test (or other suitable test for alcohol) or a urine screen test for drugs of 
abuse* at screening and at admission to the confinement/hospital unit. 
*Amphetamines, barbiturates, cocaine metabolites, marijuana, opiates, phencyclidine (PCP). 
NOTE: Results of the urine screen test can be ignored if in the opinion of the PI the results can be explained by the 
concomitant medications history. 
15. Unwillingness to abstain from engaging in strenuous physical activity (e.g. running, bicycling, 
weightlifting, competitive sports) during the course of the study. 
16. Consumption of grapefruit juice in the 48 hours before admission to the confinement/hospital unit, or 
the inability to abstain from these until completion of Day 12. 
17. A QTcF interval >450 msec (males) or >450 msec (females) at screening (Visit 00A) or admission to 
the confinement/hospital unit (Visit 00B) or a history of prolonged QTc interval. 
18. A family history* of Long QT Syndrome, premature cardiac death**, or sudden death without a 
preceding diagnosis of a condition*** that could be causative of sudden death. 
*parents 
**due to ischemic heart disease or sudden cardiac death before 55 years of age (men) or 65 years of age (women) 
***such as known coronary artery disease, congestive heart failure, or terminal cancer 
19. Any clinically significant ECG abnormality, in the opinion of the site investigator, at screening and at 
admission to the confinement/hospital unit. 
20. Donation of >500 mL blood within the 30 days prior to admission to the confinement/hospital unit. 
21. Plans to donate blood during the study or up to 14 days after dosing. 
22. Persons with a transjugular intrahepatic portosystemic shunt. 
Exclusion Criteria for Non-Hepatically Impaired Controls (Group 4) 
1. Inability to swallow tablets. 
2. Presence of any condition or finding* which would jeopardize subject safety, impact study result 
validity, or diminish the subject’s ability to undergo all study procedures and assessments**. 
*in the opinion of the site investigator 
**e.g., inability to collect PK samples 
3. History of fever or documented fever (oral temperature ≥100.4° F or ≥ 38.0° C) in the 48 hours prior 
to admission to the confinement/hospital unit. 
 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
 
08 May 2024 
 
- 9 - 
RESTRICTED 
4. Currently breastfeeding. 
5. History of chronic tobacco/nicotine use (>10 cigarettes per day for 3 months minimum prior to 
confinement/hospital unit admission). 
6. History of seizures (other than febrile seizures during childhood) or known or suspected CNS 
disorders that may predispose to seizures. 
7. History of clinically significant allergy or severe side effects with nitroimidazoles (e.g., Metronidazole 
and related substances and azole antifungals or aromatase inhibitors). 
8. Receipt of an investigational drug, vaccine or biologic in a clinical trial within 30 days prior to 
screening. 
9. Use of any over the counter (OTC) medication* within 7 days prior to admission to the 
confinement/hospital unit, unless** the substance would not likely impact the validity of the study 
results. 
*including vitamins and herbal supplements, antacids, cough and cold medications. 
**in the opinion of the site investigator 
10. Use of prescription medication except hormonal contraceptives within 30 days prior to admission to 
the confinement/hospital unit, unless* the substance would not likely impact study result validity. 
*in the opinion of the site investigator 
11. Treatment with CYP450 enzyme altering drugs* within 7 days prior to admission to the 
confinement/hospital unit, unless** the substance would not likely impact the validity of the study 
results. 
*except hormonal contraceptives 
**in the opinion of the site investigator 
NOTE: See list of CYP450 enzyme altering drugs under the concomitant medications Section 4.4.7. 
12. A positive blood screen for HIV. 
13. A positive blood screen for hepatitis B surface antigen (HBsAg), or hepatitis C antibody. 
14. A positive alcohol breath test (or other suitable test for alcohol) or a urine screen test for drugs of 
abuse* at screening and at admission to the confinement/hospital unit. 
*Amphetamines, barbiturates, benzodiazepines, cocaine metabolites, marijuana, opiates, phencyclidine (PCP). 
15. A history of alcohol abuse or dependence within the past 1 month prior to admission to the 
confinement/hospital unit. 
16. Unwillingness to abstain from engaging in strenuous physical activity (e.g. running, bicycling, 
weightlifting, competitive sports) during the course of the study. 
17. Consumption of grapefruit juice in the 48 hours before admission to the confinement/hospital unit, or 
the inability to abstain from these until completion of Day 12. 
 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
 
08 May 2024 
 
- 10 - 
RESTRICTED 
18. A QTcF interval >450 msec (males) or >450 msec (females) at screening (Visit 00A) or admission to 
the confinement/hospital unit (Visit 00B) or a history of prolonged QTc interval. 
19. A family history* of Long QT Syndrome, premature cardiac death**, or sudden death without a 
preceding diagnosis of a condition*** that could be causative of sudden death. 
*parents 
**due to ischemic heart disease or sudden cardiac death before 55 years of age (men) or 65 years of age (women) 
***such as known coronary artery disease, congestive heart failure, or terminal cancer 
20. Any clinically significant ECG abnormality, in the opinion of the site investigator, at screening and at 
admission to the confinement/hospital unit. 
21. Donation of >500 mL of blood within the 30 days prior to admission to the confinement/hospital unit. 
22. Plans to donate blood during the study or up to 14 days after dosing. 
23. Persons with a transjugular intrahepatic portosystemic shunt. 
4.4. 
Treatments 
4.4.1. 
Treatments Administered 
All participants will receive a single 200 mg tablet of Pretomanid. 
4.4.2. 
Identity of Investigational Product(s) 
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 
Mycobacterium tuberculosis cell wall biosynthesis, as well as by generating reactive nitrogen species. 
Pretomanid will be provided by the Global Alliance for TB Drug Development according to the terms of the 
Clinical Trials Agreement between the TB Alliance and NIAID. 
For this study, Pretomanid 200 mg tablets are white to off-white, odorless and oval in appearance. Study drug 
will be packaged in high-density polyethylene (HDPE) bottles, each containing 50 tablets, and in blister-strips 
comprised of a thermoformable-film and a lidding foil configuration, each strip containing 7 individual 
tablets. Sites will receive study product in either packaging depending on supply. Study product in either form 
of packaging should be stored at 15-30°C (59-86°F). 
4.4.3. 
Method of Assigning Subjects to Treatment Groups (Randomization) 
There is no randomization performed for this study. Subjects are assigned to the 3 hepatically impaired groups 
based on the Child-Pugh score, with approximately 6 subjects in each of the hepatic impairment groups 
(Groups 1, 2, and 3) and approximately 18 non-hepatically impaired subjects in Group 4. 
4.4.4. 
Selection of Doses in the Study 
The PK profile for Pretomanid following oral dosing was consistent for healthy subjects and subjects with 
pulmonary TB. Pretomanid was readily absorbed after oral administration and slowly eliminated in plasma. 
Pretomanid plasma concentrations increased in a dose-related manner after single-dose administration of up to 
1000 mg in healthy subjects and subjects with TB, but the increase was less than dose proportional, 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
 
08 May 2024 
 
- 11 - 
RESTRICTED 
particularly at doses above 200 mg/day. There is a trend towards increased side effects with increasing 
dosages (8). Furthermore, efficacy studies have shown equivalent early bacterial activity at dosages ranging 
from 200mg to 1200mg. The doses of Pretomanid that will be evaluated in regimens in Phase 3 are 100 mg 
and 200 mg. Hence, the dosage of Pretomanid for this study will be 200mg daily. 
4.4.5. 
Selection and Timing of Dose for Each Subject 
A single 200 mg tablet will be administered orally on the morning of Day 1 with 240 mL of water following 
an overnight fast. All participants will receive the same study product. 
4.4.6. 
Blinding 
Not applicable; this is an open-label study. 
4.4.7. 
Prior and Concomitant Therapy 
Administration of any medications, therapies, or vaccines will be recorded on the appropriate data collection 
form. Concomitant medications recorded will include all current medications and medications taken within 
30 days prior to signing the informed consent and during the study period. Medications reported in the 
electronic case report form (eCRF) are limited to those taken within 30 days prior to the study drug 
administration through Day 12 of the study. Prescription and over-the-counter drugs will be included as well 
as herbals, vitamins, and supplements. 
Systemic medications that might interfere with the evaluation of the investigational product should not be 
used unless absolutely necessary. A subject will be withdrawn for use of excluded medications. Medications 
in this category include the prohibited medications per the Subject Exclusion Criteria (Section 4.3.2). The 
excluded CYP450 inducers are: Carbemazepines, Rifampicin, Alcohol (of greater than one drink per day or 
seven drinks per week), Phenytoin, Griseofulvin, Phenobarbital and Sulphonylureas. The excluded CYP450 
inhibitors are: Sodium valproate, Isoniazid, Ketoconazole, Fluconazole, Chloramphenicol, Erythromycin, 
Sulfonamides, Ciprofloxacin, Metronidazole, and grapefruit juice. 
4.4.8. 
Treatment Compliance 
All subjects are to receive a single dose of study product administered in the clinic. 
4.5. 
Pharmacokinetics and Safety Variables 
See Table 3 for a schedule of study procedures. 
4.5.1. 
Pharmacokinetics Variables 
1. The pharmacokinetics of a single-dose of Pretomanid will be assessed from serial blood samples 
collected prior to dosing (Day 1 and at multiple time points post dosing: 1 h, 2 h, 4 h, 5 h, 6 h, 8 h, 12 
h, 16 h, 24 h, 36 h, 48 h, 72 h, and 96 h. The primary outcome measure will be total plasma 
concentration of Pretomanid. The following will be determined: 
a. AUC(0-∞): Area under the concentration time-curve extrapolated to infinity 
b. AUC(0-last): Area under the concentration time-curve to the last concentration above the lower limit 
of quantitation 
c. Cmax: Maximum Pretomanid concentration 
d. Tmax: Time of maximum Pretomanid concentration 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
 
08 May 2024 
 
- 12 - 
RESTRICTED 
e. t(1/2): Apparent terminal elimination half-life 
f. CL/F: Apparent oral clearance calculated from Dose/AUC(0-∞) 
g. Vd/F: Apparent Volume of Distribution 
4.5.2. 
Safety Variables 
1. The secondary outcome measures will be: 
a. Incidence and severity serious adverse events reported at any time from the time of study treatment 
through the end of the study. 
b. Incidence and severity of related adverse events reported at any time from the time of study 
treatment through Day 12. 
c. Summary of physical examination findings (height at baseline, and weight at serial time points 
from Day of Admission until Day 12), vital signs (serial time points from Day of Admission until 
Day 12), safety laboratory parameters (Day of Admission, as well as Days 2, 5, and 12), and ECG 
data (Day of Admission and Day 12). 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
 
08 May 2024 
 
- 13 - 
RESTRICTED 
5. 
SAMPLE SIZE CONSIDERATIONS 
The sample size was determined based on feasibility and FDA guidance (12). Following FDA guidance, 
enrollment is anticipated to include at least 6 subjects in each arm. This sample size is expected to estimate 
the group differences with adequate precision. Previous studies of Pretomanid have estimated coefficients of 
variation (CV) of <21% after 250 mg dosing (N=8) and <33% after 200 mg dosing (N=6) for single dose 
AUC(0-∞) and Cmax in healthy adult subjects (11). Assuming an observed two-fold difference between the 
group with severe hepatic impairment and matched controls with no correlation between matched pairs and a 
coefficient of variation of 25%, a 90% confidence interval for the fold difference between severely impaired 
and non-hepatically impaired group is (1.55, 2.59). 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
 
08 May 2024 
 
- 14 - 
RESTRICTED 
6. 
GENERAL STATISTICAL CONSIDERATIONS 
6.1. 
General Principles 
All continuous variables will be summarized using the following descriptive statistics: n (non-missing sample 
size), mean, standard deviation, median, maximum and minimum. The frequency and percentages (based on 
the non-missing sample size) of observed levels will be reported for all categorical measures. In general, all 
data will be listed, sorted by impairment group and subject, and when appropriate by visit number within 
subject. In general, the last recorded value prior to study drug administration will be considered as baseline. 
All summary tables will be structured with a column for each impairment group in the order (Mild Hepatic 
Impairment, Moderate Hepatic Impairment, Severe Hepatic Impairment, Matched Controls) and will be 
annotated with the total population size relevant to that table/impairment group, including any missing 
observations. More details will be provided for reporting pharmacokinetic results in Section 10. 
6.2. 
Timing of Analyses 
Two SMC interim safety reviews are planned. 
1. After 3 subjects with mild hepatic impairment are enrolled and completed follow-up through Day 12. 
This review will be completed prior to opening enrollment for subjects with moderate or severe 
hepatic impairment. Enrollment of subjects with mild hepatic impairment and matched controls may 
continue during the safety review. 
2. After 3 subjects with moderate or severe hepatic impairment are enrolled and complete follow-up 
through Day 12. Enrollment of subjects with mild hepatic impairment, moderate hepatic impairment, 
severe hepatic impairment, and matched controls may continue during the safety review. 
Each interim safety review will present data by impairment group including AEs, SAEs, clinical laboratory 
tests, vital signs, PK analysis and 12-lead ECG. Cumulative data for all subjects enrolled will be included in 
the safety reviews. 
Interim safety reviews will not include any statistical hypothesis testing. 
The final analysis will be performed after database lock. 
6.3. 
Analysis Populations 
Summaries and analysis of safety data will be presented for the Safety Population. Summaries and analysis of 
pharmacokinetics data will be presented for the Pharmacokinetics Population. A tabular listing of all subjects, 
visits, and observations excluded from the analysis populations will be provided in the CSR (Table 7; Listing 
1; and Listing 4). 
6.3.1. 
Safety Population 
The safety analysis set will include all participants who receive study product. 
6.3.2. 
Pharmacokinetics Population 
The PK analysis set will consist of participants in the safety population who have evaluable plasma PK 
samples for the estimation of Cmax or AUC (0-∞). Subjects may also be excluded from analysis for reasons such 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
 
08 May 2024 
 
- 15 - 
RESTRICTED 
as wrong dose or eating before a dose. What constitutes a reason for exclusion will be assessed on a case-by-
case basis by DMID and the VTEU PI. 
6.4. 
Covariates and Subgroups 
This study is not powered for formal subgroup analyses and none will be explored. 
6.5. 
Missing Data 
All attempts will be made to collect all data per protocol. As missing data are expected to be minimal, no 
imputation will be performed for missing values. Any data point that appears to be erroneous or inexplicable 
based on clinical judgment will be investigated as a possible outlier. 
6.6. 
Interim Analyses and Data Monitoring 
See Section 6.2. 
6.7. 
Multicenter Studies 
This study will take place at two VTEU sites, Duke University and St. Louis University. Data will be pooled 
across both clinical sites except for demographics which will be summarized by site and the comparison of 
PK parameters will be presented according to site and impairment group (if applicable, as described in 
Section 10.3). 
6.8. 
Multiple Comparisons/Multiplicity 
This study was designed to test the hypothesis that Pretomanid PK parameters following drug exposure will 
differ between patients with hepatic impairment and non-hepatically impaired controls. This results in three 
comparisons, however no adjustment for multiple comparisons is planned. 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
 
08 May 2024 
 
- 16 - 
RESTRICTED 
7. 
STUDY SUBJECTS 
7.1. 
Disposition of Subjects 
Table 8 will present a summary of the reasons that subjects were screened but not enrolled. 
The composition of analysis populations, including reasons for subject exclusion, by impairment group, is 
presented in Table 7. 
The disposition of subjects in the study will be tabulated by impairment group (Table 6). The table shows the 
total number of subjects screened, enrolled, who received treatment, completed all hourly assessments, and 
the number who completed the Day 12 follow-up. 
A flowchart showing the disposition of study subjects, adapted from the Consort Statement (12) will be 
included (Figure 1). This figure will present the number of subjects screened, enrolled, terminated early, and 
analyzed, by impairment group. 
A listing of subjects who are terminated from study follow-up and the reason will be included in Listing 1. 
7.2. 
Protocol Deviations 
A summary of subject-specific protocol deviations will be presented by the reason for the deviation, the 
deviation category, and impairment group for all subjects (Table 4). All subject-specific protocol deviations 
and non-subject specific protocol deviations will be included in Appendix 3 as data listings (Listing 2 and 
Listing 3, respectively). 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
 
08 May 2024 
 
- 17 - 
RESTRICTED 
8. 
EFFICACY EVALUATION 
This study is primarily a pharmacokinetics study and does not include an efficacy evaluation. 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
 
08 May 2024 
 
- 18 - 
RESTRICTED 
9. 
SAFETY EVALUATION 
All summaries and analysis of safety data will be presented for the Safety Analysis Population. Safety 
summaries will be presented overall and by impairment group. 
Listings will be sorted by impairment group, subject ID, parameter (if applicable), and visit (if applicable). 
Continuous variables will be summarized using the following descriptive statistics: n (non-missing sample 
size), mean, standard deviation, median, maximum and minimum. All categorical measures will be 
summarized by the frequency and percentages (based on the non-missing sample size) of observed levels. 
The denominator for the percentages may be based on the number of non-missing observations for an 
assessment or based on the number of subjects in a population. This will be described for each table. 
9.1. 
Demographic and Other Baseline Characteristics 
Summaries of age, height, weight (measured at screening), sex, ethnicity, and race will be presented by 
impairment group and overall (Table 11; Table 12) as well as by site (Table 9 and Table 10). Ethnicity is 
categorized as Hispanic or Latino, or not Hispanic and not Latino. In accordance with NIH reporting policy, 
subjects may self-designate as belonging to more than one race or may refuse to identify a race, the latter 
reflected in the CRF as “No” to each racial option. 
Individual subject listings (Appendix 3) will be presented for all demographics (Listing 5). 
9.1.1. 
Prior and Concurrent Medical Conditions 
Complete medical history will be obtained by interview of subjects at the screening visit and will be reviewed 
and/or updated on Day 1 prior to dosage. Subjects 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, kidney, 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. 
All current illnesses and pre-existing medical conditions will be MedDRA® coded using MedDRA dictionary 
version 21.0 or higher. Summaries of subjects’ pre-existing medical conditions will be presented by 
impairment group (Table 13). 
Individual subject listings will be presented for all medical conditions (Listing 6). 
9.1.2. 
Prior and Concomitant Medications  
Summaries of medications that were started prior to dosing and continuing at the time of dosing will be 
presented by WHO Drug Terms 2 and 3 and impairment group (Table 140). 
Individual subject listings will be presented for all concomitant medications (Listing 14). 
9.2. 
Measurements of Treatment Compliance 
Any subjects who were enrolled but not dosed will be presented by impairment group as part of the subject 
disposition table (Table 6). 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
 
08 May 2024 
 
- 19 - 
RESTRICTED 
9.3. 
Adverse Events 
When calculating the incidence of adverse events (i.e., on a per subject basis), each subject will only be 
counted once and any repetitions of adverse events within a subject will be ignored; the denominator will be 
the total population size. All adverse events reported will be included in the summaries and analyses. Adverse 
event grading scales are presented in Table 5. 
An overall summary of adverse events is presented in Table 14. 
9.3.1. 
Unsolicited Adverse Events 
The proportion of subjects reporting at least one unsolicited adverse event will be summarized by MedDRA 
system organ class and preferred term for each impairment group. Denominators for percentages are the 
number of subjects who received Pretomanid being summarized. 
Adverse events by subject will be presented in Listing 7. 
The following summaries for unsolicited adverse events will be presented by MedDRA system organ class, 
preferred term, and impairment group: 
• Subject incidence and total frequency of adverse events over time by dose with 95% CI (Days 1-5, 
Days > 5) (Table 15; Table 16; Table 17; and Table 18); 
• Summary of severity and relationship to study product (Table 19); 
• Subject listing of non-serious adverse events of moderate or greater severity (Table 21); 
• Bar chart of serious and non-serious related adverse events by severity and MedDRA system organ 
class (Figure 3 and Figure 4). 
9.4. 
Deaths, Serious Adverse Events and other Significant Adverse Events 
The following listings will be presented including Subject ID, Adverse Event Description, Reason Reported 
as an SAE, Relationship to Treatment, Alternate Etiology if not Related, Outcome, and Duration of Event 
(days): 
• Deaths and Serious Adverse Events (Table 20). 
9.5. 
Pregnancies 
Pregnancy is not considered an adverse event; however, for females, information will be collected for any 
pregnancies which occur during study drug administration until the Study Day 12 Visit. Male subjects should 
notify the study team if a pregnancy occurs in a partner within 3 months after study drug administration. If the 
male subject reports a pregnancy, information about complications during pregnancy, labor and delivery, or 
congenital birth defects will be collected from the male subject’s female partner using a site-specific Pregnant 
Partner Information and Authorization form. Certain pregnancy outcomes (congenital anomaly or birth defect 
in an offspring of a subject taking study drug) will require submission as an SAE. A listing of pregnancies 
will be presented (Listing 15; Listing 16; Listing 17; Listing 18; and Listing 19). 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
 
08 May 2024 
 
- 20 - 
RESTRICTED 
9.6. 
Clinical Laboratory Evaluations 
Clinical safety laboratory adverse events will be collected at the time of dosage, at 36 hours post dose 
(Day 2), Day 5 and Day 12. Chemistry parameters to be evaluated include: total bilirubin, serum albumin, 
potassium, magnesium, calcium, serum creatinine, blood urea nitrogen (BUN), alkaline phosphatase, alanine 
aminotransferase (ALT), and aspartate aminotransferase (AST). For patients with severe hepatic impairment 
an ammonia level will be drawn at screening and will be used as a baseline reading for safety purposes, not as 
a study entry criterion. Hematology parameters to be evaluated included: hematocrit, hemoglobin, red blood 
cell count, white blood cell count, automated differential (absolute neutrophils, absolute eosinophils, absolute 
basophils, absolute lymphocytes, absolute monocytes), and platelet count. The coagulation parameter 
international normalized ratio (INR) is to be evaluated. Urinalysis parameters to be evaluated by dipstick 
include: protein, glucose and blood. If any of the urinalysis parameters are positive by dipstick then the 
sample will be analyzed by reflex microscopy and the results for protein, glucose and blood will be 
summarized. Grading scales for safety laboratory parameters are presented in Table 5. 
The number and percentage of subjects with at least one clinical safety laboratory of mild or greater severity 
through Day 12 is presented in the overall summary of adverse events (Table 14). 
The distribution of chemistry results by severity, time point, and impairment group will be presented 
beginning at Table 26 and concluding at Table 47. The distribution of hematology results by severity, time 
point, and impairment group will be presented beginning at Table 58 and concluding at Table 79. The 
distribution of urine dipstick results by timepoint and impairment group will be shown in Table 90. The 
distribution of urinalysis results by severity, time point, and impairment group will be presented in Table 91; 
Table 92; Table 93; Table 94; Table 95; Table 96; Table 97; and Table 98. The distribution of coagulation 
results by severity, time point, and impairment group will be presented in Table 102 and Table 103. 
Descriptive statistics including mean, standard deviation, median, minimum and maximum values by time 
point, for each laboratory parameter, will be summarized in Table 48 and concluding at Table 57 (chemistry); 
Table 80 and concluding at Table 89 (hematology); Table 99 (Urinalysis); and Table 104 (Coagulation). Table 
100; and Table 101 will show distribution of categorical urinalysis results. Shift tables will be presented for 
each laboratory parameter beginning at Table 105 and concluding at Table 128. Change from baseline plots 
for continuous laboratory parameters will also be presented beginning at Figure 5 and concluding with Figure 
25. 
Listing 8; Listing 9; Listing 10; and Listing 11 will provide complete listings of individual clinical laboratory 
results with applicable reference ranges. Table 22; Table 23; Table 24;and Table 25 will provide listings of 
abnormal laboratory values. 
9.7. 
Vital Signs and Physical Evaluations 
Vital sign measurements included oral temperature, pulse, systolic blood pressure, and diastolic blood 
pressure. Vital signs will be summarized at admission (Day -1), Day 1 pre-dose (Baseline), 1-hour post-dose, 
2 hours post-dose, 4 hours post-dose, 5 hours post-dose, 6 hours post-dose, 8 hours post-dose, 12 hours 
post-dose, 16 hours post-dose, 24 hours post-dose, 36 hours post-dose, Day 3, Day 4, Day 5 and Day 12. Vital 
signs will be tabulated by visit and impairment group (Table 129 through Table 137; and Listing 12). 
Physical Examinations performed at admission and Day 12. The following body systems will be assessed: 
Abdomen, Cardiovascular/heart Extremities, General Appearance, HEENT, Lymph nodes, Musculoskeletal, 
Neck, Neurological, Pulmonary/Chest, and Skin (Listing 13). A summary of abnormal physical exam findings 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
 
08 May 2024 
 
- 21 - 
RESTRICTED 
will be shown in Table 138. Weight will be summarized at admission (Day -1), Day 1 pre-dose (Baseline), 
1-hour post-dose, 2 hours post-dose, 4 hours post-dose, 5 hours post-dose, 6 hours post-dose, 8 hours post-
dose, 12 hours post-dose, 16 hours post-dose, 24 hours post-dose, 36 hours post-dose, Day 3, Day 4, Day 5 
and Day 12. Weight will be tabulated by visit and impairment group (Table 139). 
9.8. 
Concomitant Medications 
Concomitant medications will be coded to the Anatomical Therapeutic Classification using the WHO Drug 
Dictionary. The use of prior and concomitant medications taken during the study will be recorded on the 
CRFs. A by-subject listing of concomitant medication use will be presented (Listing 14). The use of 
concomitant medications during the study will be summarized by ATC1, ATC2 code and impairment group 
for the Safety population (Table 140). 
9.9. 
Other Safety Measures 
ECG intervals (RR, QRS, QT, QTcF, PR and ventricular rate) will be summarized at the day of admission and 
Day 12 using descriptive statistics (Table 141; Table 142; Table 143; Table 144; Table 145; and Table 146). 
The proportion of subjects with bradycardia, tachycardia, conduction system disease (e.g., prolongation of the 
PR Interval, bundle branch block, fascicular block), arrhythmia (e.g., atrial fibrillation, atrial flutter, 
premature atrial/ventricular contractions, ventricular tachycardia), and Brugada pattern will be summarized by 
hepatic impairment group (Table 147). Individual overall interpretation and comments will be provided in 
Listing 20. Individual ECG interval measurements will be provided in Listing 21. 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
 
08 May 2024 
 
- 22 - 
RESTRICTED 
10. 
PHARMACOKINETICS 
Pharmacokinetic (PK) analyses will be performed using noncompartmental analysis (NCA). PK 
concentrations and noncompartmental parameters will be summarized by impairment group. Statistics include 
the arithmetic mean, geometric mean (GM), standard deviation (SD), coefficient of variation (CV), minimum 
(min), maximum (max), and median. PK parameters (AUC0-last, AUC0-∞, and Cmax) will be compared between 
impairment groups using ANOVA models with or without random effects. Tmax will be compared using 90% 
confidence intervals calculated using the inverted rank score method. Concentrations below the quantitation 
limit (BQL) prior to first measurable concentration will be imputed as zero. 
10.1. 
Summary of Pharmacokinetic Sampling and Sample Properties 
Samples with bioanalytical errors reported by the laboratory will be excluded. Collection times of samples 
missing the actual collection time will be imputed using the nominal collection time. Such samples will be 
identified in the analysis report (Listing 22). 
10.2. 
Pharmacokinetic Analysis 
10.2.1. 
Concentration Summaries 
Drug plasma concentrations will be listed by impairment group, and subject, out of sample time window, and 
PK analyses-excluded samples indicated (Listing 22). The listings will also indicate the nominal and actual 
time associated with the sample (nominal time is defined as the time in hours since the first dose). 
Potentially important bioanalytical errors and their effect on the PK analysis will be discussed. 
Plasma drug concentrations will also be summarized by impairment group (Table 148; Table 149; Table 150; 
and Table 151) and plotted. 
• Figure 26; Figure 27; Figure 28; and Figure 29 (linear) and Figure 33; Figure 34; Figure 35; and 
Figure 36 (semilogarithmic) will plot all subject plasma PK profiles together by impairment group, 
as linear and semilogarithmic plots. 
• Linear plots of subjects with hepatic impairment with their matched control (Figure 30; Figure 31; 
and Figure 32). 
• Linear plots of plasma mean concentration curves will be shown in Figure 37, with error bars 
representing +/- 1 standard deviation. 
• Semi-logarithmic plots of geometric mean plasma concentration curves will be shown in Figure 
38. 
10.2.2. 
Pharmacokinetic Parameters 
NCA PK parameters will be calculated using actual post-dose time. Samples with concentrations greater than 
the LLOQ will be considered for the estimation of λz. This slope will be computed from log-transformed 
concentration data. The correlation between time and concentration in the time points used to estimate λz 
should be sufficiently high (𝑅𝑅𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎
2
>0.9 for λz. to be estimated reliably. At least three samples will be used 
for the calculation of λz. The range of selected time points should include all timepoints post 12 hours 
inclusive if appropriate. 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
 
08 May 2024 
 
- 23 - 
RESTRICTED 
Samples used to calculate λz along with the number of samples used for the calculation will be included in 
subject listings (Listing 22). 
The AUC will be computed using the linear-up log-down (linear-log) trapezoidal method in WinNonlin 
(Pharsight Corporation, Cary, NC). 
All PK parameters will also be summarized by impairment group using descriptive statistics (Table 152; 
Table 153; Table 154; and Table 155). Additionally, subject-level PK parameters will be presented by 
participant in the table in the final report. 
The following parameters will be estimated: Cmax, Tmax, t(1/2), AUC(0-last), AUC(0-∞), CL/F and Vd/F. See 
Section 3.3 for parameter definitions. 
10.3. 
Comparison of Impairment Groups 
If at least one matching participant in the healthy volunteer group is available in the impairment groups, the 
following random effects ANOVA model will be used to test for a group by site interaction and if significant 
(p<0.10), estimate group and site level parameters and compare impairment groups for primary PK 
parameters: 
𝑌𝑌𝑖𝑖𝑖𝑖= 𝜇𝜇+ 𝜏𝜏[𝑖𝑖𝑖𝑖] + 𝛼𝛼𝑖𝑖+ 𝛾𝛾𝑘𝑘+ 𝜏𝜏[𝑖𝑖𝑖𝑖]𝛾𝛾𝑘𝑘+ 𝜀𝜀𝑖𝑖𝑖𝑖. 
Here, i represents the matched block, j represents the participant in matched block i, Yij is the log-transformed 
PK parameter for participant j in block i, τ[ij] is the impairment group effect for the group in which participant 
j in block i belongs, αi is the random group effect for matched block i, γk is the indicator variable for the fixed 
effect of study site k, and τ[ij]γk is the interaction between subject impairment group and site. If no matching 
participants are available with PK parameters, the standard fixed effects ANOVA model without random 
effect αi will be used. The following SAS code may be used to estimate the model above: 
proc mixed data=impairment; 
class match group (ref=”Matched Control”) site; 
model logPKpar = group site group*site / solution cl alpha=0.10; 
random match; 
lsmeans group site group*site; 
run;. 
The estimates from this model can be exponentiated to get fold differences. 
If the group by site interaction is not significant then the following model will be used to estimate group level 
parameters: 
𝑌𝑌𝑖𝑖𝑖𝑖= 𝜇𝜇+ 𝜏𝜏[𝑖𝑖𝑖𝑖] + 𝛼𝛼𝑖𝑖+ 𝛾𝛾𝑘𝑘+𝜀𝜀𝑖𝑖𝑖𝑖 
The following SAS code may be used to estimate the model above: 
proc mixed data=impairment; 
class match group (ref=”Matched Control”) site; 
model logPKpar = group site / solution cl alpha=0.10; 
random match; 
lsmeans group; 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
 
08 May 2024 
 
- 24 - 
RESTRICTED 
run;. 
The estimates from this model can be exponentiated to get fold differences. 
 
Pairwise fold differences in drug exposure will be calculated to compare each of the mild, moderate, and 
severe impairment groups with non-hepatically impaired controls. Fold difference and mean will be estimated 
by ANOVA and shown using 90% confidence intervals. An adjustment to the confidence level for multiple 
comparisons is not planned (Table 156). 
Tmax will be summarized in each impairment group using the median, and group differences will be assessed 
using nonparametric confidence intervals computed using the inverted rank score method (Table 157). 
Medians and confidence intervals will also be computed for each site.  If the confidence intervals do not 
overlap between sites, then the Tmax will also be summarized by site.  
Summary box plots of PK parameters by impairment group (and site if appropriate) will also be prepared 
(Figure 39; Figure 40; Figure 41; Figure 42; Figure 43; and Figure 44). 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
 
08 May 2024 
 
- 25 - 
RESTRICTED 
11. 
IMMUNOGENICITY 
Not applicable. 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
 
08 May 2024 
 
- 26 - 
RESTRICTED 
12. 
OTHER ANALYSES 
Not Applicable. 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
 
08 May 2024 
 
- 27 - 
RESTRICTED 
13. 
REPORTING CONVENTIONS 
P-values ≥0.001 and ≤0.999 will be reported to 3 decimal places; p-values less than 0.001 will be reported as 
“<0.001” The mean, standard deviation, and other statistics will be reported to 1 decimal place greater than 
the original data. The minimum and maximum will use the same number of decimal places as the original 
data. Proportions will be presented as 2 decimal places; values greater than zero but <0.01 will be presented 
as “<0.01”. Percentages will be reported to the nearest whole number; values greater than zero but < 1% will 
be presented as “<1”; values greater than 99% but less than 100% will be reported as >99%. Estimated 
parameters, not on the same scale as raw observations (e.g. regression coefficients) will be reported to 
3 significant figures. Drug concentrations, AUCs, and Cmax and their summary statistics will have the same 
number of significant digits as the drug concentrations reported by the bioanalytical laboratory. Other PK 
parameters will be reported to 1 decimal place. 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
 
08 May 2024 
 
- 28 - 
RESTRICTED 
14. 
TECHNICAL DETAILS 
Estimation of NCA parameters will be performed in a validated version of WinNonlin version 6.3 or later, or 
a similar software package. WinNonlin, SAS version 9.3 or later or R statistical computing software 3.4.2 or 
higher will be used to generate all tables, figures, and listings. 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
 
08 May 2024 
 
- 29 - 
RESTRICTED 
15. 
SUMMARY OF CHANGES IN THE CONDUCT OF THE STUDY OR 
PLANNED ANALYSES 
No changes in the conduct of the study or planned analysis. 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
 
08 May 2024 
 
- 30 - 
RESTRICTED 
16. 
REFERENCES 
1. ICH. International Conference on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use (ICH) Efficacy Guidelines. Available from: 
https://www.ich.org/products/guidelines/efficacy/article/efficacy-guidelines.html; 
E3: https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E3/E3_Guideline.pdf; 
E8: https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E8/Step4/E8_Guideline.pdf; 
E9: https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E9/Step4/E9_Guideline.pdf 
2. Organization WH. Global Tuberculosis Report2016. 
3. Murray CJ, Ortblad KF, Guinovart C, Lim SS, Wolock TM, Roberts DA, Dansereau EA, Graetz N, 
Barber RM, Brown JC, Wang H, Duber HC, Naghavi M, Dicker D, Dandona L, Salomon JA, Heuton 
KR, Foreman K, Phillips DE, Fleming TD, Flaxman AD, Phillips BK, Johnson EK, Coggeshall MS, 
Abd-Allah F, Abera SF, Abraham JP, Abubakar I, Abu-Raddad LJ, Abu-Rmeileh NM, Achoki T, 
Adeyemo AO, Adou AK, Adsuar JC, Agardh EE, Akena D, Al Kahbouri MJ, Alasfoor D, Albittar MI, 
Alcala-Cerra G, Alegretti MA, Alemu ZA, Alfonso-Cristancho R, Alhabib S, Ali R, Alla F, Allen PJ, 
Alsharif U, Alvarez E, Alvis-Guzman N, Amankwaa AA, Amare AT, Amini H, Ammar W, Anderson 
BO, Antonio CA, Anwari P, Arnlov J, Arsenijevic VS, Artaman A, Asghar RJ, Assadi R, Atkins LS, 
Badawi A, Balakrishnan K, Banerjee A, Basu S, Beardsley J, Bekele T, Bell ML, Bernabe E, Beyene 
TJ, Bhala N, Bhalla A, Bhutta ZA, Abdulhak AB, Binagwaho A, Blore JD, Basara BB, Bose D, 
Brainin M, Breitborde N, Castaneda-Orjuela CA, Catala-Lopez F, Chadha VK, Chang JC, Chiang PP, 
Chuang TW, Colomar M, Cooper LT, Cooper C, Courville KJ, Cowie BC, Criqui MH, Dandona R, 
Dayama A, De Leo D, Degenhardt L, Del Pozo-Cruz B, Deribe K, Des Jarlais DC, Dessalegn M, 
Dharmaratne SD, Dilmen U, Ding EL, Driscoll TR, Durrani AM, Ellenbogen RG, Ermakov SP, 
Esteghamati A, Faraon EJ, Farzadfar F, Fereshtehnejad SM, Fijabi DO, Forouzanfar MH, Fra Paleo U, 
Gaffikin L, Gamkrelidze A, Gankpe FG, Geleijnse JM, Gessner BD, Gibney KB, Ginawi IA, Glaser 
EL, Gona P, Goto A, Gouda HN, Gugnani HC, Gupta R, Hafezi-Nejad N, Hamadeh RR, Hammami 
M, Hankey GJ, Harb HL, Haro JM, Havmoeller R, Hay SI, Hedayati MT, Pi IB, Hoek HW, 
Hornberger JC, Hosgood HD, Hotez PJ, Hoy DG, Huang JJ, Iburg KM, Idrisov BT, Innos K, Jacobsen 
KH, Jeemon P, Jensen PN, Jha V, Jiang G, Jonas JB, Juel K, Kan H, Kankindi I, Karam NE, Karch A, 
Karema CK, Kaul A, Kawakami N, Kazi DS, Kemp AH, Kengne AP, Keren A, Kereselidze M, 
Khader YS, Khalifa SE, Khan EA, Khang YH, Khonelidze I, Kinfu Y, Kinge JM, Knibbs L, Kokubo 
Y, Kosen S, Defo BK, Kulkarni VS, Kulkarni C, Kumar K, Kumar RB, Kumar GA, Kwan GF, Lai T, 
Balaji AL, Lam H, Lan Q, Lansingh VC, Larson HJ, Larsson A, Lee JT, Leigh J, Leinsalu M, Leung 
R, Li Y, De Lima GM, Lin HH, Lipshultz SE, Liu S, Liu Y, Lloyd BK, Lotufo PA, Machado VM, 
Maclachlan JH, Magis-Rodriguez C, Majdan M, Mapoma CC, Marcenes W, Marzan MB, Masci JR, 
Mashal MT, Mason-Jones AJ, Mayosi BM, Mazorodze TT, McKay AC, Meaney PA, Mehndiratta 
MM, Mejia-Rodriguez F, Melaku YA, Memish ZA, Mendoza W, Miller TR, Mills EJ, Mohammad 
KA, Mokdad AH, Mola GL, Monasta L, Montico M, Moore AR, Mori R, Moturi WN, Mukaigawara 
M, Murthy KS, Naheed A, Naidoo KS, Naldi L, Nangia V, Narayan KM, Nash D, Nejjari C, Nelson 
RG, Neupane SP, Newton CR, Ng M, Nisar MI, Nolte S, Norheim OF, Nowaseb V, Nyakarahuka L, 
Oh IH, Ohkubo T, Olusanya BO, Omer SB, Opio JN, Orisakwe OE, Pandian JD, Papachristou C, 
Caicedo AJ, Patten SB, Paul VK, Pavlin BI, Pearce N, Pereira DM, Pervaiz A, Pesudovs K, Petzold 
M, Pourmalek F, Qato D, Quezada AD, Quistberg DA, Rafay A, Rahimi K, Rahimi-Movaghar V, Ur 
Rahman S, Raju M, Rana SM, Razavi H, Reilly RQ, Remuzzi G, Richardus JH, Ronfani L, Roy N, 
Sabin N, Saeedi MY, Sahraian MA, Samonte GM, Sawhney M, Schneider IJ, Schwebel DC, Seedat S, 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
 
08 May 2024 
 
- 31 - 
RESTRICTED 
Sepanlou SG, Servan-Mori EE, Sheikhbahaei S, Shibuya K, Shin HH, Shiue I, Shivakoti R, 
Sigfusdottir ID, Silberberg DH, Silva AP, Simard EP, Singh JA, Skirbekk V, Sliwa K, Soneji S, 
Soshnikov SS, Sreeramareddy CT, Stathopoulou VK, Stroumpoulis K, Swaminathan S, Sykes BL, 
Tabb KM, Talongwa RT, Tenkorang EY, Terkawi AS, Thomson AJ, Thorne-Lyman AL, Towbin JA, 
Traebert J, Tran BX, Dimbuene ZT, Tsilimbaris M, Uchendu US, Ukwaja KN, Uzun SB, Vallely AJ, 
Vasankari TJ, Venketasubramanian N, Violante FS, Vlassov VV, Vollset SE, Waller S, Wallin MT, 
Wang L, Wang X, Wang Y, Weichenthal S, Weiderpass E, Weintraub RG, Westerman R, White RA, 
Wilkinson JD, Williams TN, Woldeyohannes SM, Wong JQ, Xu G, Yang YC, Yano Y, Yentur GK, 
Yip P, Yonemoto N, Yoon SJ, Younis M, Yu C, Jin KY, El Sayed Zaki M, Zhao Y, Zheng Y, Zhou 
M, Zhu J, Zou XN, Lopez AD, Vos T. Global, regional, and national incidence and mortality for HIV, 
tuberculosis, and malaria during 1990-2013: a systematic analysis for the Global Burden of Disease 
Study 2013. Lancet. 2014;384(9947):1005-70. Epub 2014/07/26. doi: 10.1016/S0140-6736(14)60844-
8 
S0140-6736(14)60844-8 [pii]. PubMed PMID: 25059949. 
4. Organization WH. Global tuberculosis report (2012). Geneva, Switzerland: 2012. 
5. Comstock GW. Epidemiology of tuberculosis. Am Rev Respir Dis. 1982;125(3 Pt 2):8-15. Epub 
1982/03/01. PubMed PMID: 7073104. 
6. Maggi N, Pasqualucci CR, Ballotta R, Sensi P. Rifampicin: a new orally active rifamycin. 
Chemotherapy. 1966;11(5):285-92. Epub 1966/01/01. PubMed PMID: 5958716. 
7. Organization WH. Treatment of tuberculosis. Guidelines for national programmes, 3rd ed. Geneva, 
Switzerland 2003. Available from: http://www.who.int/tb/publications/2008/en/index.html. 
8. Diacon AH, Dawson R, Hanekom M, Narunsky K, Maritz SJ, Venter A, Donald PR, van Niekerk C, 
Whitney K, Rouse DJ, Laurenzi MW, Ginsberg AM, Spigelman MK. Early bactericidal activity and 
pharmacokinetics of PA-824 in smear-positive tuberculosis patients. Antimicrob Agents Chemother. 
2010;54(8):3402-7. Epub 2010/05/26. doi: 10.1128/AAC.01354-09 
AAC.01354-09 [pii]. PubMed PMID: 20498324; PMCID: 2916303. 
9. Chang KC, Leung CC, Yew WW, Chan SL, Tam CM. Dosing schedules of 6-month regimens and 
relapse for pulmonary tuberculosis. Am J Respir Crit Care Med. 2006;174(10):1153-8. Epub 
2006/08/16. doi: 200605-637OC [pii] 
10.1164/rccm.200605-637OC. PubMed PMID: 16908866. 
10. Kruk ME, Schwalbe NR, Aguiar CA. Timing of default from tuberculosis treatment: a systematic 
review. Trop Med Int Health. 2008;13(5):703-12. Epub 2008/02/13. doi: 10.1111/j.1365-
3156.2008.02042.x 
TMI2042 [pii]. PubMed PMID: 18266783. 
11. Caminero JA, Sotgiu G, Zumla A, Migliori GB. Best drug treatment for multidrug-resistant and 
extensively drug-resistant tuberculosis. Lancet Infect Dis. 2010;10(9):621-9. Epub 2010/08/28. doi: 
10.1016/S1473-3099(10)70139-0 
S1473-3099(10)70139-0 [pii]. PubMed PMID: 20797644. 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
 
08 May 2024 
 
- 32 - 
RESTRICTED 
12. FDA. Guidance for Industry: Pharmacokinetics in Patients with Impaired Hepatic Function: Study 
Design, Data Analysis, and Impact on Dosing and Labeling. 2003. Available from: 
http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm07212
3.pdf 
13. Drummond R. CONSORT Revised: Improving the Reporting of Randomized Clinical Trials. JAMA. 
2001; 285(15):2006-2007. 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
 
08 May 2024 
 
- 33 - 
RESTRICTED 
17. 
LISTING OF TABLES, FIGURES, AND LISTINGS 
Table, figure, and listing shells are presented in Appendices 1, 2, and 3. 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
 
08 May 2024 
 
- 34 - 
RESTRICTED 
APPENDICES 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
 
08 May 2024 
 
- 35 - 
RESTRICTED 
APPENDIX 1. TABLE MOCK-UPS 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
 
08 May 2024 
 
- 36 - 
RESTRICTED 
LIST OF TABLES 
Table 1: 
Study Design ...............................................................................................................44 
Table 2: 
Summary of 4 Pretomanid Phase 2 studies .................................................................44 
Table 3: 
Schedule of Study Procedures ....................................................................................45 
Table 4: 
Distribution of Protocol Deviations by Category, Type, and Impairment Group ......47 
Table 5: 
Laboratory/Clinical Adverse Event Grading Scale ....................................................49 
Table 6: 
Subject Disposition by Impairment Group .................................................................52 
Table 7: 
Analysis Populations by Impairment Group ...............................................................53 
Table 8: 
Ineligibility Summary of Screen Failures ...................................................................54 
Table 9: 
Summary of Categorical Demographic and Baseline Characteristics by Site ............56 
Table 10: Summary of Continuous Demographic and Baseline Characteristics by Site ............57 
Table 11: Summary of Categorical Demographic and Baseline Characteristics by Impairment Group
 ....................................................................................................................................58 
Table 12: Summary of Continuous Demographic and Baseline Characteristics by Impairment Group
 ....................................................................................................................................59 
Table 13: Summary of Subjects with Pre-Existing Medical Conditions by MedDRA System Organ 
Class and Impairment Group ......................................................................................60 
Table 14: Overall Summary of Adverse Events .........................................................................62 
Table 15: Summary of Unsolicited Adverse Events by MedDRA System Organ Class and Preferred 
Term, and Impairment Group – Mild Hepatic Impairment ........................................64 
Table 16: Summary of Unsolicited Adverse Events by MedDRA System Organ Class and Preferred 
Term, and Impairment Group – Moderate Hepatic Impairment .................................64 
Table 17: Summary of Unsolicited Adverse Events by MedDRA System Organ Class and Preferred 
Term, and Impairment Group – Severe Hepatic Impairment .....................................64 
Table 18: Summary of Unsolicited Adverse Events by MedDRA System Organ Class and Preferred 
Term, and Impairment Group – Matched Controls ....................................................64 
Table 19: Incidence of Unsolicited Adverse Events by MedDRA System Organ Class and Preferred 
Term, Maximum Severity, Relationship, and Impairment Group ..............................65 
Table 20: Listing of Serious Adverse Events .............................................................................66 
Table 21: Listing of Non-Serious, Unsolicited, Moderate or Severe Adverse Events ...............67 
Table 22: Listing of Abnormal Laboratory Results - Chemistry ................................................68 
Table 23: Listing of Abnormal Laboratory Results - Hematology .............................................69 
Table 24: Listing of Abnormal Laboratory Results - Urinalysis ................................................70 
Table 25: Listing of Abnormal Laboratory Results - Coagulation .............................................71 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
 
08 May 2024 
 
LIST OF TABLES (continued) 
- 37 - 
RESTRICTED 
Table 26: Chemistry Laboratory Results by Maximum Severity, Time Point, and Impairment Group 
– Any Chemistry Parameter ........................................................................................72 
Table 27: Chemistry Laboratory Results by Maximum Severity, Time Point, and Impairment Group 
– Total Bilirubin .........................................................................................................73 
Table 28: Chemistry Laboratory Results by Maximum Severity, Time Point, and Impairment Group 
– Serum Albumin ........................................................................................................73 
Table 29: Chemistry Laboratory Results by Range, Maximum Severity, Time Point, and 
Impairment Group – Potassium ..................................................................................74 
Table 30: Chemistry Laboratory Results by Maximum Severity, Time Point, and Impairment Group 
– Magnesium ..............................................................................................................76 
Table 31: Chemistry Laboratory Results by Range, Maximum Severity, Time Point, and 
Impairment Group – Calcium .....................................................................................78 
Table 32: Chemistry Laboratory Results by Maximum Severity, Time Point, and Impairment Group 
– Serum Creatinine .....................................................................................................79 
Table 33: Chemistry Laboratory Results by Maximum Severity, Time Point, and Impairment Group 
– BUN .........................................................................................................................80 
Table 34: Chemistry Laboratory Results by Maximum Severity, Time Point, and Impairment Group 
– Alkaline Phosphatase ...............................................................................................81 
Table 35: Chemistry Laboratory Results by Maximum Severity, Time Point, and Impairment Group 
– ALT ..........................................................................................................................81 
Table 36: Chemistry Laboratory Results by Maximum Severity, Time Point, and Impairment Group 
– AST ..........................................................................................................................81 
Table 37: Abnormal Chemistry Laboratory Results Related to Study Treatment by Maximum 
Severity, Time Point, and Impairment Group – Any Chemistry Parameter ...............82 
Table 38: Abnormal Chemistry Laboratory Results Related to Study Treatment by Maximum 
Severity, Time Point, and Impairment Group – Total Bilirubin .................................83 
Table 39: Abnormal Chemistry Laboratory Results Related to Study Treatment by Maximum 
Severity, Time Point, and Impairment Group – Serum Albumin ...............................83 
Table 40: Abnormal Chemistry Laboratory Results Related to Study Treatment by Range, 
Maximum Severity, Time Point, and Impairment Group – Potassium ......................84 
Table 41: Abnormal Chemistry Laboratory Results Related to Study Treatment by Maximum 
Severity, Time Point, and Impairment Group – Magnesium ......................................86 
Table 42: Abnormal Chemistry Laboratory Results Related to Study Treatment by Range, 
Maximum Severity, Time Point, and Impairment Group – Calcium .........................87 
Table 43: Abnormal Chemistry Laboratory Results Related to Study Treatment by Maximum 
Severity, Time Point, and Impairment Group – Serum Creatinine ............................88 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
 
08 May 2024 
 
LIST OF TABLES (continued) 
- 38 - 
RESTRICTED 
Table 44: Abnormal Chemistry Laboratory Results Related to Study Treatment by Maximum 
Severity, Time Point, and Impairment Group – BUN ................................................89 
Table 45: Abnormal Chemistry Laboratory Results Related to Study Treatment by Maximum 
Severity, Time Point, and Impairment Group – Alkaline Phosphatase ......................90 
Table 46: Abnormal Chemistry Laboratory Results Related to Study Treatment by Maximum 
Severity, Time Point, and Impairment Group – ALT .................................................90 
Table 47: Abnormal Chemistry Laboratory Results Related to Study Treatment by Maximum 
Severity, Time Point, and Impairment Group – AST .................................................90 
Table 48: Chemistry Laboratory Summary Statistics by Time Point and Impairment Group – Total 
Bilirubin (mg/dL) ........................................................................................................91 
Table 49: Chemistry Laboratory Summary Statistics by Time Point and Impairment Group – Serum 
Albumin (g/dL) ...........................................................................................................92 
Table 50: Chemistry Laboratory Summary Statistics by Range, Time Point, and Impairment Group 
– Potassium (mmol/dL) ..............................................................................................92 
Table 51: Chemistry Laboratory Summary Statistics by Time Point and Impairment Group – 
Magnesium (mg/dL) ...................................................................................................92 
Table 52: Chemistry Laboratory Summary Statistics by Time Point and Impairment Group – 
Calcium (mg/dL) ........................................................................................................92 
Table 53: Chemistry Laboratory Summary Statistics by Time Point and Impairment Group – Serum 
Creatinine (mg/dL) .....................................................................................................92 
Table 54: Chemistry Laboratory Summary Statistics by Time Point and Impairment Group – BUN 
(mg/dL) .......................................................................................................................92 
Table 55: Chemistry Laboratory Summary Statistics by Time Point and Impairment Group – 
Alkaline Phosphatase (U/L) ........................................................................................92 
Table 56: Chemistry Laboratory Summary Statistics by Time Point and Impairment Group – ALT 
(U/L) ...........................................................................................................................92 
Table 57: Chemistry Laboratory Summary Statistics by Time Point and Impairment Group – AST 
(U/L) ...........................................................................................................................92 
Table 58: Hematology Laboratory Results by Maximum Severity, Time Point, and Impairment 
Group – Any Hematology Parameter .........................................................................93 
Table 59: Hematology Laboratory Results by Maximum Severity, Time Point, and Impairment 
Group – Hematocrit ....................................................................................................94 
Table 60: Hematology Laboratory Results by Maximum Severity, Time Point, and Impairment 
Group – Hemoglobin ..................................................................................................94 
Table 61: Hematology Laboratory Results by Maximum Severity, Time Point, and Impairment 
Group – Red Blood Cell Count ..................................................................................94 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
 
08 May 2024 
 
LIST OF TABLES (continued) 
- 39 - 
RESTRICTED 
Table 62: Hematology Laboratory Results by Range, Maximum Severity, Time Point, and 
Impairment Group – White Blood Cell Count ...........................................................95 
Table 63: Hematology Laboratory Results by Maximum Severity, Time Point, and Impairment 
Group – Absolute Neutrophils ....................................................................................97 
Table 64: Hematology Laboratory Results by Maximum Severity, Time Point, and Impairment 
Group – Absolute Eosinophils ....................................................................................98 
Table 65: Hematology Laboratory Results by Maximum Severity, Time Point, and Impairment 
Group – Absolute Basophils .......................................................................................98 
Table 66: Hematology Laboratory Results by Maximum Severity, Time Point, and Impairment 
Group – Absolute Lymphocytes .................................................................................98 
Table 67: Hematology Laboratory Results by Maximum Severity, Time Point, and Impairment 
Group – Absolute Monocytes .....................................................................................98 
Table 68: Hematology Laboratory Results by Maximum Severity, Time Point, and Impairment 
Group – Platelets .........................................................................................................98 
Table 69: Abnormal Hematology Laboratory Results Related to Study Treatment by Maximum 
Severity, Time Point, and Impairment Group – Any Hematology Parameter ............99 
Table 70: Abnormal Hematology Laboratory Results Related to Study Treatment by Maximum 
Severity, Time Point, and Impairment Group – Hematocrit ....................................100 
Table 71: Abnormal Hematology Laboratory Results Related to Study Treatment by Maximum 
Severity, Time Point, and Impairment Group – Hemoglobin ..................................100 
Table 72: Abnormal Hematology Laboratory Results Related to Study Treatment by Maximum 
Severity, Time Point, and Impairment Group – Red Blood Cell Count ...................100 
Table 73: Abnormal Hematology Laboratory Results Related to Study Treatment by Maximum 
Severity, Time Point, and Impairment Group – White Blood Cell Count ...............101 
Table 74: Abnormal Hematology Laboratory Results Related to Study Treatment by Maximum 
Severity, Time Point, and Impairment Group – Absolute Neutrophils ....................103 
Table 75: Abnormal Hematology Laboratory Results Related to Study Treatment by Maximum 
Severity, Time Point, and Impairment Group – Absolute Eosinophils ....................104 
Table 76: Abnormal Hematology Laboratory Results Related to Study Treatment by Maximum 
Severity, Time Point, and Impairment Group – Absolute Basophils .......................104 
Table 77: Abnormal Hematology Laboratory Results Related to Study Treatment by Maximum 
Severity, Time Point, and Impairment Group – Absolute Lymphocytes .................104 
Table 78: Abnormal Hematology Laboratory Results Related to Study Treatment by Maximum 
Severity, Time Point, and Impairment Group – Absolute Monocytes .....................104 
Table 79: Abnormal Hematology Laboratory Results Related to Study Treatment by Maximum 
Severity, Time Point, and Impairment Group – Platelets .........................................104 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
 
08 May 2024 
 
LIST OF TABLES (continued) 
- 40 - 
RESTRICTED 
Table 80: Hematology Laboratory Summary Statistics by Time Point and Impairment Group – 
Hematocrit (%) .........................................................................................................105 
Table 81: Hematology Laboratory Summary Statistics by Time Point and Impairment Group – 
Hemoglobin (g/dL) ...................................................................................................106 
Table 82: Hematology Laboratory Summary Statistics by Time Point and Impairment Group – Red 
Blood Cell Count (x1012/L) ......................................................................................106 
Table 83: Hematology Laboratory Summary Statistics by Time Point and Impairment Group – 
White Blood Cell Count (x109/L) .............................................................................106 
Table 84: Hematology Laboratory Summary Statistics by Time Point and Impairment Group – 
Absolute Neutrophils (x109/L) .................................................................................106 
Table 85: Hematology Laboratory Summary Statistics by Time Point and Impairment Group – 
Absolute Eosinophils (x109/L) .................................................................................106 
Table 86: Hematology Laboratory Summary Statistics by Time Point and Impairment Group – 
Absolute Basophils (x109/L) .....................................................................................106 
Table 87: Hematology Laboratory Summary Statistics by Time Point and Impairment Group – 
Absolute Lymphocytes (x109/L)...............................................................................106 
Table 88: Hematology Laboratory Summary Statistics by Time Point and Impairment Group – 
Absolute Monocytes (x109/L)...................................................................................106 
Table 89: Hematology Laboratory Summary Statistics by Time Point and Impairment Group – 
Platelets (x109/L) ......................................................................................................106 
Table 90: Urinalysis Laboratory Results by Parameter, Time Point, and Impairment Group ..107 
Table 91: Urinalysis Laboratory Results by Maximum Severity, Time Point, and Impairment Group 
– Any Urinalysis Parameter ......................................................................................108 
Table 92: Urinalysis Laboratory Results by Maximum Severity, Time Point, and Impairment Group 
– Protein ....................................................................................................................109 
Table 93: Urinalysis Laboratory Results by Maximum Severity, Time Point, and Impairment Group 
– Glucose ..................................................................................................................109 
Table 94: Urinalysis Laboratory Results by Maximum Severity, Time Point, and Impairment Group 
– Urine Blood ...........................................................................................................109 
Table 95: Abnormal Urinalysis Laboratory Results Related to Study Treatment by Maximum 
Severity, Time Point, and Impairment Group – Any Urinalysis Parameter .............110 
Table 96: Abnormal Urinalysis Laboratory Results Related to Study Treatment by Maximum 
Severity, Time Point, and Impairment Group – Protein ...........................................111 
Table 97: Abnormal Urinalysis Laboratory Results Related to Study Treatment by Maximum 
Severity, Time Point, and Impairment Group – Glucose .........................................111 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
 
08 May 2024 
 
LIST OF TABLES (continued) 
- 41 - 
RESTRICTED 
Table 98: Abnormal Urinalysis Laboratory Results Related to Study Treatment by Maximum 
Severity, Time Point, and Impairment Group – Urine Blood ...................................111 
Table 99: Urinalysis Laboratory Summary Statistics by Time Point and Impairment Group – Blood 
(rbc/hpf) ....................................................................................................................112 
Table 100: Urinalysis Laboratory Summary Statistics by Time Point and Impairment Group – Protein
 ..................................................................................................................................114 
Table 101: Urinalysis Laboratory Summary Statistics by Time Point and Impairment Group – 
Glucose .....................................................................................................................115 
Table 102: Coagulation Laboratory Results by Maximum Severity, Time Point, and Impairment 
Group – INR .............................................................................................................116 
Table 103: Abnormal Coagulation Laboratory Results Related to Study Treatment by Maximum 
Severity, Time Point, and Impairment Group – INR ................................................118 
Table 104: Coagulation Laboratory Summary Statistics by Time Point and Impairment Group – INR
 ..................................................................................................................................119 
Table 105: Chemistry Shift Tables by Time Point and Impairment Group – Total Bilirubin ....121 
Table 106: Chemistry Shift Tables by Time Point and Impairment Group – Serum Albumin ..121 
Table 107: Chemistry Shift Tables by Time Point and Impairment Group – Potassium ...........121 
Table 108: Chemistry Shift Tables by Time Point and Impairment Group – Magnesium .........121 
Table 109: Chemistry Shift Tables by Time Point and Impairment Group – Calcium ..............122 
Table 110: Chemistry Shift Tables by Time Point and Impairment Group – Serum Creatinine 122 
Table 111: Chemistry Shift Tables by Time Point and Impairment Group – BUN ...................122 
Table 112: Chemistry Shift Tables by Time Point and Impairment Group – Alkaline Phosphatase
 ..................................................................................................................................122 
Table 113: Chemistry Shift Tables by Time Point and Impairment Group – ALT ....................122 
Table 114: Chemistry Shift Tables by Time Point and Impairment Group – AST ....................122 
Table 115: Hematology Shift Tables by Time Point and Impairment Group – Hematocrit .......122 
Table 116: Hematology Shift Tables by Time Point and Impairment Group – Hemoglobin .....122 
Table 117: Hematology Shift Tables by Time Point and Impairment Group – Red Blood Cell Count
 ..................................................................................................................................122 
Table 118: Hematology Shift Tables by Time Point and Impairment Group – White Blood Cell 
Count.........................................................................................................................122 
Table 119: Hematology Shift Tables by Time Point and Impairment Group – Neutrophils ......122 
Table 120: Hematology Shift Tables by Time Point and Impairment Group – Eosinophils ......122 
Table 121: Hematology Shift Tables by Time Point and Impairment Group – Basophils .........122 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
 
08 May 2024 
 
LIST OF TABLES (continued) 
- 42 - 
RESTRICTED 
Table 122: Hematology Shift Tables by Time Point and Impairment Group – Lymphocytes ...122 
Table 123: Hematology Shift Tables by Time Point and Impairment Group – Monocytes .......122 
Table 124: Hematology Shift Tables by Time Point and Impairment Group – Platelets ...........122 
Table 125: Coagulation Shift Tables by Time Point and Impairment Group – INR ..................122 
Table 126: Urinalysis Shift Tables by Time Point and Impairment Group – Protein ................122 
Table 127: Urinalysis Shift Tables by Time Point and Impairment Group – Glucose ...............122 
Table 128: Urinalysis Shift Tables by Time Point and Impairment Group – Blood ..................122 
Table 129: Vital Signs by Maximum Severity, Time Point, and Impairment Group – Any Assessment
 ..................................................................................................................................123 
Table 130: Vital Signs by Maximum Severity, Time Point, and Impairment Group – Oral 
Temperature ..............................................................................................................126 
Table 131: Vital Signs by Maximum Severity, Time Point, and Impairment Group – Pulse ....127 
Table 132: Vital Signs by Maximum Severity, Time Point, and Impairment Group – Systolic Blood 
Pressure .....................................................................................................................131 
Table 133: Vital Signs by Maximum Severity, Time Point, and Impairment Group – Diastolic Blood 
Pressure .....................................................................................................................132 
Table 134: Vital Signs Summary Statistics by Time Point and Impairment Group – Oral Temperature
 ..................................................................................................................................136 
Table 135: Vital Signs Summary Statistics by Time Point and Impairment Group – Pulse ......141 
Table 136: Vital Signs Summary Statistics by Time Point and Impairment Group – Systolic Blood 
Pressure .....................................................................................................................141 
Table 137: Vital Signs Summary Statistics by Time Point and Impairment Group – Diastolic Blood 
Pressure .....................................................................................................................141 
Table 138: Summary of Abnormal Physical Exam Findings by Impairment Group .................142 
Table 139: Physical Exam Summary Statistics by Time Point and Impairment Group – Weight144 
Table 140: Number and Percentage of Subjects with Prior and Concurrent Medications by WHO 
Drug Classification and Impairment Group .............................................................150 
Table 141: ECG Summary Statistics by Time Point and Impairment Group – RR ...................151 
Table 142: ECG Summary Statistics by Time Point and Impairment Group – QRS .................151 
Table 143: ECG Summary Statistics by Time Point and Impairment Group – QT ...................151 
Table 144: ECG Summary Statistics by Time Point and Impairment Group – QTcF ...............151 
Table 145: ECG Summary Statistics by Time Point and Impairment Group – PR ....................151 
Table 146: ECG Summary Statistics by Time Point and Impairment Group – Ventricular Rate151 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
 
08 May 2024 
 
LIST OF TABLES (continued) 
- 43 - 
RESTRICTED 
Table 147: Number and Percentage of Subjects Experiencing ECG Events by Symptom, and 
Impairment Group ....................................................................................................152 
Table 148: Individual and Summary Statistics for Plasma Concentrations by Nominal Time (hours) – 
Mild Hepatic Impairment .........................................................................................153 
Table 149: Individual and Summary Statistics for Plasma Concentrations by Nominal Time (hours) – 
Moderate Hepatic Impairment ..................................................................................153 
Table 150: Individual and Summary Statistics for Plasma Concentrations by Nominal Time (hours) – 
Severe Hepatic Impairment ......................................................................................153 
Table 151: Individual and Summary Statistics for Plasma Concentrations by Nominal Time (hours) – 
Matched Controls ......................................................................................................153 
Table 152: Individual and Summary Statistics for Noncompartmental PK Parameters – Mild Hepatic 
Impairment ................................................................................................................154 
Table 153: Individual and Summary Statistics for Noncompartmental PK Parameters – Moderate 
Hepatic Impairment ..................................................................................................154 
Table 154: Individual and Summary Statistics for Noncompartmental PK Parameters – Severe 
Hepatic Impairment ..................................................................................................154 
Table 155: Individual and Summary Statistics for Noncompartmental PK Parameters – Matched 
Controls.....................................................................................................................154 
Table 156: Estimated Impairment Group Fold Change for Noncompartmental PK Parameters155 
Table 157: Estimated Impairment Group Shift for Noncompartmental PK Parameters ............157 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
 
08 May 2024 
 
- 44 - 
RESTRICTED 
9.1 
Overall Study Design and Plan Description 
Table 1: 
Study Design 
Study Group 
Severity 
N 
Group 1 
Child-Pugh A = 5 to 6 points (Mild Hepatic Impairment) 
6 
Group 2 
Child-Pugh B = 7 to 9 points (Moderate Hepatic Impairment) 
6 
Group 3 
Child-Pugh C = 10 to 15 points (Severe Hepatic Impairment) 
6 
Group 4 
Non-hepatically impaired controls (Matched Controls) 
≤18 
 
Table 2: 
Summary of 4 Pretomanid Phase 2 studies 
Year 
N 
Pretomanid 
Regimen 
Dosage 
Primary 
Outcome 
Mean daily fall in CFU 
2010 
60 
Once Daily 
200, 600, 1000,and 
1200 mg/day 
Mean rate of 
decline in log 
CFU of TB over 
14 days 
0.098 (+/-0.072)  was equivalent for all 
four dosages 
2012 
60 
Once Daily 
50, 100, 150, and 
200 mg/day 
Mean rate of 
decline in log 
CFU of TB over 
14 days 
50mg 0.063 ± 0.058 
100mg 0.091 ± 0.073 
150mg 0.078 ± 0.074 
200mg 0.112 ± 0.070 
2012 
81 
Once Daily 
Pretomanid + bedaquiline 
Pretomanid + pyrazinamide 
 Pretomanid + pyrazinamide + 
moxifloxacin 
 
(all Pretomanid dosages were 
200mg/day) 
Mean rate of 
decline in log 
CFU of TB over 
56 days 
Pretomanid+ 
moxifloxacin+pyrazinamide (0.233) 
was significantly higher than 
bedaquiline (0.061), 
bedaquiline+pyrazinamide (0.131), and 
comparable with that of standard 
treatment 
2014 
207 
Once Daily 
Pretomanid 200mg + 
pyrazinamide + moxifloxacin 
Pretomanid 100mg + 
pyrazinamide + moxifloxacin 
Pretomanid 200mg + 
pyrazinamide + moxifloxacin 
(Tx MDR-TB) 
Mean rate of 
decline in log 
CFU of TB over 
14 days 
Pretomanid 200mg + pyrazinamide + 
moxifloxacin (0.155) 
Pretomanid 100mg + pyrazinamide + 
moxifloxacin (0.133) 
Pretomanid 200mg + pyrazinamide + 
moxifloxacin  
(Tx MDR-TB) (0.117) 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 1: Table Mock-Ups 
08 May 2024 
 
- 45 - 
RESTRICTED 
9.5.1 Efficacy/Immunogenicity and Safety Measurements Assessed and Flow Chart 
Table 3: 
Schedule of Study Procedures 
Study Visit  
00A  
00B  
01  
01A  
01B  
01C  
01D  
01E  
01F 
01G 
01H 
01I  
01J  
02  
03  
04  
05  
Early 
Term  
Study Day  
Screen 
-22 to -
2 
Admission 
-1 
1  
1  
1  
1  
1  
1  
1 
1  
1 
2  
2  
3  
4  
5  
12  
 
Time (Window)  
 
 
0  
(-10 
min)  
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 hrs 
(+/- 
10 
min) 
16 hr 
(+/-
10 
min) 
24 hrs 
(+/- 
1 hr)  
36 hrs 
(+/- 
1 hr) 
48 hrs 
(+/- 
4 hrs)  
72 hrs 
(+/- 
4 hrs) 
96 hrs 
(+/- 
4 hrs)  
 
 
Informed Consent  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review Inclusion/ 
Exclusion Criteria  
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/Surgical 
History2  
X 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
Physical Examination3  
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Targeted Review of 
Body Systems12 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
Concomitant 
Medication  
X 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
12-Lead ECG 
(Resting) 
X 
X1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Vital Signs6  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Safety Laboratory 
Testing (Hematology, 
Chemistry)9,11  
X4 
X13 
 
 
 
 
 
 
 
 
 
 
X10 
 
 
X 
X 
 
Coagulation9  
X4 
X13 
 
 
 
 
 
 
 
 
 
 
X10 
 
 
X 
X 
 
Urinalysis9  
X4 
X13 
 
 
 
 
 
 
 
 
 
 
X10 
 
 
X 
X 
 
Pregnancy Test9  
X4 
X13 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Drug and Alcohol 
Screen 5,8  
X4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood for HIV, HCV, 
HBsAg testing8 
X4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood for PK 
Sampling7  
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Discharge from the 
confinement/hospital 
unit14 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 1: Table Mock-Ups 
08 May 2024 
 
Table 3: 
Schedule of Study Procedures (continued) 
- 46 - 
RESTRICTED 
Study Visit  
00A  
00B  
01  
01A  
01B  
01C  
01D  
01E  
01F 
01G 
01H 
01I  
01J  
02  
03  
04  
05  
Early 
Term  
Study Day  
Screen 
-22 to -
2 
Admission 
-1 
1  
1  
1  
1  
1  
1  
1 
1  
1 
2  
2  
3  
4  
5  
12  
 
Time (Window)  
 
 
0  
(-10 
min)  
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 hrs 
(+/- 
10 
min) 
16 hr 
(+/-
10 
min) 
24 hrs 
(+/- 
1 hr)  
36 hrs 
(+/- 
1 hr) 
48 hrs 
(+/- 
4 hrs)  
72 hrs 
(+/- 
4 hrs) 
96 hrs 
(+/- 
4 hrs)  
 
 
Study Product 
Administration7b  
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE Assessment  
 
 
X  
X  
X  
X  
X  
X  
X 
X  
X 
X  
X  
X  
X  
X  
X  
X 
SAE Assessment  
 
 
X  
X  
X  
X  
X  
X  
X 
X  
X 
X  
X  
X  
X  
X  
X  
X 
Total blood drawn  
27.5mL 
11.5mL 
6mL 
6mL 
6mL 
6mL 
6mL 
6mL 
6mL 
6mL 
6mL 
6mL 
17.5mL 
6mL 
6mL 
17.5mL 
14.5mL 
0mL 
 
1 Child-Pugh Score calculated for hepatically-impaired subjects at 
screening 
2 Complete medical/surgical history taken at screening and interim 
medical/surgical history as sequent indicated visits.  
3 Physical examination must include the following organ or body 
system assessments: skin; head, eyes, ears, nose, and throat; 
thyroid; neurological; chest and lungs; cardiovascular; abdomen 
(liver and spleen); lymph nodes; musculoskeletal, and 
extremities. At early termination visit, a physical examination 
will be performed.  
4 If screening laboratory tests are performed within 72 hours of 
admission to the confinement/hospital unit, the tests do not have 
to be repeated with the exception of the urine pregnancy test for 
females of child bearing potential and the urine drug screen for 
all subjects, which will be repeated. 
5 Alcohol screen includes alcohol breath test or other suitable test 
for alcohol (e.g., blood alcohol test). 
6 Vital sign measurements must include the subject’s sitting heart 
rate, sitting blood pressure (mm Hg), height (screening only), 
and oral body temperature (ºC). Vital signs will be obtained at 
screening, and on Days -1 to 12 at the following time points:, 
admission day, prior to dosing, and 30 minutes after dosing, 1, 2, 
4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96 hours and Day 12. Weight 
will be collected at screening, admission day, prior to dosing, 36, 
48, 72, 96 hours and Day 12 time points. 
7 Blood samples for pharmacokinetic assessments of 
Pretomanid will be obtained on Days 1 to 5 at the following 
time points: pre-dose and 1, 2, 4, 5, 6, 8, 12, 16, 24, 36, 48, 
72, and 96 hours post-dose. 
a. The following collection windows are allowed for the 
PK blood sample time points: 
i. 
Pre-dose: -10 minutes 
ii. 
Dosing through 16 hours post-dose inclusive: 
 ± 10 minutes 
iii. 
24 and 36 hours post-dose: ± 1 hour 
iv. 
48, 72, and 96 hours: ± 4 hours 
b. Subjects will receive the single oral dose of Pretomanid 
200 mg taken with 240 mL of water after overnight fast. 
c. The following parameters will be used for PK 
assessments: AUC0-inf, AUC0-t, Cmax, tmax, half-life 
and CL/F. 
8 Screening labs include: blood screen for hepatitis B surface 
antigen (HBsAg) and hepatitis C antibody, alcohol breath 
test or other suitable test for alcohol (e.g., blood alcohol 
test), urine screen test for drugs of abuse [amphetamines, 
barbiturates, benzodiazepines, cocaine metabolites, opiates, 
cannabinoids, phencyclidine (PCP)] and a blood screen for 
HIV. 
 
9 Safety labs (also performed at screening and 2 hour fasting) 
include: total bilirubin, serum albumin, electrolytes including 
potassium, magnesium, and calcium levels, serum creatinine, 
BUN, alkaline phosphatase, AST, ALT, INR (PT 
prolongation), CBC w/differential, urinalysis, and pregnancy 
testing. Pregnancy testing at screening and Day 12 will be 
serum, and testing at admission will be a urine test. 
10 Chemistry (2 hour fasting), hematology, coagulation and 
urinalysis to be done prior to discharge.  
11 For patients with severe hepatic impairment (Child-Pugh C) 
an ammonia level will be drawn at screening and will be 
used as a baseline reading for safety purposes, not as a study 
entry criterion. 
12 A targeted review of body systems will be obtained at these 
visits focused on liver disease and will include questions 
pertaining to development of ascites, jaundice, pruritis, 
gastrointestinal bleeding, and encephalopathy. If the subject 
answers yes to any of these questions, a targeted physical 
exam will be performed. 
13 Baseline admissions labs and resting 12-Lead ECG 
recording may be done within 72 hours of admission or at 
the time of admission depending on ability to obtain lab 
results at the site. 
14 Discharge from confinement/hospital unit either after Visit 
01J or Visit 2 depending upon site preference. 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 1: Table Mock-Ups 
08 May 2024 
 
- 47 - 
RESTRICTED 
10.2 
Protocol Deviations 
Table 4: 
Distribution of Protocol Deviations by Category, Type, and Impairment Group 
Category 
Deviation Type 
Mild Hepatic 
Impairment  
(N=X) 
Moderate 
Hepatic 
Impairment 
(N=X) 
Severe 
Hepatic 
Impairment 
(N=X) 
Matched 
Controls 
(N=X) 
All Subjects 
(N=X) 
No. 
of 
Subj. 
No. of 
Dev. 
No. of 
Subj. 
No. of 
Dev. 
No. of 
Subj. 
No. of 
Dev. 
No. of 
Subj. 
No. of 
Dev. 
No. of 
Subj. 
No. 
of 
Dev. 
Eligibility/enrollment Any type 
 
 
 
 
 
 
 
 
 
 
 
Did not meet inclusion 
criterion 
x 
x 
x 
x 
 
 
 
 
x 
x 
 
Met exclusion criterion 
 
 
 
 
 
 
 
 
 
 
 
ICF not signed prior to study 
procedures 
 
 
 
 
 
 
 
 
 
 
 
Other 
 
 
 
 
 
 
 
 
 
 
Follow-up visit 
schedule 
Any type 
 
 
 
 
 
 
 
 
 
 
 
Out of window visit 
 
 
 
 
 
 
 
 
 
 
 
Missed visit/visit not 
conducted 
 
 
 
 
 
 
 
 
 
 
 
Other 
 
 
 
 
 
 
 
 
 
 
Protocol 
procedure/assessment Any type 
 
 
 
 
 
 
 
 
 
 
 
Incorrect version of ICF signed  
 
 
 
 
 
 
 
 
 
 
Blood not collected 
 
 
 
 
 
 
 
 
 
 
 
Urine not collected 
 
 
 
 
 
 
 
 
 
 
 
Stool not collected 
 
 
 
 
 
 
 
 
 
 
 
Other specimen not collected 
 
 
 
 
 
 
 
 
 
 
 
Too few aliquots obtained 
 
 
 
 
 
 
 
 
 
 
 
Specimen result not obtained 
 
 
 
 
 
 
 
 
 
 
 
Required procedure not 
conducted 
 
 
 
 
 
 
 
 
 
 
 
Required procedure done 
incorrectly 
 
 
 
 
 
 
 
 
 
 
 
Study product temperature 
excursion 
 
 
 
 
 
 
 
 
 
 
 
Specimen temperature 
excursion 
 
 
 
 
 
 
 
 
 
 
 
Other 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 1: Table Mock-Ups 
08 May 2024 
 
Table 4: 
Distribution of Protocol Deviations by Category, Type, and Treatment Group (continued) 
- 48 - 
RESTRICTED 
Category 
Deviation Type 
Mild Hepatic 
Impairment  
(N=X) 
Moderate 
Hepatic 
Impairment 
(N=X) 
Severe 
Hepatic 
Impairment 
(N=X) 
Matched 
Controls 
(N=X) 
All Subjects 
(N=X) 
No. 
of 
Subj. 
No. of 
Dev. 
No. of 
Subj. 
No. of 
Dev. 
No. of 
Subj. 
No. of 
Dev. 
No. of 
Subj. 
No. of 
Dev. 
No. of 
Subj. 
No. 
of 
Dev. 
Treatment 
administration 
Any type 
 
 
 
 
 
 
 
 
 
 
 
Required procedure done 
incorrectly 
 
 
 
 
 
 
 
 
 
 
 
Study product temperature 
excursion 
 
 
 
 
 
 
 
 
 
 
 
Other 
 
 
 
 
 
 
 
 
 
 
Note: N= All Enrolled Subjects 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 1: Table Mock-Ups 
08 May 2024 
 
- 49 - 
RESTRICTED 
12.4.1 Individual Laboratory Measurements and Abnormal Laboratory Values 
Table 5: 
Laboratory/Clinical Adverse Event Grading Scale 
Category 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Comments 
VITAL SIGNS 
Fever (°C) ** 
38.0 – 38.4 
38.5 – 38.9 
≥ 39.0 
** Oral temperature; no 
recent hot or cold 
beverages or smoking. 
A protocol should select 
either °C or °F for 
inclusion. 
 
(°F) ** 
100.4 – 101.1 
101.2 – 102.0 
≥ 102.1  
Tachycardia – beats per minute 
101 – 115 
116 – 130 
> 130 or 
ventricular 
dysrhythmias 
Bradycardia – beats per minute 
50 – 54 or 45-50 
bpm if pre-dose 
visit rate < 60 bpm 
45 – 49 or 40-44 
if pre-dose visit 
rate < 60bpm 
< 45 or <40bpm if 
pre-dose visit rate 
<60bpm 
Hypertension (systolic) – mm Hg 
141 – 150 
151 – 160 
> 160 
Assume supine position 
for 10 min at rest in non-
sleeping subjects; for 
adverse events, need 
three measurements on 
the same arm with 
concordant results. 
Hypertension (diastolic) – mm Hg 
91 – 95 
96 – 100 
> 100 
Hypotension (systolic) –mm Hg 
85 – 89 
80 – 84 
< 80 
Tachypnea – breaths per minute 
23 – 25 
26 – 30 
> 30 
CARDIOVASCULAR 
Arrhythmia 
Asymptomatic, 
transient signs, 
no Rx required  
Recurrent/ 
persistent; 
symptomatic; 
Rx required  
Unstable 
dysrhythmia; 
hospitalization and 
treatment required 
 
Hemorrhage, Blood Loss 
Estimated blood 
loss < 100 mL 
Estimated blood 
loss > 100 mL, 
no transfusion 
required 
Transfusion 
required  
 
QT/QTc prolongation 
Male: 
441-470 msec 
 
Female: 
451-470 msec 
Male: 
471-500 msec 
 
Female: 
471-500 msec: 
> 500 msec 
OR 
> 60 msec change 
from admission visit  
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 1: Table Mock-Ups 
08 May 2024 
 
Table 5: 
Laboratory/Clinical Event Grading Scale (continued) 
- 50 - 
RESTRICTED 
Category 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Comments 
RESPIRATORY 
Cough 
Transient- no 
treatment 
Persistent cough; 
Interferes with 
daily activities 
 
Bronchospasm, Acute 
Transient; no 
treatment; 71% - 
80% FEV1 of peak 
flow  
Requires 
treatment; 
normalizes with 
bronchodilator; 
FEV1 60% - 
70% (of peak 
flow)  
No normalization 
with 
bronchodilator; 
FEV1 < 60% of 
peak flow 
 
Dyspnea 
Does not interfere 
with usual and 
social activities 
Interferes with 
usual and social 
activities, no 
treatment 
Prevents daily and 
usual social 
activity or requires 
treatment 
 
GASTROINTESTINAL 
Nausea 
No interference 
with activity 
Some 
interference with 
activity 
Prevents daily 
activities 
 
Vomiting 
No interference 
with activity or 1 – 
2 episodes/24 
hours 
Some 
interference with 
activity or > 2 
episodes/24 
hours 
Prevents daily 
activity or requires 
IV hydration 
 
Diarrhea 
2 – 3 loose or 
watery stools or < 
400 gms/24 hours 
4 – 5 loose or 
watery stools or 
400 – 800 
gms/24 hours 
6 or more loose or 
watery stools or > 
800gms/24 hours 
or requires IV 
hydration 
 
LABORATORY ADVERSE EVENTS 
Blood, Serum, or Plasma * 
Potassium – Hypokalemia mmol/L 
3.1 – <LLN 
2.7 – 3.0 
<2.7 
 
Potassium – Hyperkalemia mmol/L 
>ULN – 5.6 
>5.6 – 6.5  
>6.5 
 
Glucose – Hypoglycemia Fasting – 
mg/dL # 
61 – <LLN 
55 – <61 
<55 
 
Glucose – Hyperglycemia 
Fasting – mg/dL # 
>ULN – 120 
>120 – 130 
>130 
 
Blood Urea Nitrogen mg/dL 
>ULN – 29 
30 – 35 
>35 
 
Creatinine – mg/dL 
>ULN – 1.7 
1.8 – 2.0 
>2.0 
 
Calcium – hypocalcemia mg/dL 
8.0 – <LLN 
7.5 – 7.9 
<7.5 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 1: Table Mock-Ups 
08 May 2024 
 
Table 5: 
Laboratory/Clinical Event Grading Scale (continued) 
- 51 - 
RESTRICTED 
Category 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Comments 
Calcium – hypercalcemia mg/dL 
>ULN – 11.0 
11.1 – 11.5 
>11.5 
 
Magnesium – hypomagnesemia 
mg/dL 
1.3 – <LLN 
1.0 – <1.3 
<1.0 
 
Albumin – Hypoalbuminemia g/dL  
2.8 – <LLN 
2.5 – 2.7 
<2.5 
 
Alkaline phosphatase – U/L(Age 18 
years) 
>ULN – 240 
241 – 360 
>360 
 
AST U/L 
>ULN – 105 
106 – 175 
>175 
 
ALT U/L 
>ULN – 105 
106 – 175 
>175 
 
Bilirubin (serum total) mg/dL 
>ULN – 2.0 
2.1 – 2.5 
>2.5 
 
Hemoglobin - g/dL 
10.5 – <LLN 
9.5 – 10.4 
< 9.5 
 
Hematocrit - %  
32.3 – <LLN 
28.0 – 32.2 
< 28.0 
 
RBC Decrease (Female) X10^12/L 
3.61 – <LLN 
3.14 – 3.60 
< 3.14 
 
RBC Decrease (Male) 
X10E6/uL  X10^12/L 
3.89 – <LLN 
3.28 – 3.88 
< 3.28 
 
WBC Increase X10^9/L 
>ULN – 15.0 
15.1 – 20.0 
> 20.0 
 
WBC Decrease X10^9/L 
2.5 – <LLN 
1.5 – 2.4 
< 1.5 
 
Lymphocytes Decrease - X10^9/L 
0.5 – <LLN 
0.3 – 0.4 
<0.3 
 
Neutrophils Decrease - X10^9/L 
1.0 – <LLN 
0.5 – 1.0 
< 0.5 
 
Monocytes Increased X10^9/L 
>ULN – 2.5 
2.6 – 3.0 
>3.0 
 
Eosinophils Increased X10^9/L 
>ULN – 0.75 
0.76-1.50 
>1.50 
 
Basophils Increased X10^9/L 
>ULN – 0.40 
0.41 – 0.80 
>0. 80 
 
Platelets Decreased - X10^9/L 
120 – <LLN 
100 – 119 
<100 
 
INR 
>ULN – 1.3 
1.4 – 1.6 
>1.6 
 
Urine * 
Protein 
1+ 
2+ 
> 2+ 
 
Glucose 
Trace – 1+ 
2+ 
> 2+ 
 
Blood (microscopic) - red blood 
cells per high power field (rbc/hpf) 
3 – 10  
11 – 50 
> 50 and/or 
gross blood 
 
* The laboratory values provided in the tables serve as guidelines and are dependent upon institutional normal parameters.  
* Institutional normal reference ranges should be provided to demonstrate that they are appropriate. 
# Laboratory Parameter will not be used as halting criteria. 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 1: Table Mock-Ups 
08 May 2024 
 
- 52 - 
RESTRICTED 
14.1 
Description of Study Subjects 
14.1.1 Disposition of Subjects 
Table 6: 
Subject Disposition by Impairment Group 
Subject 
Disposition  
Mild Hepatic 
Impairment  
(N=X) 
Moderate 
Hepatic 
Impairment 
(N=X) 
Severe Hepatic 
Impairment 
(N=X) 
Matched 
Controls (N=X) 
All Subjects 
(N=X) 
n 
% 
n 
% 
 
 
 
 
n 
% 
Screened 
-- 
-- 
-- 
-- 
 
 
 
 
x 
-- 
Enrolled 
x 
100 
x 
100 
 
 
 
 
x 
100 
Received Treatment 
x 
xx 
x 
xx 
 
 
 
 
x 
xx 
Completed all hourly 
assessments 
x 
xx 
x 
xx 
 
 
 
 
x 
xx 
Completed Follow-up 
(Study Day 12)a, b 
 
 
 
 
 
 
 
 
 
 
a  Refer to Listing 16.2.1 for reasons subjects discontinued or terminated early. 
b Completed all daily assessments following discharge through study day 12. 
Note: N=All Enrolled Subjects 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 1: Table Mock-Ups 
08 May 2024 
 
- 53 - 
RESTRICTED 
Table 7: 
Analysis Populations by Impairment Group 
Analysis 
Populations 
Reason Subjects 
Excluded 
Mild Hepatic 
Impairment  
(N=X) 
Moderate 
Hepatic 
Impairment 
(N=X) 
Severe 
Hepatic 
Impairment 
(N=X) 
Matched Controls 
(N=X) 
All Subjects 
(N=X) 
n 
% 
n 
% 
n 
% 
n 
% 
% 
n 
Safety Population 
Any Reason 
x 
xx 
x 
xx 
x 
xx 
Did not receive study 
product 
 
 
 
 
Pharmacokinetics 
Population 
Any Reason 
 
 
 
 
Insufficient number of 
samples for estimation of 
PK parameters 
 
 
 
 
Did not meet all 
inclusion criteria or met 
exclusion criteria 
 
 
 
 
Note: N= Number of subjects enrolled 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 1: Table Mock-Ups 
08 May 2024 
 
- 54 - 
RESTRICTED 
Table 8: 
Ineligibility Summary of Screen Failures 
Subjects with 
Hepatic 
Impairment/ 
Non-Hepatically 
Impaired Controls 
Inclusion/ 
Exclusion 
Category 
Inclusion/Exclusion Criterion 
na 
%b 
All Subjects 
Inclusion 
and 
Exclusion 
Number of subjects failing any eligibility criterion 
x 
100 
Subjects with 
Hepatic Impairment 
Inclusion 
and 
Exclusion 
Number of subjects failing any eligibility criterion 
x 
100 
 
Inclusion 
Any inclusion criterion 
x 
xx 
 
 
Subject is able to give voluntary written informed consent before any study 
related procedure is performed 
x 
xx 
 
 
18-70 years of age, inclusive 
x 
xx 
 
 
…. (continued) 
x 
xx 
 
Exclusion 
Any exclusion criterion 
x 
xx 
 
 
Hypokalemia (< 3.5mEq/L), severe hypomagnesemia (< 1.1 mg/dL) or severe 
hypocalcemia (< 7.5 mg/dL) 
x 
xx 
 
 
AST or ALT > 10 times the upper limit of normal 
x 
xx 
 
 
…. (continued) 
x 
xx 
 
Eligible but 
Not Enrolled Any Reason 
x 
xx 
 
 
Time Commitment 
x 
xx 
 
 
Concern of Potential Risks 
x 
xx 
 
 
Number of Procedures/Blood Draws 
x 
xx 
 
 
Unable to Contact Subjects 
x 
xx 
 
 
Other 
x 
xx 
Non-Hepatically 
Impaired Controls 
Inclusion 
and 
Exclusion 
Number of subjects failing any eligibility criterion 
x 
100 
 
Inclusion 
Any inclusion criterion 
x 
xx 
 
 
Subject is able to give voluntary written informed consent before any study 
related procedure is performed 
x 
xx 
 
 
18-70 years of age, inclusive 
x 
xx 
 
 
… (continued) 
x 
xx 
 
Exclusion 
Any exclusion criterion 
x 
Xx 
 
 
Inability to swallow tablets 
x 
Xx 
 
 
Presence of any condition or finding which would jeopardize subject safety, 
impact study result validity, or diminish the subject’s ability to undergo all study 
procedures and assessments 
x 
Xx 
 
 
… (continued) 
x 
Xx 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 1: Table Mock-Ups 
08 May 2024 
 
Table 8: 
Ineligibility Summary of Screen Failures (continued) 
- 55 - 
RESTRICTED 
Subjects with 
Hepatic 
Impairment/ 
Non-Hepatically 
Impaired Controls 
Inclusion/ 
Exclusion 
Category 
Inclusion/Exclusion Criterion 
na 
%b 
 
Eligible but 
Not Enrolled Any Reason 
x 
xx 
 
 
Time Commitment 
x 
xx 
Non-Hepatically 
Impaired Controls 
(continued) 
Eligible but 
Not Enrolled 
(continued) 
Concern of Potential Risks 
x 
xx 
 
 
Number of Procedures/Blood Draws 
x 
xx 
 
 
Unable to Contact Subjects 
x 
xx 
 
 
Other 
x 
xx 
a More than one criterion may be marked per subject. 
b Denominator for percentages is the total number of screen failures. 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 1: Table Mock-Ups 
08 May 2024 
 
- 56 - 
RESTRICTED 
14.1.2 Demographic Data by Impairment Group 
Table 9: 
Summary of Categorical Demographic and Baseline Characteristics by Site 
Variable 
Characteristic 
Duke  
(N=X) 
Saint Louis 
(N=X) 
All Subjects 
(N=X) 
n 
% 
n 
% 
n 
% 
Sex  
Male 
x 
xx 
x 
xx 
x 
xx 
 
Female 
x 
xx 
x 
xx 
x 
xx 
Ethnicity  
Not Hispanic or Latino 
x 
xx 
x 
xx 
x 
xx 
 
Hispanic or Latino 
x 
xx 
x 
xx 
x 
xx 
 
Not Reported 
x 
xx 
x 
xx 
x 
xx 
 
Unknown 
x 
xx 
x 
xx 
x 
xx 
Race  
American Indian or Alaska Native 
x 
xx 
x 
xx 
x 
xx 
 
Asian 
x 
xx 
x 
xx 
x 
xx 
 
Native Hawaiian or Other Pacific 
Islander 
x 
xx 
x 
xx 
x 
xx 
 
Black or African American 
x 
xx 
x 
xx 
x 
xx 
 
White 
x 
xx 
x 
xx 
x 
xx 
 
Multi-Racial 
x 
xx 
x 
xx 
x 
xx 
 
Unknown 
x 
xx 
x 
xx 
x 
xx 
Note: N= All Enrolled Subjects 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 1: Table Mock-Ups 
08 May 2024 
 
- 57 - 
RESTRICTED 
Table 10: 
Summary of Continuous Demographic and Baseline Characteristics by Site 
Variable 
Statistic 
Duke  
(N=X) 
Saint Louis 
(N=X) 
All Subjects 
(N=X) 
Age (years) 
Mean 
xx 
xx 
xx 
 
Standard Deviation 
xx 
xx 
xx 
 
Median 
x 
x 
x 
 
25th Quartile 
x 
x 
x 
 
75th Quartile 
x 
x 
x 
 
Minimum 
x 
x 
x 
 
Maximum 
x 
x 
x 
Weight* (kg) 
Mean 
xx 
xx 
xx 
 
Standard Deviation 
xx 
xx 
xx 
 
Median 
x 
x 
x 
 
25th Quartile 
x 
x 
x 
 
75th Quartile 
x 
x 
x 
 
Minimum 
x 
x 
x 
 
Maximum 
x 
x 
x 
Height (cm) 
Mean 
xx 
xx 
xx 
 
Standard Deviation 
xx 
xx 
xx 
 
Median 
x 
x 
x 
 
25th Quartile 
x 
x 
x 
 
75th Quartile 
x 
x 
x 
 
Minimum 
x 
x 
x 
 
Maximum 
x 
x 
x 
BMI (kg/m2) 
Mean 
xx 
xx 
xx 
 
Standard Deviation 
xx 
xx 
xx 
 
Median 
x 
x 
x 
 
25th Quartile 
x 
x 
x 
 
75th Quartile 
x 
x 
x 
 
Minimum 
x 
x 
x 
 
Maximum 
x 
x 
x 
Note: N=All Enrolled Subjects 
*Weight measured at screening 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 1: Table Mock-Ups 
08 May 2024 
 
- 58 - 
RESTRICTED 
Table 11: 
Summary of Categorical Demographic and Baseline Characteristics by Impairment 
Group 
Variable 
Characteristic 
Mild Hepatic 
Impairment  
(N=X) 
Moderate 
Hepatic 
Impairment 
(N=X) 
Severe 
Hepatic 
Impairment 
(N=X) 
Matched 
Controls 
(N=X) 
All Subjects 
(N=X) 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Sex  
Male 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Female 
 
 
 
 
 
 
 
 
 
 
Ethnicity  
Not Hispanic or Latino 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Hispanic or Latino 
 
 
 
 
 
 
 
 
 
 
 
Not Reported 
 
 
 
 
 
 
 
 
 
 
 
Unknown 
 
 
 
 
 
 
 
 
 
 
Race  
American Indian or Alaska 
Native 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Asian 
 
 
 
 
 
 
 
 
 
 
 
Native Hawaiian or Other 
Pacific Islander 
 
 
 
 
 
 
 
 
 
 
 
Black or African American 
 
 
 
 
 
 
 
 
 
 
 
White 
 
 
 
 
 
 
 
 
 
 
 
Multi-Racial 
 
 
 
 
 
 
 
 
 
 
 
Unknown 
 
 
 
 
 
 
 
 
 
 
Note: N= All Enrolled Subjects 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 1: Table Mock-Ups 
08 May 2024 
 
- 59 - 
RESTRICTED 
Table 12: 
Summary of Continuous Demographic and Baseline Characteristics by Impairment 
Group 
Variable 
Statistic 
Mild Hepatic 
Impairment  
(N=X) 
Moderate Hepatic 
Impairment 
(N=X) 
Severe Hepatic 
Impairment 
(N=X) 
Matched 
Controls 
(N=X) 
All Subjects 
(N=X) 
Age (years) 
Mean 
xx 
xx 
xx 
xx 
xx 
 
Standard Deviation xx 
xx 
xx 
xx 
xx 
 
Median 
x 
x 
x 
x 
x 
 
25th Quartile 
x 
x 
x 
x 
x 
 
75th Quartile 
x 
x 
x 
x 
x 
 
Minimum 
x 
x 
x 
x 
x 
 
Maximum 
x 
x 
x 
x 
x 
Weight* (kg) 
Mean 
xx 
xx 
xx 
xx 
xx 
 
Standard Deviation xx 
xx 
xx 
xx 
xx 
 
Median 
x 
x 
x 
x 
x 
 
25th Quartile 
x 
x 
x 
x 
x 
 
75th Quartile 
x 
x 
x 
x 
x 
 
Minimum 
x 
x 
x 
x 
x 
 
Maximum 
x 
x 
x 
x 
x 
Height (cm) 
Mean 
xx 
xx 
xx 
xx 
xx 
 
Standard Deviation xx 
xx 
xx 
xx 
xx 
 
Median 
x 
x 
x 
x 
x 
 
25th Quartile 
x 
x 
x 
x 
x 
 
75th Quartile 
x 
x 
x 
x 
x 
 
Minimum 
x 
x 
x 
x 
x 
 
Maximum 
x 
x 
x 
x 
x 
BMI (kg/m2) 
Mean 
xx 
xx 
xx 
xx 
xx 
 
Standard Deviation xx 
xx 
xx 
xx 
xx 
 
Median 
x 
x 
x 
x 
x 
 
25th Quartile 
x 
x 
x 
x 
x 
 
75th Quartile 
x 
x 
x 
x 
x 
 
Minimum 
x 
x 
x 
x 
x 
 
Maximum 
x 
x 
x 
x 
x 
Note: N=All Enrolled Subjects 
*Weight measured at screening 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 1: Table Mock-Ups 
08 May 2024 
 
- 60 - 
RESTRICTED 
14.1.3 Prior and Concurrent Medical Conditions 
Table 13: 
Summary of Subjects with Pre-Existing Medical Conditions by MedDRA System Organ Class and Impairment Group 
MedDRA System Organ Class 
Mild Hepatic 
Impairment  
(N=X) 
Moderate Hepatic 
Impairment 
(N=X) 
Severe Hepatic 
Impairment (N=X) 
Matched Controls 
(N=X) 
All Subjects 
(N=X) 
n 
% 
n 
% 
 
 
 
 
n 
% 
Any SOC 
x 
xx 
x 
xx 
 
 
 
 
x 
xx 
[SOC 1] 
 
 
 
 
 
 
 
 
 
 
[SOC 2] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: N= Number of subjects in the Safety Population 
n = Number of subjects reporting medical history within the specified SOC. A subject is only counted once per SOC. 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 1: Table Mock-Ups 
08 May 2024 
 
- 61 - 
RESTRICTED 
14.2 
Efficacy/Immunogenicity Data 
Not Applicable. 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 1: Table Mock-Ups 
08 May 2024 
 
- 62 - 
RESTRICTED 
14.3 
Safety Data 
14.3.1 Displays of Adverse Events 
Table 14: 
Overall Summary of Adverse Events 
 
Mild Hepatic 
Impairment  
(N=X) 
Moderate Hepatic 
Impairment 
(N=X) 
Severe Hepatic 
Impairment 
(N=X) 
Matched 
Controls 
(N=X) 
All Subjects 
(N = X) 
Subjectsa with 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
At least one unsolicited adverse event 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
At least one clinical safety laboratory of mild or greater severity through 
Day 12 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
At least one related unsolicited adverse event 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Mild (Grade 1) 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Moderate (Grade 2)  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Severe (Grade 3)  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Not yet assessed 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
At least one severe (Grade 3) unsolicited adverse event 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Related  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Unrelated 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 1: Table Mock-Ups 
08 May 2024 
 
Table 14: 
Overall Summary of Adverse Events (continued) 
- 63 - 
RESTRICTED 
 
Mild Hepatic 
Impairment  
(N=X) 
Moderate Hepatic 
Impairment 
(N=X) 
Severe Hepatic 
Impairment 
(N=X) 
Matched 
Controls 
(N=X) 
All Subjects 
(N = X) 
Subjectsa with 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
At least one serious adverse eventb 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
At least one related, serious adverse event 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
At least one adverse event leading to early terminationc  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
N = Number of subjects in the Safety Population 
a Subjects are counted once for each category regardless of the number of events. 
b A listing of Serious Adverse Events is included in Table 18. 
c As reported on the Adverse Event eCRF. 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 1: Table Mock-Ups 
08 May 2024 
 
- 64 - 
RESTRICTED 
14.3.1.1 
Solicited Adverse Events 
Not Applicable. 
14.3.1.2 
Unsolicited Adverse Events 
Table 15: 
Summary of Unsolicited Adverse Events by MedDRA System Organ Class and Preferred Term, and Impairment Group – Mild 
Hepatic Impairment 
MedDRA 
System Organ 
Class 
MedDRA 
Preferred 
Term 
Day 1-5 
(N=X) 
Day  6-12 
(N=X) 
Any Time Post Dose 
(N=X) 
n 
% 
95% CI 
Events 
n 
% 
95% CI 
Events 
n 
% 
95% CI 
Events 
Any SOC 
Any PT 
x 
xx 
xx, xx 
x 
x 
xx 
xx, xx 
x 
x 
xx 
xx, xx 
x 
[SOC 1] 
Any PT 
 
 
 
 
 
 
 
 
 
 
 
 
 
[PT 1] 
 
 
 
 
 
 
 
 
 
 
 
 
 
[PT 2] 
 
 
 
 
 
 
 
 
 
 
 
 
[SOC 2] 
Any PT 
 
 
 
 
 
 
 
 
 
 
 
 
 
[PT 1] 
 
 
 
 
 
 
 
 
 
 
 
 
 
[PT 2] 
 
 
 
 
 
 
 
 
 
 
 
 
Note: N = number of subjects in the Safety Population. This table presents number and percentage of subjects. A subject is only counted once per PT/time point. 
 
Tables with similar format: 
Table 16: 
Summary of Unsolicited Adverse Events by MedDRA System Organ Class and Preferred Term, and Impairment Group – 
Moderate Hepatic Impairment 
Table 17: 
Summary of Unsolicited Adverse Events by MedDRA System Organ Class and Preferred Term, and Impairment Group – Severe 
Hepatic Impairment 
Table 18: 
Summary of Unsolicited Adverse Events by MedDRA System Organ Class and Preferred Term, and Impairment Group – 
Matched Controls 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 1: Table Mock-Ups 
08 May 2024 
 
- 65 - 
RESTRICTED 
Table 19: 
Incidence of Unsolicited Adverse Events by MedDRA System Organ Class and Preferred Term, Maximum Severity, Relationship, 
and Impairment Group 
MedDRA 
System Organ 
Class 
Preferred 
Term 
Severity 
Mild Hepatic Impairment 
(N = X) 
Moderate Hepatic Impairment 
(N = X) 
Severe Hepatic Impairment 
(N = X) 
Matched Controls 
(N = X) 
Related 
Not 
Related 
Total 
Related 
Not 
Related 
Total 
Related 
Not 
Related 
Total 
Related 
Not 
Related 
Total 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Any SOC 
Any PT 
Any 
Severity 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
 
 
Mild 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
 
 
Moderate 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
 
 
Severe 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
SOC 1 
PT 1 
Any 
Severity 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
 
 
Mild 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
 
 
Moderate 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
 
 
Severe 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
 
PT 2 
Any 
Severity 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
 
 
Mild 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
 
 
Moderate 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
 
 
Severe 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
Note: N = Number of subjects in the Safety Population. 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 1: Table Mock-Ups 
08 May 2024 
 
- 66 - 
RESTRICTED 
14.3.2 Listing of Deaths, Other Serious and Significant Adverse Events 
Table 20: 
Listing of Serious Adverse Events 
Adverse 
Event 
MedDRA 
System 
Organ 
Class 
MedDRA 
Preferred 
Term 
No. of Days Post 
Dose  
Duration 
No. of 
Days 
Post 
Dose the 
Event 
Became 
Serious  
Reason 
Reported 
as an 
SAE  
Severity  
Relationship 
to Study 
Treatment  
If Not 
Related, 
Alternative 
Etiology  
Action 
Taken with 
Study 
Treatment  
Subject 
Discontinued 
Due to AE  
Outcome  
Impairment Group: Subject ID: 
 AE Number:  
 
 
 
 
 
 
 
 
 
 
 
 
 
Comments: 
 
Impairment Group: Subject ID: 
 AE Number:  
 
 
 
 
 
 
 
 
 
 
 
 
 
Comments: 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 1: Table Mock-Ups 
08 May 2024 
 
- 67 - 
RESTRICTED 
Table 21: 
Listing of Non-Serious, Unsolicited, Moderate or Severe Adverse Events 
Adverse 
Event 
MedDRA 
System 
Organ 
Class 
MedDRA 
Preferred 
Term 
No. of Days 
Post  Dose  
Duration 
No. of 
Days 
Post 
Dose 
the 
Event 
Became 
Serious  
Reason 
Reported 
as an 
SAE  
Severity  
Relationship 
to Study 
Treatment  
If Not 
Related, 
Alternative 
Etiology  
Action 
Taken 
with Study 
Treatment  
Subject 
Discontinued 
Due to AE  
Outcome  
Impairment Group: Subject ID:  AE Number:  
 
 
 
 
 
 
 
 
 
 
 
 
 
Comments: 
 
Impairment Group: Subject ID:  AE Number:  
 
 
 
 
 
 
 
 
 
 
 
 
 
Comments: 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 1: Table Mock-Ups 
08 May 2024 
 
- 68 - 
RESTRICTED 
14.3.3 Narratives of Deaths, Other Serious and Significant Adverse Events 
(not included in SAP, but this is a placeholder for the CSR) 
 
14.3.4 Abnormal Laboratory Value Listings (by Subject) 
Table 22: 
Listing of Abnormal Laboratory Results - Chemistry 
Impairment Group 
Subject 
ID 
Sex 
Age (years) 
Planned Time 
Point 
Actual Study 
Day 
Laboratory Parameter 
(Units) 
Result (Severity) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 1: Table Mock-Ups 
08 May 2024 
 
- 69 - 
RESTRICTED 
Table 23: 
Listing of Abnormal Laboratory Results - Hematology 
Impairment 
Group  
Subject 
ID  
Sex 
Age (years) 
Planned Time Point 
Actual Study Day 
Laboratory Parameter 
(Units) 
Result (Severity) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 1: Table Mock-Ups 
08 May 2024 
 
- 70 - 
RESTRICTED 
Table 24: 
Listing of Abnormal Laboratory Results - Urinalysis 
Impairment Group 
Subject 
ID  
Sex 
Age (years) 
Planned Time Point 
Actual Study Day 
Laboratory Parameter 
(Units) 
Result (Severity) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 1: Table Mock-Ups 
08 May 2024 
 
- 71 - 
RESTRICTED 
Table 25: 
Listing of Abnormal Laboratory Results - Coagulation 
Impairment Group 
Subject 
ID  
Sex 
Age (years) 
Planned Time Point 
Actual Study Day 
Laboratory Parameter 
(Units) 
Result (Severity) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 1: Table Mock-Ups 
08 May 2024 
 
- 72 - 
RESTRICTED 
14.3.5 Displays of Laboratory Results 
14.3.5.1 
Chemistry Results 
Table 26: 
Chemistry Laboratory Results by Maximum Severity, Time Point, and Impairment Group – Any Chemistry Parameter 
Time Point 
Impairment Group 
N 
None 
Mild/ 
Grade 1 
Moderate/ 
Grade 2 
Severe/ 
Grade 3 
Missing 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Baseline 
Mild Hepatic Impairment 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Moderate Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
 
 
Day 2 
Mild Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
 
 
Day 5 
Mild Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
 
 
Day 12 
Mild Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 1: Table Mock-Ups 
08 May 2024 
 
Table 26: 
Chemistry Laboratory Results by Maximum Severity, Time Point, and Impairment Group – Any Chemistry Parameter 
(continued) 
- 73 - 
RESTRICTED 
Time Point 
Impairment Group 
N 
None 
Mild/ 
Grade 1 
Moderate/ 
Grade 2 
Severe/ 
Grade 3 
Missing 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Max Severity Post Baseline 
Mild Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
 
 
Note: The “Max Post Baseline” rows indicate the maximum severity experienced by each subject at any time point post baseline, including unscheduled assessments.  
N= Number of subjects in the Safety Population with labs available at each visit. 
 
Tables with similar format: 
Table 27: 
Chemistry Laboratory Results by Maximum Severity, Time Point, and Impairment Group – Total Bilirubin 
Table 28: 
Chemistry Laboratory Results by Maximum Severity, Time Point, and Impairment Group – Serum Albumin 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 1: Table Mock-Ups 
08 May 2024 
 
- 74 - 
RESTRICTED 
Table 29: 
Chemistry Laboratory Results by Range, Maximum Severity, Time Point, and Impairment Group – Potassium 
Time Point 
Impairment Group 
N 
None 
Mild/ 
Grade 1 
(Low) 
Mild/ 
Grade 1 
(High) 
Moderate/ 
Grade 2 
(Low) 
Moderate/ 
Grade 2 
(High) 
Severe/ 
Grade 3 
(Low) 
Severe/ 
Grade 3 
(High) 
Missing 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Baseline 
Mild Hepatic 
Impairment 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Moderate Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 2 
Mild Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 5 
Mild Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 1: Table Mock-Ups 
08 May 2024 
 
Table 29: 
Chemistry Laboratory Results by Range, Maximum Severity, Time Point, and Impairment Group – Potassium (continued) 
- 75 - 
RESTRICTED 
Time Point 
Impairment Group 
N 
None 
Mild/ 
Grade 1 
(Low) 
Mild/ 
Grade 1 
(High) 
Moderate/ 
Grade 2 
(Low) 
Moderate/ 
Grade 2 
(High) 
Severe/ 
Grade 3 
(Low) 
Severe/ 
Grade 3 
(High) 
Missing 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Day 12 
Mild Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Max Severity Post 
Baseline 
Mild Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: The “Max Post Baseline” rows indicate the maximum severity experienced by each subject at any time point post baseline, including unscheduled assessments. 
N=Number of subjects in the Safety Population with labs available at each visit. 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 1: Table Mock-Ups 
08 May 2024 
 
- 76 - 
RESTRICTED 
Table 30: 
Chemistry Laboratory Results by Maximum Severity, Time Point, and Impairment Group – Magnesium 
Time Point 
Impairment Group 
N 
None 
Mild/ 
Grade 1 
Moderate/ 
Grade 2 
Severe/ 
Grade 3 
Missing 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Baseline 
Mild Hepatic Impairment 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Moderate Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
 
 
Day 2 
Mild Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
 
 
Day 5 
Mild Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
 
 
Day 12 
Mild Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 1: Table Mock-Ups 
08 May 2024 
 
Table 30: 
Chemistry Laboratory Results by Maximum Severity, Time Point, and Impairment Group – Magnesium (continued) 
- 77 - 
RESTRICTED 
Time Point 
Impairment Group 
N 
None 
Mild/ 
Grade 1 
Moderate/ 
Grade 2 
Severe/ 
Grade 3 
Missing 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Max Severity Post Baseline 
Mild Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
 
 
Note: The “Max Post Baseline” rows indicate the maximum severity experienced by each subject at any time point post baseline, including unscheduled assessments.  
N= Number of subjects in the Safety Population with labs available at each visit. 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 1: Table Mock-Ups 
08 May 2024 
 
- 78 - 
RESTRICTED 
Table 31: 
Chemistry Laboratory Results by Range, Maximum Severity, Time Point, and Impairment Group – Calcium 
Time Point 
Impairment Group 
N 
None 
Mild/ 
Grade 1 
(Low) 
Mild/ 
Grade 1 
(High) 
Moderate/ 
Grade 2 
(Low) 
Moderate/ 
Grade 2 
(High) 
Severe/ 
Grade 3 
(Low) 
Severe/ 
Grade 3 
(High) 
Missing 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Baseline 
Mild Hepatic 
Impairment 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Moderate Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 2 
Mild Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 5 
Mild Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 1: Table Mock-Ups 
08 May 2024 
 
Table 31: 
Chemistry Laboratory Results by Range, Maximum Severity, Time Point, and Impairment Group – Calcium (continued) 
- 79 - 
RESTRICTED 
Time Point 
Impairment Group 
N 
None 
Mild/ 
Grade 1 
(Low) 
Mild/ 
Grade 1 
(High) 
Moderate/ 
Grade 2 
(Low) 
Moderate/ 
Grade 2 
(High) 
Severe/ 
Grade 3 
(Low) 
Severe/ 
Grade 3 
(High) 
Missing 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Day 12 
Mild Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Max Severity Post 
Baseline 
Mild Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: The “Max Post Baseline” rows indicate the maximum severity experienced by each subject at any time point post baseline, including unscheduled assessments. 
N=Number of subjects in the Safety Population with labs available at each visit. 
 
Table with similar format: 
Table 32: 
Chemistry Laboratory Results by Maximum Severity, Time Point, and Impairment Group – Serum Creatinine 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 1: Table Mock-Ups 
08 May 2024 
 
- 80 - 
RESTRICTED 
Table 33: 
Chemistry Laboratory Results by Maximum Severity, Time Point, and Impairment Group – BUN  
Time Point 
Impairment Group 
N 
None 
Mild/ 
Grade 1 
Moderate/ 
Grade 2 
Severe/ 
Grade 3 
Missing 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Baseline 
Mild Hepatic Impairment 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Moderate Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
 
 
Day 2 
Mild Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
 
 
Day 5 
Mild Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
 
 
Day 12 
Mild Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 1: Table Mock-Ups 
08 May 2024 
 
Table 33: 
Chemistry Laboratory Results by Maximum Severity, Time Point, and Impairment Group – BUN (continued) 
- 81 - 
RESTRICTED 
Time Point 
Impairment Group 
N 
None 
Mild/ 
Grade 1 
Moderate/ 
Grade 2 
Severe/ 
Grade 3 
Missing 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Max Severity Post Baseline 
Mild Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
 
 
Note: The “Max Post Baseline” rows indicate the maximum severity experienced by each subject at any time point post baseline, including unscheduled assessments.  
N= Number of subjects in the Safety Population with labs available at each visit. 
 
Tables with Similar format: 
Table 34: 
Chemistry Laboratory Results by Maximum Severity, Time Point, and Impairment Group – Alkaline Phosphatase 
Table 35: 
Chemistry Laboratory Results by Maximum Severity, Time Point, and Impairment Group – ALT 
Table 36: 
Chemistry Laboratory Results by Maximum Severity, Time Point, and Impairment Group – AST 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 1: Table Mock-Ups 
08 May 2024 
 
- 82 - 
RESTRICTED 
Table 37: 
Abnormal Chemistry Laboratory Results Related to Study Treatment by Maximum Severity, Time Point, and Impairment 
Group – Any Chemistry Parameter 
Time Point 
Impairment Group 
N 
Mild/ 
Grade 1 
Moderate/ 
Grade 2 
Severe/ 
Grade 3 
n 
% 
n 
% 
n 
% 
Baseline 
Mild Hepatic Impairment 
x 
x 
xx 
x 
xx 
x 
xx 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
Day 2 
Mild Hepatic Impairment 
 
 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
Day 5 
Mild Hepatic Impairment 
 
 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
Day 12 
Mild Hepatic Impairment 
 
 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
Max Severity Post Baseline 
Mild Hepatic Impairment 
 
 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
Note: The “Max Post Baseline” rows indicate the maximum severity experienced by each subject at any time point post baseline, including unscheduled assessments.  
N= Number of subjects in the Safety Population with labs available at each visit. 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 1: Table Mock-Ups 
08 May 2024 
 
- 83 - 
RESTRICTED 
 
Tables with similar format: 
Table 38: 
Abnormal Chemistry Laboratory Results Related to Study Treatment by Maximum Severity, Time Point, and Impairment 
Group – Total Bilirubin 
Table 39: 
Abnormal Chemistry Laboratory Results Related to Study Treatment by Maximum Severity, Time Point, and Impairment 
Group – Serum Albumin 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 1: Table Mock-Ups 
08 May 2024 
 
- 84 - 
RESTRICTED 
Table 40: 
Abnormal Chemistry Laboratory Results Related to Study Treatment by Range, Maximum Severity, Time Point, and 
Impairment Group – Potassium 
Time Point 
Impairment Group 
N 
Mild/ 
Grade 1 
(Low) 
Mild/ 
Grade 1 
(High) 
Moderate/ 
Grade 2 
(Low) 
Moderate/ 
Grade 2 
(High) 
Severe/ 
Grade 3 
(Low) 
Severe/ 
Grade 3 
(High) 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Baseline 
Mild Hepatic Impairment 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Moderate Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 2 
Mild Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 5 
Mild Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 12 
Mild Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 1: Table Mock-Ups 
08 May 2024 
 
Table 40: 
Abnormal Chemistry Laboratory Results Related to Study Treatment by Range, Maximum Severity, Time Point, and 
Impairment Group – Potassium (continued) 
- 85 - 
RESTRICTED 
Time Point 
Impairment Group 
N 
Mild/ 
Grade 1 
(Low) 
Mild/ 
Grade 1 
(High) 
Moderate/ 
Grade 2 
(Low) 
Moderate/ 
Grade 2 
(High) 
Severe/ 
Grade 3 
(Low) 
Severe/ 
Grade 3 
(High) 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Max Severity Post 
Baseline 
Mild Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: The “Max Post Baseline” rows indicate the maximum severity experienced by each subject at any time point post baseline, including unscheduled assessments. 
N=Number of subjects in the Safety Population with labs available at each visit. 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 1: Table Mock-Ups 
08 May 2024 
 
- 86 - 
RESTRICTED 
Table 41: 
Abnormal Chemistry Laboratory Results Related to Study Treatment by Maximum Severity, Time Point, and Impairment 
Group – Magnesium 
Time Point 
Impairment Group 
N 
Mild/ 
Grade 1 
Moderate/ 
Grade 2 
Severe/ 
Grade 3 
n 
% 
n 
% 
n 
% 
Baseline 
Mild Hepatic Impairment 
x 
x 
xx 
x 
xx 
x 
xx 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
Day 2 
Mild Hepatic Impairment 
 
 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
Day 5 
Mild Hepatic Impairment 
 
 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
Day 12 
Mild Hepatic Impairment 
 
 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
Max Severity Post Baseline 
Mild Hepatic Impairment 
 
 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
Note: The “Max Post Baseline” rows indicate the maximum severity experienced by each subject at any time point post baseline, including unscheduled assessments.  
N= Number of subjects in the Safety Population with labs available at each visit. 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 1: Table Mock-Ups 
08 May 2024 
 
- 87 - 
RESTRICTED 
Table 42: 
Abnormal Chemistry Laboratory Results Related to Study Treatment by Range, Maximum Severity, Time Point, and 
Impairment Group – Calcium 
Time Point 
Impairment Group 
N 
Mild/ 
Grade 1 
(Low) 
Mild/ 
Grade 1 
(High) 
Moderate/ 
Grade 2 
(Low) 
Moderate/ 
Grade 2 
(High) 
Severe/ 
Grade 3 
(Low) 
Severe/ 
Grade 3 
(High) 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Baseline 
Mild Hepatic Impairment 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Moderate Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 2 
Mild Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 5 
Mild Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 12 
Mild Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 1: Table Mock-Ups 
08 May 2024 
 
Table 42: 
Abnormal Chemistry Laboratory Results Related to Study Treatment by Range, Maximum Severity, Time Point, and 
Impairment Group – Calcium (continued) 
- 88 - 
RESTRICTED 
Time Point 
Impairment Group 
N 
Mild/ 
Grade 1 
(Low) 
Mild/ 
Grade 1 
(High) 
Moderate/ 
Grade 2 
(Low) 
Moderate/ 
Grade 2 
(High) 
Severe/ 
Grade 3 
(Low) 
Severe/ 
Grade 3 
(High) 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Max Severity Post 
Baseline 
Mild Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: The “Max Post Baseline” rows indicate the maximum severity experienced by each subject at any time point post baseline, including unscheduled assessments. 
N=Number of subjects in the Safety Population with labs available at each visit. 
 
Table with Similar Format: 
Table 43: 
Abnormal Chemistry Laboratory Results Related to Study Treatment by Maximum Severity, Time Point, and Impairment 
Group – Serum Creatinine 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 1: Table Mock-Ups 
08 May 2024 
 
- 89 - 
RESTRICTED 
Table 44: 
Abnormal Chemistry Laboratory Results Related to Study Treatment by Maximum Severity, Time Point, and Impairment 
Group – BUN 
Time Point 
Impairment Group 
N 
Mild/ 
Grade 1 
Moderate/ 
Grade 2 
Severe/ 
Grade 3 
n 
% 
n 
% 
n 
% 
Baseline 
Mild Hepatic Impairment 
x 
x 
xx 
x 
xx 
x 
xx 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
Day 2 
Mild Hepatic Impairment 
 
 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
Day 5 
Mild Hepatic Impairment 
 
 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
Day 12 
Mild Hepatic Impairment 
 
 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
Max Severity Post Baseline 
Mild Hepatic Impairment 
 
 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
Note: The “Max Post Baseline” rows indicate the maximum severity experienced by each subject at any time point post baseline, including unscheduled assessments.  
N= Number of subjects in the Safety Population with labs available at each visit. 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 1: Table Mock-Ups 
08 May 2024 
 
- 90 - 
RESTRICTED 
Tables with Similar Format: 
Table 45: 
Abnormal Chemistry Laboratory Results Related to Study Treatment by Maximum Severity, Time Point, and Impairment 
Group – Alkaline Phosphatase 
Table 46: 
Abnormal Chemistry Laboratory Results Related to Study Treatment by Maximum Severity, Time Point, and Impairment 
Group – ALT 
Table 47: 
Abnormal Chemistry Laboratory Results Related to Study Treatment by Maximum Severity, Time Point, and Impairment 
Group – AST 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 1: Table Mock-Ups 
08 May 2024 
 
- 91 - 
RESTRICTED 
Table 48: 
Chemistry Laboratory Summary Statistics by Time Point and Impairment Group – Total Bilirubin (mg/dL) 
Time Point 
Impairment Group 
N 
Mean 
Standard Deviation 
Median 
Min, Max 
Baseline 
Mild Hepatic Impairment 
x 
xx.x 
xx.x 
xx.x 
xx.x, xx.x 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
Day 2 
Mild Hepatic Impairment 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
Day 2, Change from Baseline 
Mild Hepatic Impairment 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
Day 5 
Mild Hepatic Impairment 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
Day 5, Change from Baseline 
Mild Hepatic Impairment 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
Day 12 
Mild Hepatic Impairment 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 1: Table Mock-Ups 
08 May 2024 
 
Table 48: 
Chemistry Laboratory Statistics by Time Point, and Impairment Group – Total Bilirubin (mg/dL) (continued) 
- 92 - 
RESTRICTED 
Time Point 
Impairment Group 
N 
Mean 
Standard Deviation 
Median 
Min, Max 
Day 12, Change from Baseline 
Mild Hepatic Impairment 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
Note: N= Number of subjects in the Safety Population with labs available at each visit. 
 
Tables with similar format: 
Table 49: 
Chemistry Laboratory Summary Statistics by Time Point and Impairment Group – Serum Albumin (g/dL) 
Table 50: 
Chemistry Laboratory Summary Statistics by Range, Time Point, and Impairment Group – Potassium (mmol/dL) 
Table 51: 
Chemistry Laboratory Summary Statistics by Time Point and Impairment Group – Magnesium (mg/dL) 
Table 52: 
Chemistry Laboratory Summary Statistics by Time Point and Impairment Group – Calcium (mg/dL) 
Table 53: 
Chemistry Laboratory Summary Statistics by Time Point and Impairment Group – Serum Creatinine (mg/dL) 
Table 54: 
Chemistry Laboratory Summary Statistics by Time Point and Impairment Group – BUN (mg/dL) 
Table 55: 
Chemistry Laboratory Summary Statistics by Time Point and Impairment Group – Alkaline Phosphatase (U/L) 
Table 56: 
Chemistry Laboratory Summary Statistics by Time Point and Impairment Group – ALT (U/L) 
Table 57: 
Chemistry Laboratory Summary Statistics by Time Point and Impairment Group – AST (U/L) 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 1: Table Mock-Ups 
08 May 2024 
 
- 93 - 
RESTRICTED 
14.3.5.2 
Hematology Results 
Table 58: 
Hematology Laboratory Results by Maximum Severity, Time Point, and Impairment Group – Any Hematology Parameter 
Time Point 
Impairment Group 
N 
None 
Mild/ 
Grade 1 
Moderate/ 
Grade 2 
Severe/ 
Grade 3 
Missing 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Baseline 
Mild Hepatic Impairment 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Moderate Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
 
 
Day 2 
Mild Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
 
 
Day 5 
Mild Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
 
 
Day 12 
Mild Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 1: Table Mock-Ups 
08 May 2024 
 
Table 58: 
Hematology Laboratory Results by Maximum Severity, Time Point, and Impairment Group – Any Hematology Parameter 
(continued) 
- 94 - 
RESTRICTED 
Time Point 
Impairment Group 
N 
None 
Mild/ 
Grade 1 
Moderate/ 
Grade 2 
Severe/ 
Grade 3 
Missing 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Max Severity Post Baseline 
Mild Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
 
 
Note: The “Max Post Baseline” rows indicate the maximum severity experienced by each subject at any time point post baseline, including unscheduled assessments.  
N= Number of subjects in the Safety Population with labs available at each visit. 
 
Tables with similar format: 
Table 59: 
Hematology Laboratory Results by Maximum Severity, Time Point, and Impairment Group – Hematocrit 
Table 60: 
Hematology Laboratory Results by Maximum Severity, Time Point, and Impairment Group – Hemoglobin 
Table 61: 
Hematology Laboratory Results by Maximum Severity, Time Point, and Impairment Group – Red Blood Cell Count 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 1: Table Mock-Ups 
08 May 2024 
 
- 95 - 
RESTRICTED 
Table 62: 
Hematology Laboratory Results by Range, Maximum Severity, Time Point, and Impairment Group – White Blood Cell Count 
Time Point 
Impairment Group 
N 
None 
Mild/ 
Grade 1 
(Low) 
Mild/ 
Grade 1 
(High) 
Moderate/ 
Grade 2 
(Low) 
Moderate/ 
Grade 2 
(High) 
Severe/ 
Grade 3 
(Low) 
Severe/ 
Grade 3 
(High) 
Missing 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Baseline 
Mild Hepatic 
Impairment 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Moderate Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 2 
Mild Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 5 
Mild Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 1: Table Mock-Ups 
08 May 2024 
 
Table 62: 
Hematology Laboratory Results by Range, Maximum Severity, Time Point, and Impairment Group – White Blood Cell Count 
(continued) 
- 96 - 
RESTRICTED 
Time Point 
Impairment Group 
N 
None 
Mild/ 
Grade 1 
(Low) 
Mild/ 
Grade 1 
(High) 
Moderate/ 
Grade 2 
(Low) 
Moderate/ 
Grade 2 
(High) 
Severe/ 
Grade 3 
(Low) 
Severe/ 
Grade 3 
(High) 
Missing 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Day 12 
Mild Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Max Severity Post 
Baseline 
Mild Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: The “Max Post Baseline” rows indicate the maximum severity experienced by each subject at any time point post baseline, including unscheduled assessments. 
N=Number of subjects in the Safety Population with labs available at each visit. 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 1: Table Mock-Ups 
08 May 2024 
 
- 97 - 
RESTRICTED 
Table 63: 
Hematology Laboratory Results by Maximum Severity, Time Point, and Impairment Group – Absolute Neutrophils 
 
Time Point 
Impairment Group 
N 
None 
Mild/ 
Grade 1 
Moderate/ 
Grade 2 
Severe/ 
Grade 3 
Missing 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Baseline 
Mild Hepatic Impairment 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Moderate Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
 
 
Day 2 
Mild Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
 
 
Day 5 
Mild Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
 
 
Day 12 
Mild Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 1: Table Mock-Ups 
08 May 2024 
 
Table 63: 
Hematology Laboratory Results by Maximum Severity, Time Point, and Impairment Group – Absolute Neutrophils (continued) 
- 98 - 
RESTRICTED 
 
Time Point 
Impairment Group 
N 
None 
Mild/ 
Grade 1 
Moderate/ 
Grade 2 
Severe/ 
Grade 3 
Missing 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Max Severity Post Baseline 
Mild Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
 
 
Note: The “Max Post Baseline” rows indicate the maximum severity experienced by each subject at any time point post baseline, including unscheduled assessments.  
N= Number of subjects in the Safety Population with labs available at each visit. 
 
Tables with similar format 
Table 64: 
Hematology Laboratory Results by Maximum Severity, Time Point, and Impairment Group – Absolute Eosinophils 
Table 65: 
Hematology Laboratory Results by Maximum Severity, Time Point, and Impairment Group – Absolute Basophils 
Table 66: 
Hematology Laboratory Results by Maximum Severity, Time Point, and Impairment Group – Absolute Lymphocytes 
Table 67: 
Hematology Laboratory Results by Maximum Severity, Time Point, and Impairment Group – Absolute Monocytes 
Table 68: 
Hematology Laboratory Results by Maximum Severity, Time Point, and Impairment Group – Platelets 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 1: Table Mock-Ups 
08 May 2024 
 
- 99 - 
RESTRICTED 
Table 69: 
Abnormal Hematology Laboratory Results Related to Study Treatment by Maximum Severity, Time Point, and 
Impairment Group – Any Hematology Parameter 
 
Time Point 
Impairment Group 
N 
Mild/ 
Grade 1 
Moderate/ 
Grade 2 
Severe/ 
Grade 3 
n 
% 
n 
% 
n 
% 
Baseline 
Mild Hepatic Impairment 
x 
x 
xx 
x 
xx 
x 
xx 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
Day 2 
Mild Hepatic Impairment 
 
 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
Day 5 
Mild Hepatic Impairment 
 
 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
Day 12 
Mild Hepatic Impairment 
 
 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
Max Severity Post Baseline 
Mild Hepatic Impairment 
 
 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
Note: The “Max Post Baseline” rows indicate the maximum severity experienced by each subject at any time point post baseline, including unscheduled assessments.  
N= Number of subjects in the Safety Population with labs available at each visit. 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 1: Table Mock-Ups 
08 May 2024 
 
- 100 - 
RESTRICTED 
Tables with similar format: 
Table 70: 
Abnormal Hematology Laboratory Results Related to Study Treatment by Maximum Severity, Time Point, and 
Impairment Group – Hematocrit 
Table 71: 
Abnormal Hematology Laboratory Results Related to Study Treatment by Maximum Severity, Time Point, and 
Impairment Group – Hemoglobin 
Table 72: 
Abnormal Hematology Laboratory Results Related to Study Treatment by Maximum Severity, Time Point, and 
Impairment Group – Red Blood Cell Count 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 1: Table Mock-Ups 
08 May 2024 
 
- 101 - 
RESTRICTED 
Table 73: 
Abnormal Hematology Laboratory Results Related to Study Treatment by Maximum Severity, Time Point, and 
Impairment Group – White Blood Cell Count 
Time Point 
Impairment Group 
N 
Mild/ 
Grade 1 
(Low) 
Mild/ 
Grade 1 
(High) 
Moderate/ 
Grade 2 
(Low) 
Moderate/ 
Grade 2 
(High) 
Severe/ 
Grade 3 
(Low) 
Severe/ 
Grade 3 
(High) 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Baseline 
Mild Hepatic Impairment 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Moderate Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 2 
Mild Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 5 
Mild Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 12 
Mild Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 1: Table Mock-Ups 
08 May 2024 
 
Table 73: 
Abnormal Hematology Laboratory Results Related to Study Treatment by Maximum Severity, Time Point, and Impairment 
Group – White Blood Cell Count (continued) 
- 102 - 
RESTRICTED 
Time Point 
Impairment Group 
N 
Mild/ 
Grade 1 
(Low) 
Mild/ 
Grade 1 
(High) 
Moderate/ 
Grade 2 
(Low) 
Moderate/ 
Grade 2 
(High) 
Severe/ 
Grade 3 
(Low) 
Severe/ 
Grade 3 
(High) 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Max Severity Post 
Baseline 
Mild Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: The “Max Post Baseline” rows indicate the maximum severity experienced by each subject at any time point post baseline, including unscheduled assessments. 
N=Number of subjects in the Safety Population with labs available at each visit. 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 1: Table Mock-Ups 
08 May 2024 
 
- 103 - 
RESTRICTED 
Table 74: 
Abnormal Hematology Laboratory Results Related to Study Treatment by Maximum Severity, Time Point, and 
Impairment Group – Absolute Neutrophils 
Time Point 
Impairment Group 
N 
Mild/ 
Grade 1 
Moderate/ 
Grade 2 
Severe/ 
Grade 3 
n 
% 
n 
% 
n 
% 
Baseline 
Mild Hepatic Impairment 
x 
x 
xx 
x 
xx 
x 
xx 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
Day 2 
Mild Hepatic Impairment 
 
 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
Day 5 
Mild Hepatic Impairment 
 
 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
Day 12 
Mild Hepatic Impairment 
 
 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
Max Severity Post Baseline 
Mild Hepatic Impairment 
 
 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
Note: The “Max Post Baseline” rows indicate the maximum severity experienced by each subject at any time point post baseline, including unscheduled assessments.  
N= Number of subjects in the Safety Population with labs available at each visit. 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 1: Table Mock-Ups 
08 May 2024 
 
- 104 - 
RESTRICTED 
Tables with similar format 
Table 75: 
Abnormal Hematology Laboratory Results Related to Study Treatment by Maximum Severity, Time Point, and 
Impairment Group – Absolute Eosinophils 
Table 76: 
Abnormal Hematology Laboratory Results Related to Study Treatment by Maximum Severity, Time Point, and 
Impairment Group – Absolute Basophils 
Table 77: 
Abnormal Hematology Laboratory Results Related to Study Treatment by Maximum Severity, Time Point, and 
Impairment Group – Absolute Lymphocytes 
Table 78: 
Abnormal Hematology Laboratory Results Related to Study Treatment by Maximum Severity, Time Point, and 
Impairment Group – Absolute Monocytes 
Table 79: 
Abnormal Hematology Laboratory Results Related to Study Treatment by Maximum Severity, Time Point, and 
Impairment Group – Platelets 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 1: Table Mock-Ups 
08 May 2024 
 
- 105 - 
RESTRICTED 
Table 80: 
Hematology Laboratory Summary Statistics by Time Point and Impairment Group – Hematocrit (%) 
Time Point 
Impairment Group 
N 
Mean 
Standard Deviation 
Median 
Min, Max 
Baseline 
Mild Hepatic Impairment 
x 
xx.x 
xx.x 
xx.x 
xx.x, xx.x 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
Day 2 
Mild Hepatic Impairment 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
Day 2, Change from Baseline 
Mild Hepatic Impairment 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
Day 5 
Mild Hepatic Impairment 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
Day 5, Change from Baseline 
Mild Hepatic Impairment 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
Day 12 
Mild Hepatic Impairment 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 1: Table Mock-Ups 
08 May 2024 
 
Table 80: 
Hematology Laboratory Statistics by Time Point and Impairment Group – Hematocrit (%) (continued) 
- 106 - 
RESTRICTED 
Time Point 
Impairment Group 
N 
Mean 
Standard Deviation 
Median 
Min, Max 
Day 12, Change from Baseline 
Mild Hepatic Impairment 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
Note: N= Number of subjects in the Safety Population with labs available at each visit. 
 
Tables with similar format: 
Table 81: 
Hematology Laboratory Summary Statistics by Time Point and Impairment Group – Hemoglobin (g/dL) 
Table 82: 
Hematology Laboratory Summary Statistics by Time Point and Impairment Group – Red Blood Cell Count (x1012/L) 
Table 83: 
Hematology Laboratory Summary Statistics by Time Point and Impairment Group – White Blood Cell Count (x109/L) 
Table 84: 
Hematology Laboratory Summary Statistics by Time Point and Impairment Group – Absolute Neutrophils (x109/L) 
Table 85: 
Hematology Laboratory Summary Statistics by Time Point and Impairment Group – Absolute Eosinophils (x109/L) 
Table 86: 
Hematology Laboratory Summary Statistics by Time Point and Impairment Group – Absolute Basophils (x109/L) 
Table 87: 
Hematology Laboratory Summary Statistics by Time Point and Impairment Group – Absolute Lymphocytes (x109/L) 
Table 88: 
Hematology Laboratory Summary Statistics by Time Point and Impairment Group – Absolute Monocytes (x109/L) 
Table 89: 
Hematology Laboratory Summary Statistics by Time Point and Impairment Group – Platelets (x109/L) 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 1: Table Mock-Ups 
08 May 2024 
 
- 107 - 
RESTRICTED 
14.3.5.3 
Urinalysis Results 
Table 90: 
Urinalysis Laboratory Results by Parameter, Time Point, and Impairment Group 
Time Point 
Impairment Group 
N 
Urine Blood 
Urine Protein 
Urine Glucose 
Any Parameter 
n 
% 
n 
% 
n 
% 
n 
% 
Baseline 
Mild Hepatic Impairment 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
Day 2 
Mild Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
Day 5 
Mild Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
Day 12 
Mild Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
N= Number in the safety population with labs available at each visit. 
n= Number with positive dipstick results. 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 1: Table Mock-Ups 
08 May 2024 
 
- 108 - 
RESTRICTED 
Table 91: 
Urinalysis Laboratory Results by Maximum Severity, Time Point, and Impairment Group – Any Urinalysis Parameter 
Time Point 
Impairment Group 
N 
None 
Mild/ 
Grade 1 
Moderate/ 
Grade 2 
Severe/ 
Grade 3 
Missing 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Baseline 
Mild Hepatic Impairment 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Moderate Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
 
 
Day 2 
Mild Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
 
 
Day 5 
Mild Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
 
 
Day 12 
Mild Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 1: Table Mock-Ups 
08 May 2024 
 
Table 91: 
Urinalysis Laboratory Results by Maximum Severity, Time Point, and Impairment Group – Any Urinalysis Parameter 
(continued) 
- 109 - 
RESTRICTED 
Time Point 
Impairment Group 
N 
None 
Mild/ 
Grade 1 
Moderate/ 
Grade 2 
Severe/ 
Grade 3 
Missing 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Max Severity Post Baseline 
Mild Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
 
 
Note: The “Max Post Baseline” rows indicate the maximum severity experienced by each subject at any time point post baseline, including unscheduled assessments.  
N= Number of subjects in the Safety Population with labs available at each visit. 
 
Tables with similar format: 
Table 92: 
Urinalysis Laboratory Results by Maximum Severity, Time Point, and Impairment Group – Protein 
Table 93: 
Urinalysis Laboratory Results by Maximum Severity, Time Point, and Impairment Group – Glucose 
Table 94: 
Urinalysis Laboratory Results by Maximum Severity, Time Point, and Impairment Group – Urine Blood 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 1: Table Mock-Ups 
08 May 2024 
 
- 110 - 
RESTRICTED 
Table 95: 
Abnormal Urinalysis Laboratory Results Related to Study Treatment by Maximum Severity, Time Point, and Impairment Group 
– Any Urinalysis Parameter 
Time Point 
Impairment Group 
N 
Mild/ 
Grade 1 
Moderate/ 
Grade 2 
Severe/ 
Grade 3 
n 
% 
n 
% 
n 
% 
Baseline 
Mild Hepatic Impairment 
x 
x 
xx 
x 
xx 
x 
xx 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
Day 2 
Mild Hepatic Impairment 
 
 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
Day 5 
Mild Hepatic Impairment 
 
 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
Day 12 
Mild Hepatic Impairment 
 
 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
Max Severity Post Baseline 
Mild Hepatic Impairment 
 
 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
Note: The “Max Post Baseline” rows indicate the maximum severity experienced by each subject at any time point post baseline, including unscheduled assessments.  
N= Number of subjects in the Safety Population with labs available at each visit. 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 1: Table Mock-Ups 
08 May 2024 
 
- 111 - 
RESTRICTED 
Tables with similar format: 
Table 96: 
Abnormal Urinalysis Laboratory Results Related to Study Treatment by Maximum Severity, Time Point, and Impairment Group 
– Protein 
Table 97: 
Abnormal Urinalysis Laboratory Results Related to Study Treatment by Maximum Severity, Time Point, and Impairment Group 
– Glucose 
Table 98: 
Abnormal Urinalysis Laboratory Results Related to Study Treatment by Maximum Severity, Time Point, and Impairment Group 
– Urine Blood 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 1: Table Mock-Ups 
08 May 2024 
 
- 112 - 
RESTRICTED 
Table 99: 
Urinalysis Laboratory Summary Statistics by Time Point and Impairment Group – Blood (rbc/hpf) 
[Implementation Note: Microscopic urine analysis is only performed if there is an abnormal urine result. Therefore, there may not be enough data to 
present this table.] 
Time Point 
Impairment Group 
N 
Mean 
Standard Deviation 
Median 
Min, Max 
Baseline 
Mild Hepatic Impairment 
x 
xx.x 
xx.x 
xx.x 
xx.x, xx.x 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
Day 2 
Mild Hepatic Impairment 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
Day 2, Change from Baseline 
Mild Hepatic Impairment 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
Day 5 
Mild Hepatic Impairment 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
Day 5, Change from Baseline 
Mild Hepatic Impairment 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 1: Table Mock-Ups 
08 May 2024 
 
Table 99: 
Urinalysis Laboratory Summary Statistics by Time Point and Impairment Group – Blood (rbc/hpf) (continued) 
- 113 - 
RESTRICTED 
Time Point 
Impairment Group 
N 
Mean 
Standard Deviation 
Median 
Min, Max 
Day 12 
Mild Hepatic Impairment 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
Day 12, Change from Baseline 
Mild Hepatic Impairment 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
Note: N= Number of subjects in the Safety Population with a positive urine dipstick result and with labs available at each visit. 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 1: Table Mock-Ups 
08 May 2024 
 
- 114 - 
RESTRICTED 
Table 100: 
Urinalysis Laboratory Summary Statistics by Time Point and Impairment Group – Protein 
[Implementation Note: Microscopic urine analysis is only performed if there is an abnormal urine result. Therefore, there may not be enough data to 
present this table.] 
 
Time Point 
Impairment Group 
N 
Negative 
Trace  
1+ 
2+ 
3+ 
4+ 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Baseline 
Mild Hepatic Impairment x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Moderate Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 2 
Mild Hepatic Impairment  
 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 5 
Mild Hepatic Impairment  
 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 1: Table Mock-Ups 
08 May 2024 
 
vvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvTable 100: 
Urinalysis Laboratory Summary Statistics by Time Point and Impairment Group – 
Protein (continued) 
- 115 - 
RESTRICTED 
 
Time Point 
Impairment Group 
N 
Negative 
Trace  
1+ 
2+ 
3+ 
4+ 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Day 12 
Mild Hepatic Impairment  
 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
 
 
 
 
Max Post Baseline 
Mild Hepatic Impairment  
 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: The “Max Post Baseline” rows indicate the maximum experienced by each subject at any time point post baseline, including unscheduled assessments.  
N= Number of subjects in the Safety Population with labs available at each visit. 
 
Table with similar format: 
Table 101: 
Urinalysis Laboratory Summary Statistics by Time Point and Impairment Group – Glucose 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 1: Table Mock-Ups 
08 May 2024 
 
- 116 - 
RESTRICTED 
14.3.5.4 
Coagulation Results 
Table 102: 
Coagulation Laboratory Results by Maximum Severity, Time Point, and Impairment Group – INR 
 
Time Point 
Impairment Group 
N 
None 
Mild/ 
Grade 1 
Moderate/ 
Grade 2 
Severe/ 
Grade 3 
Missing 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Baseline 
Mild Hepatic Impairment 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Moderate Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
 
 
Day 2 
Mild Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
 
 
Day 5 
Mild Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
 
 
Day 12 
Mild Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 1: Table Mock-Ups 
08 May 2024 
 
Table 102: 
Coagulation Laboratory Results by Maximum Severity, Time Point, and Impairment Group – INR (continued) 
- 117 - 
RESTRICTED 
 
Time Point 
Impairment Group 
N 
None 
Mild/ 
Grade 1 
Moderate/ 
Grade 2 
Severe/ 
Grade 3 
Missing 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Max Severity Post Baseline 
Mild Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
 
 
Note: The “Max Post Baseline” rows indicate the maximum severity experienced by each subject at any time point post baseline, including unscheduled assessments.  
N= Number of subjects in the Safety Population with labs available at each visit. 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 1: Table Mock-Ups 
08 May 2024 
 
- 118 - 
RESTRICTED 
Table 103: 
Abnormal Coagulation Laboratory Results Related to Study Treatment by Maximum Severity, Time Point, and Impairment 
Group – INR 
 
Time Point 
Impairment Group 
N 
Mild/ 
Grade 1 
Moderate/ 
Grade 2 
Severe/ 
Grade 3 
n 
% 
n 
% 
n 
% 
Baseline 
Mild Hepatic Impairment 
x 
x 
xx 
x 
xx 
x 
xx 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
Day 2 
Mild Hepatic Impairment 
 
 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
Day 5 
Mild Hepatic Impairment 
 
 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
Day 12 
Mild Hepatic Impairment 
 
 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
Max Severity Post Baseline 
Mild Hepatic Impairment 
 
 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
Note: The “Max Post Baseline” rows indicate the maximum severity experienced by each subject at any time point post baseline, including unscheduled assessments.  
N= Number of subjects in the Safety Population with labs available at each visit. 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 1: Table Mock-Ups 
08 May 2024 
 
- 119 - 
RESTRICTED 
Table 104: 
Coagulation Laboratory Summary Statistics by Time Point and Impairment Group – INR 
Time Point 
Impairment Group 
N 
Mean 
Standard Deviation 
Median 
Min, Max 
Baseline 
Mild Hepatic Impairment 
x 
xx.x 
xx.x 
xx.x 
xx.x, xx.x 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
Day 2 
Mild Hepatic Impairment 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
Day 2, Change from Baseline 
Mild Hepatic Impairment 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
Day 5 
Mild Hepatic Impairment 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
Day 5, Change from Baseline 
Mild Hepatic Impairment 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
Day 12 
Mild Hepatic Impairment 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 1: Table Mock-Ups 
08 May 2024 
 
Table 104: 
Coagulation Laboratory Summary Statistics by Time Point and Impairment Group – INR (continued) 
- 120 - 
RESTRICTED 
Time Point 
Impairment Group 
N 
Mean 
Standard Deviation 
Median 
Min, Max 
Day 12, Change from Baseline 
Mild Hepatic Impairment 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
Note: N= Number of subjects in the Safety Population with labs available at each visit. 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 1: Table Mock-Ups 
08 May 2024 
 
- 121 - 
RESTRICTED 
Table 105: 
Chemistry Shift Tables by Time Point and Impairment Group – Total Bilirubin 
[Implementation Note: If there is no low range then those columns will be removed.] 
 
Mild Hepatic Impairment 
(N=X) 
Baseline 
Moderate Hepatic Impairment 
(N=X) 
Baseline 
Severe Hepatic Impairment 
(N=X) 
Baseline 
Matched Controls 
(N=X) 
Baseline 
Day Post Dose 
Low  
Normal 
High  
Total 
Low  
Normal 
High  
Total 
Low  
Normal 
High  
Total 
Low  
Normal 
High  
Total 
Day 2 
Low 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
Normal 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
High 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
Total 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
Day 5 
Low 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
Normal 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
High 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
Total 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
Day 12 
Low 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
Normal 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
High 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
Total 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
Tables with similar format: 
Table 106: 
Chemistry Shift Tables by Time Point and Impairment Group – Serum Albumin 
Table 107: 
Chemistry Shift Tables by Time Point and Impairment Group – Potassium 
Table 108: 
Chemistry Shift Tables by Time Point and Impairment Group – Magnesium 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 1: Table Mock-Ups 
08 May 2024 
 
- 122 - 
RESTRICTED 
Table 109: 
Chemistry Shift Tables by Time Point and Impairment Group – Calcium 
Table 110: 
Chemistry Shift Tables by Time Point and Impairment Group – Serum Creatinine 
Table 111: 
Chemistry Shift Tables by Time Point and Impairment Group – BUN 
Table 112: 
Chemistry Shift Tables by Time Point and Impairment Group – Alkaline Phosphatase 
Table 113: 
Chemistry Shift Tables by Time Point and Impairment Group – ALT 
Table 114: 
Chemistry Shift Tables by Time Point and Impairment Group – AST 
Table 115: 
Hematology Shift Tables by Time Point and Impairment Group – Hematocrit 
Table 116: 
Hematology Shift Tables by Time Point and Impairment Group – Hemoglobin 
Table 117: 
Hematology Shift Tables by Time Point and Impairment Group – Red Blood Cell Count 
Table 118: 
Hematology Shift Tables by Time Point and Impairment Group – White Blood Cell Count 
Table 119: 
Hematology Shift Tables by Time Point and Impairment Group – Neutrophils 
Table 120: 
Hematology Shift Tables by Time Point and Impairment Group – Eosinophils 
Table 121: 
Hematology Shift Tables by Time Point and Impairment Group – Basophils 
Table 122: 
Hematology Shift Tables by Time Point and Impairment Group – Lymphocytes 
Table 123: 
Hematology Shift Tables by Time Point and Impairment Group – Monocytes 
Table 124: 
Hematology Shift Tables by Time Point and Impairment Group – Platelets 
Table 125: 
Coagulation Shift Tables by Time Point and Impairment Group – INR 
Table 126: 
Urinalysis Shift Tables by Time Point and Impairment Group – Protein 
Table 127: 
Urinalysis Shift Tables by Time Point and Impairment Group – Glucose 
Table 128: 
Urinalysis Shift Tables by Time Point and Impairment Group – Blood 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 1: Table Mock-Ups 
08 May 2024 
 
- 123 - 
RESTRICTED 
14.3.6 Displays of Vital Signs 
Table 129: 
Vital Signs by Maximum Severity, Time Point, and Impairment Group – Any Assessment 
 
Time Point 
Impairment Group 
N 
None 
Mild/ 
Grade 1 
Moderate/ 
Grade 2 
Severe/ 
Grade 3 
n 
% 
n 
% 
n 
% 
n 
% 
Admission 
Mild Hepatic Impairment 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
Baseline 
Mild Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
1 hour post-dose 
Mild Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
2 hours post-dose 
Mild Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
4 hours post-dose 
Mild Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 1: Table Mock-Ups 
08 May 2024 
 
Table 129: 
Vital Signs by Maximum Severity, Time Point, and Impairment Group – Any Assessment (continued) 
- 124 - 
RESTRICTED 
 
Time Point 
Impairment Group 
N 
None 
Mild/ 
Grade 1 
Moderate/ 
Grade 2 
Severe/ 
Grade 3 
n 
% 
n 
% 
n 
% 
n 
% 
5 hours post-dose 
Mild Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
6 hours post-dose 
Mild Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
8 hours post-dose 
Mild Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
12 hours post-dose 
Mild Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
16 hours post-dose 
Mild Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 1: Table Mock-Ups 
08 May 2024 
 
Table 129: 
Vital Signs by Maximum Severity, Time Point, and Impairment Group – Any Assessment (continued) 
- 125 - 
RESTRICTED 
 
Time Point 
Impairment Group 
N 
None 
Mild/ 
Grade 1 
Moderate/ 
Grade 2 
Severe/ 
Grade 3 
n 
% 
n 
% 
n 
% 
n 
% 
24 hours post-dose 
Mild Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
36 hours post-dose 
Mild Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
Day 3 
Mild Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
Day 4 
Mild Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
Day 5 
Mild Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 1: Table Mock-Ups 
08 May 2024 
 
Table 129: 
Vital Signs by Maximum Severity, Time Point, and Impairment Group – Any Assessment (continued) 
- 126 - 
RESTRICTED 
 
Time Point 
Impairment Group 
N 
None 
Mild/ 
Grade 1 
Moderate/ 
Grade 2 
Severe/ 
Grade 3 
n 
% 
n 
% 
n 
% 
n 
% 
Day 12 
Mild Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
Max Severity Post Baseline 
Mild Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
 
Table with similar format: 
Table 130: 
Vital Signs by Maximum Severity, Time Point, and Impairment Group – Oral Temperature 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 1: Table Mock-Ups 
08 May 2024 
 
- 127 - 
RESTRICTED 
Table 131: 
Vital Signs by Maximum Severity, Time Point, and Impairment Group – Pulse 
Time Point 
Impairment Group 
N 
None 
Mild 
(Low) 
Mild 
(High) 
Moderate 
(Low) 
Moderate 
(High) 
Severe 
(Low) 
Severe 
(High) 
Missing 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Admission  
Mild Hepatic 
Impairment 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Moderate Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Baseline 
Mild Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 hour post-dose 
Mild Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2 hours post-dose 
Mild Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 1: Table Mock-Ups 
08 May 2024 
 
Table 131: 
Vital Signs by Maximum Severity, Time Point, and Impairment Group – Pulse (continued) 
- 128 - 
RESTRICTED 
Time Point 
Impairment Group 
N 
None 
Mild 
(Low) 
Mild 
(High) 
Moderate 
(Low) 
Moderate 
(High) 
Severe 
(Low) 
Severe 
(High) 
Missing 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
4 hours post-dose 
Mild Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5 hours post-dose 
Mild Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6 hours post-dose 
Mild Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8 hours post-dose 
Mild Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 1: Table Mock-Ups 
08 May 2024 
 
Table 131: 
Vital Signs by Maximum Severity, Time Point, and Impairment Group – Pulse (continued) 
- 129 - 
RESTRICTED 
Time Point 
Impairment Group 
N 
None 
Mild 
(Low) 
Mild 
(High) 
Moderate 
(Low) 
Moderate 
(High) 
Severe 
(Low) 
Severe 
(High) 
Missing 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
12 hours post-dose 
Mild Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
16 hours post-dose 
Mild Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
24 hours post-dose 
Mild Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
36 hours post-dose 
Mild Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 1: Table Mock-Ups 
08 May 2024 
 
Table 131: 
Vital Signs by Maximum Severity, Time Point, and Impairment Group – Pulse (continued) 
- 130 - 
RESTRICTED 
Time Point 
Impairment Group 
N 
None 
Mild 
(Low) 
Mild 
(High) 
Moderate 
(Low) 
Moderate 
(High) 
Severe 
(Low) 
Severe 
(High) 
Missing 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Day 3 
Mild Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 4 
Mild Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 5 
Mild Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 12 
Mild Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 1: Table Mock-Ups 
08 May 2024 
 
Table 131: 
Vital Signs by Maximum Severity, Time Point, and Impairment Group – Pulse (continued) 
- 131 - 
RESTRICTED 
Time Point 
Impairment Group 
N 
None 
Mild 
(Low) 
Mild 
(High) 
Moderate 
(Low) 
Moderate 
(High) 
Severe 
(Low) 
Severe 
(High) 
Missing 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Max Severity Post 
Baseline 
Mild Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: The “Max Post Baseline” rows indicate the maximum severity experienced by each subject at any time point post baseline, including unscheduled assessments. N = [define the 
population for this table, e.g., Number of subjects in the Safety Population] 
 
Table with similar format: 
Table 132: 
Vital Signs by Maximum Severity, Time Point, and Impairment Group – Systolic Blood Pressure 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 1: Table Mock-Ups 
08 May 2024 
 
- 132 - 
RESTRICTED 
Table 133: 
Vital Signs by Maximum Severity, Time Point, and Impairment Group – Diastolic Blood Pressure 
 
Time Point 
Impairment Group 
N 
None 
Mild/ 
Grade 1 
Moderate/ 
Grade 2 
Severe/ 
Grade 3 
Missing 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Admission 
Mild Hepatic Impairment 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Moderate Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
 
 
Baseline 
Mild Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
 
 
1 hour post-dose 
Mild Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
 
 
2 hours post-dose 
Mild Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
 
 
4 hours post-dose 
Mild Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 1: Table Mock-Ups 
08 May 2024 
 
Table 133: 
Vital Signs by Maximum Severity, Time Point, and Impairment Group – Diastolic Blood Pressure (continued) 
- 133 - 
RESTRICTED 
 
Time Point 
Impairment Group 
N 
None 
Mild/ 
Grade 1 
Moderate/ 
Grade 2 
Severe/ 
Grade 3 
Missing 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
5 hours post-dose 
Mild Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
 
 
6 hours post-dose 
Mild Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
 
 
8 hours post-dose 
Mild Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
 
 
12 hours post-dose 
Mild Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
 
 
16 hours post-dose 
Mild Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 1: Table Mock-Ups 
08 May 2024 
 
Table 133: 
Vital Signs by Maximum Severity, Time Point, and Impairment Group – Diastolic Blood Pressure (continued) 
- 134 - 
RESTRICTED 
 
Time Point 
Impairment Group 
N 
None 
Mild/ 
Grade 1 
Moderate/ 
Grade 2 
Severe/ 
Grade 3 
Missing 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
24 hours post-dose 
Mild Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
 
 
36 hours post-dose 
Mild Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
 
 
Day 3 
Mild Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
 
 
Day 4 
Mild Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
 
 
Day 5 
Mild Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 1: Table Mock-Ups 
08 May 2024 
 
Table 133: 
Vital Signs by Maximum Severity, Time Point, and Impairment Group – Diastolic Blood Pressure (continued) 
- 135 - 
RESTRICTED 
 
Time Point 
Impairment Group 
N 
None 
Mild/ 
Grade 1 
Moderate/ 
Grade 2 
Severe/ 
Grade 3 
Missing 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Day 12 
Mild Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
 
 
Max Severity Post Baseline 
Mild Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate Hepatic 
Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
 
 
 
 
 
 
Note: The “Max Post Baseline” rows indicate the maximum severity experienced by each subject at any time point post baseline, including unscheduled assessments.  
N= Number of subjects in the Safety Population at each visit. 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 1: Table Mock-Ups 
08 May 2024 
 
- 136 - 
RESTRICTED 
Table 134: 
Vital Signs Summary Statistics by Time Point and Impairment Group – Oral Temperature 
Time Point 
Impairment Group 
N 
Mean 
Standard Deviation 
Median 
Min, Max 
Admission 
Mild Hepatic Impairment 
x 
xx.x 
xx.x 
xx.x 
xx.x, xx.x 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
Baseline 
Mild Hepatic Impairment 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
1 hour post-dose 
Mild Hepatic Impairment 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
1 hour post-dose, Change from Baseline 
Mild Hepatic Impairment 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
2 hours post-dose 
Mild Hepatic Impairment 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
2 hours post-dose, Change from Baseline 
Mild Hepatic Impairment 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 1: Table Mock-Ups 
08 May 2024 
 
Table 134: 
Vital Signs Summary Statistics by Time Point and Impairment Group – Oral Temperature (continued) 
- 137 - 
RESTRICTED 
Time Point 
Impairment Group 
N 
Mean 
Standard Deviation 
Median 
Min, Max 
4 hours post-dose 
Mild Hepatic Impairment 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
4 hours post-dose, Change from Baseline 
Mild Hepatic Impairment 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
5 hours post-dose 
Mild Hepatic Impairment 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
5 hours post-dose, Change from Baseline 
Mild Hepatic Impairment 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
6 hours post-dose 
Mild Hepatic Impairment 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
6 hours post-dose, Change from Baseline 
Mild Hepatic Impairment 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 1: Table Mock-Ups 
08 May 2024 
 
Table 134: 
Vital Signs Summary Statistics by Time Point and Impairment Group – Oral Temperature (continued) 
- 138 - 
RESTRICTED 
Time Point 
Impairment Group 
N 
Mean 
Standard Deviation 
Median 
Min, Max 
8 hours post-dose 
Mild Hepatic Impairment 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
8 hours post-dose, Change from Baseline 
Mild Hepatic Impairment 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
12 hours post-dose 
Mild Hepatic Impairment 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
12 hours post-dose, Change from Baseline 
Mild Hepatic Impairment 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
16 hours post-dose 
Mild Hepatic Impairment 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
16 hours post-dose, Change from Baseline 
Mild Hepatic Impairment 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 1: Table Mock-Ups 
08 May 2024 
 
Table 134: 
Vital Signs Summary Statistics by Time Point and Impairment Group – Oral Temperature (continued) 
- 139 - 
RESTRICTED 
Time Point 
Impairment Group 
N 
Mean 
Standard Deviation 
Median 
Min, Max 
24 hours post-dose 
Mild Hepatic Impairment 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
24 hours post-dose, Change from Baseline 
Mild Hepatic Impairment 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
36 hours post-dose 
Mild Hepatic Impairment 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
36 hours post-dose, Change from Baseline 
Mild Hepatic Impairment 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
Day 3 
Mild Hepatic Impairment 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
Day 3, Change from Baseline 
Mild Hepatic Impairment 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 1: Table Mock-Ups 
08 May 2024 
 
Table 134: 
Vital Signs Summary Statistics by Time Point and Impairment Group – Oral Temperature (continued) 
- 140 - 
RESTRICTED 
Time Point 
Impairment Group 
N 
Mean 
Standard Deviation 
Median 
Min, Max 
Day 4 
Mild Hepatic Impairment 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
Day 4, Change from Baseline 
Mild Hepatic Impairment 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
Day 5 
Mild Hepatic Impairment 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
Day 5, Change from Baseline 
Mild Hepatic Impairment 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
Day 12 
Mild Hepatic Impairment 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
Day 12, Change from Baseline 
Mild Hepatic Impairment 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 1: Table Mock-Ups 
08 May 2024 
 
Table 134: 
Vital Signs Summary Statistics by Time Point and Impairment Group – Oral Temperature (continued) 
- 141 - 
RESTRICTED 
Time Point 
Impairment Group 
N 
Mean 
Standard Deviation 
Median 
Min, Max 
Max Severity Post Baseline 
Mild Hepatic Impairment 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
Note: N= Number of subjects in the Safety Population at each visit 
 
Tables with similar format: 
Table 135: 
Vital Signs Summary Statistics by Time Point and Impairment Group – Pulse 
Table 136: 
Vital Signs Summary Statistics by Time Point and Impairment Group – Systolic Blood Pressure 
Table 137: 
Vital Signs Summary Statistics by Time Point and Impairment Group – Diastolic Blood Pressure 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 1: Table Mock-Ups 
08 May 2024 
 
- 142 - 
RESTRICTED 
Table 138: 
Summary of Abnormal Physical Exam Findings by Impairment Group 
 
 
Time Point 
Body System 
Mild Hepatic 
Impairment  
(N=X) 
Moderate Hepatic 
Impairment 
(N=X) 
Severe Hepatic 
Impairment (N=X) 
Matched Controls 
(N=X) 
All Subjects 
(N=X) 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Admission 
Any Body System 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Abdomen 
 
 
 
 
 
 
 
 
 
 
 
Cardiovascular/Heart 
 
 
 
 
 
 
 
 
 
 
 
Extremities 
 
 
 
 
 
 
 
 
 
 
 
General Appearance 
 
 
 
 
 
 
 
 
 
 
 
HEENT 
 
 
 
 
 
 
 
 
 
 
 
Lymph Nodes 
 
 
 
 
 
 
 
 
 
 
 
Musculoskeletal 
 
 
 
 
 
 
 
 
 
 
 
Neck (Thyroid) 
 
 
 
 
 
 
 
 
 
 
 
Neurological 
 
 
 
 
 
 
 
 
 
 
 
Pulmonary/Chest 
 
 
 
 
 
 
 
 
 
 
 
Skin 
 
 
 
 
 
 
 
 
 
 
Day 12 
Any Body System 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
 
Abdomen 
 
 
 
 
 
 
 
 
 
 
 
Cardiovascular/Heart 
 
 
 
 
 
 
 
 
 
 
 
Extremities 
 
 
 
 
 
 
 
 
 
 
 
General Appearance 
 
 
 
 
 
 
 
 
 
 
 
HEENT 
 
 
 
 
 
 
 
 
 
 
 
Lymph Nodes 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 1: Table Mock-Ups 
08 May 2024 
 
Table 138: 
Summary of Abnormal Physical Exam Findings by Impairment Group (continued) 
- 143 - 
RESTRICTED 
 
 
Time Point 
Body System 
Mild Hepatic 
Impairment  
(N=X) 
Moderate Hepatic 
Impairment 
(N=X) 
Severe Hepatic 
Impairment (N=X) 
Matched Controls 
(N=X) 
All Subjects 
(N=X) 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
 
Musculoskeletal 
 
 
 
 
 
 
 
 
 
 
 
Neck (Thyroid) 
 
 
 
 
 
 
 
 
 
 
 
Neurological 
 
 
 
 
 
 
 
 
 
 
 
Pulmonary/Chest 
 
 
 
 
 
 
 
 
 
 
 
Skin 
 
 
 
 
 
 
 
 
 
 
Note: N= Number of subjects in the Safety Population at each visit 
n = Number of subjects with physical exam findings. 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 1: Table Mock-Ups 
08 May 2024 
 
- 144 - 
RESTRICTED 
Table 139: 
Physical Exam Summary Statistics by Time Point and Impairment Group – Weight 
Time Point 
Impairment Group 
N 
Mean 
Standard Deviation 
Median 
Min, Max 
Admission 
Mild Hepatic Impairment 
x 
xx.x 
xx.x 
xx.x 
xx.x, xx.x 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
Baseline 
Mild Hepatic Impairment 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
1 hour post-dose 
Mild Hepatic Impairment 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
1 hour post-dose, Change from Baseline 
Mild Hepatic Impairment 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
2 hours post-dose 
Mild Hepatic Impairment 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
2 hours post-dose, Change from Baseline 
Mild Hepatic Impairment 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 1: Table Mock-Ups 
08 May 2024 
 
Table 139: 
Physical Exam Summary Statistics by Time Point and Impairment Group – Weight (continued) 
- 145 - 
RESTRICTED 
Time Point 
Impairment Group 
N 
Mean 
Standard Deviation 
Median 
Min, Max 
4 hours post-dose 
Mild Hepatic Impairment 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
4 hours post-dose, Change from Baseline 
Mild Hepatic Impairment 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
5 hours post-dose 
Mild Hepatic Impairment 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
5 hours post-dose, Change from Baseline 
Mild Hepatic Impairment 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
6 hours post-dose 
Mild Hepatic Impairment 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
6 hours post-dose, Change from Baseline 
Mild Hepatic Impairment 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 1: Table Mock-Ups 
08 May 2024 
 
Table 139: 
Physical Exam Summary Statistics by Time Point and Impairment Group – Weight (continued) 
- 146 - 
RESTRICTED 
Time Point 
Impairment Group 
N 
Mean 
Standard Deviation 
Median 
Min, Max 
8 hours post-dose 
Mild Hepatic Impairment 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
8 hours post-dose, Change from Baseline 
Mild Hepatic Impairment 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
12 hours post-dose 
Mild Hepatic Impairment 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
12 hours post-dose, Change from Baseline 
Mild Hepatic Impairment 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
16 hours post-dose 
Mild Hepatic Impairment 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
16 hours post-dose, Change from Baseline 
Mild Hepatic Impairment 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 1: Table Mock-Ups 
08 May 2024 
 
Table 139: 
Physical Exam Summary Statistics by Time Point and Impairment Group – Weight (continued) 
- 147 - 
RESTRICTED 
Time Point 
Impairment Group 
N 
Mean 
Standard Deviation 
Median 
Min, Max 
24 hours post-dose 
Mild Hepatic Impairment 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
24 hours post-dose, Change from Baseline 
Mild Hepatic Impairment 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
36 hours post-dose 
Mild Hepatic Impairment 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
36 hours post-dose, Change from Baseline 
Mild Hepatic Impairment 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
Day 3 
Mild Hepatic Impairment 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
Day 3, Change from Baseline 
Mild Hepatic Impairment 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 1: Table Mock-Ups 
08 May 2024 
 
Table 139: 
Physical Exam Summary Statistics by Time Point and Impairment Group – Weight (continued) 
- 148 - 
RESTRICTED 
Time Point 
Impairment Group 
N 
Mean 
Standard Deviation 
Median 
Min, Max 
Day 4 
Mild Hepatic Impairment 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
Day 4, Change from Baseline 
Mild Hepatic Impairment 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
Day 5 
Mild Hepatic Impairment 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
Day 5, Change from Baseline 
Mild Hepatic Impairment 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
Day 12 
Mild Hepatic Impairment 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
Day 12, Change from Baseline 
Mild Hepatic Impairment 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 1: Table Mock-Ups 
08 May 2024 
 
Table 139: 
Physical Exam Summary Statistics by Time Point and Impairment Group – Weight (continued) 
- 149 - 
RESTRICTED 
Time Point 
Impairment Group 
N 
Mean 
Standard Deviation 
Median 
Min, Max 
Max Severity Post Baseline 
Mild Hepatic Impairment 
 
 
 
 
 
 
Moderate Hepatic Impairment 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
Note: N= Number of subjects in the Safety Population at each visit 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 1: Table Mock-Ups 
08 May 2024 
 
- 150 - 
RESTRICTED 
14.4 
Summary of Concomitant Medications 
Table 140: 
Number and Percentage of Subjects with Prior and Concurrent Medications by WHO 
Drug Classification and Impairment Group 
WHO Drug Code 
Level 1, Anatomic 
Group 
WHO Drug Code 
Level 2, 
Therapeutic 
Subgroup 
Mild Hepatic 
Impairment  
(N=X) 
Moderate 
Hepatic 
Impairment 
(N=X) 
Severe Hepatic 
Impairment 
(N=X) 
Matched 
Controls (N=X) 
All Subjects 
(N=X) 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Any Level 1 Codes 
Any Level 2 Codes x 
xx 
x 
xx 
 
 
 
 
x 
xx 
[ATC Level 1 - 1] 
Any [ATC 1 – 1] 
 
 
 
 
 
 
 
 
 
 
 
[ATC 2 - 1] 
 
 
 
 
 
 
 
 
 
 
 
[ATC 2 - 2] 
 
 
 
 
 
 
 
 
 
 
 
[ATC 2 - 3] 
 
 
 
 
 
 
 
 
 
 
[ATC Level 1 – 2] 
[ATC 2 - 1] 
 
 
 
 
 
 
 
 
 
 
 
[ATC 2 - 2] 
 
 
 
 
 
 
 
 
 
 
 
[ATC 2 - 3] 
 
 
 
 
 
 
 
 
 
 
N = Number of subjects in the Safety Population 
n=Number of subjects reporting taking at least one medication in the specific WHO Drug Class. 
 
 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 1: Table Mock-Ups 
08 May 2024 
 
- 151 - 
RESTRICTED 
14.5 
Other Safety Measures 
Table 141: 
ECG Summary Statistics by Time Point and Impairment Group – RR 
Time Point 
Impairment Group 
N 
Mean 
Standard 
Deviation 
Median 
Min, Max 
Admission 
Mild Hepatic Impairment 
x 
xx.x 
xx.x 
xx.x 
xx.x, xx.x 
 
Moderate Hepatic 
Impairment 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
Day 12 
Mild Hepatic Impairment 
 
 
 
 
 
 
Moderate Hepatic 
Impairment 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
Change from Baseline 
Mild Hepatic Impairment 
 
 
 
 
 
 
Moderate Hepatic 
Impairment 
 
 
 
 
 
 
Severe Hepatic Impairment 
 
 
 
 
 
 
Matched Controls 
 
 
 
 
 
Note: N= Number of subjects in the Safety Population at each visit. 
 
Tables with similar format: 
Table 142: 
ECG Summary Statistics by Time Point and Impairment Group – QRS 
Table 143: 
ECG Summary Statistics by Time Point and Impairment Group – QT 
Table 144: 
ECG Summary Statistics by Time Point and Impairment Group – QTcF 
Table 145: 
ECG Summary Statistics by Time Point and Impairment Group – PR 
Table 146: 
ECG Summary Statistics by Time Point and Impairment Group – Ventricular Rate 
 
 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 1: Table Mock-Ups 
08 May 2024 
 
- 152 - 
RESTRICTED 
Table 147: 
Number and Percentage of Subjects Experiencing ECG Events by Symptom, and 
Impairment Group 
Symptom 
Visit 
Mild Hepatic 
Impairment 
(N=X) 
Moderate Hepatic 
Impairment 
(N=X) 
Severe Hepatic 
Impairment 
(N=X) 
Matched Controls 
(N=X) 
n 
% 
95% CI 
n 
% 
95% CI 
n 
% 
95% CI 
n 
% 
95% CI 
Any Symptom 
Admission 
x 
xx 
x.x, x.x 
x 
xx 
x.x, x.x 
x 
xx 
x.x, x.x 
x 
xx 
x.x, x.x 
 
Day 12 
 
 
 
 
 
 
 
 
 
 
 
 
Bradycardia 
Admission 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 12 
 
 
 
 
 
 
 
 
 
 
 
 
Tachycardia 
Admission 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 12 
 
 
 
 
 
 
 
 
 
 
 
 
Conduction System 
Disease 
Admission 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 12 
 
 
 
 
 
 
 
 
 
 
 
 
Arrhythmia 
Admission 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 12 
 
 
 
 
 
 
 
 
 
 
 
 
Brugada Pattern 
Admission 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 12 
 
 
 
 
 
 
 
 
 
 
 
 
Note: N = Number of subjects in the Safety Population at each visit. 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 1: Table Mock-Ups 
08 May 2024 
 
- 153 - 
RESTRICTED 
14.6 
Pharmacokinetics Results 
Table 148: 
Individual and Summary Statistics for Plasma Concentrations by Nominal Time (hours) 
– Mild Hepatic Impairment 
Pre-
Dose 
1 
2 
4 
5 
6 
8 
12 
16 
24 
36 
48 
72 
96 
001 
 
 
 
 
 
 
 
 
 
002 
 
 
 
 
 
 
 
 
 
003 
 
 
 
 
 
 
 
 
 
N 
 
 
 
 
 
 
 
 
 
N Not Evaluable 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Number < LLOQa 
 
 
 
 
 
 
 
 
 
Mean 
 
 
 
 
 
 
 
 
 
SD 
 
 
 
 
 
 
 
 
 
Min 
 
 
 
 
 
 
 
 
 
Median 
 
 
 
 
 
 
 
 
 
Max 
 
 
 
 
 
 
 
 
 
a LLOQ=10 ng/mL 
 
Tables with similar format: 
Table 149: 
Individual and Summary Statistics for Plasma Concentrations by Nominal Time (hours) 
– Moderate Hepatic Impairment 
Table 150: 
Individual and Summary Statistics for Plasma Concentrations by Nominal Time (hours) 
– Severe Hepatic Impairment 
Table 151: 
Individual and Summary Statistics for Plasma Concentrations by Nominal Time (hours) 
– Matched Controls 
 
 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 1: Table Mock-Ups 
08 May 2024 
 
- 154 - 
RESTRICTED 
Table 152: 
Individual and Summary Statistics for Noncompartmental PK Parameters – Mild 
Hepatic Impairment 
Subject ID 
AUC0-last  
(ng·hr/mL) 
AUC0-∞ 
(ng·hr/mL) 
Tmax (hr) 
Cmax 
(ng/mL) 
CL/F 
(L/hr) 
Vd/F 
(L) 
t1/2) (hr) 
001 
 
 
 
 
002 
 
 
 
 
003 
 
 
 
 
N 
 
 
 
 
Mean 
 
 
 
 
SD 
 
 
 
 
Min 
 
 
 
 
Max 
 
 
 
 
CV % 
 
 
 
 
GM 
 
 
 
 
 
Tables with similar format: 
Table 153: 
Individual and Summary Statistics for Noncompartmental PK Parameters – Moderate 
Hepatic Impairment 
Table 154: 
Individual and Summary Statistics for Noncompartmental PK Parameters – Severe 
Hepatic Impairment 
Table 155: 
Individual and Summary Statistics for Noncompartmental PK Parameters – Matched 
Controls 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 1: Table Mock-Ups 
08 May 2024 
 
- 155 - 
RESTRICTED 
Table 156: 
Estimated Impairment Group Fold Change for Noncompartmental PK Parameters 
[Implementation Note:  The site column will only be included if the group by site interaction is significant at a 
p-value < 0.10 level.] 
 
Site 
Impairment Group 
Statistic 
AUC0-last  
(ng·hr/mL) 
AUC0-∞ 
(ng·hr/mL) 
Cmax 
(ng/mL) 
Duke 
Mild 
 Mean 
 
 
 
90% CI of Mean 
 
 
 
 
Fold Changea 
 
 
 
 
90% CI of Mean 
 
 
 
Moderate 
 Mean 
 
 
 
 
90% CI of Mean 
 
 
 
 
Fold Changea 
 
 
 
90% CI of Mean 
 
 
 
Severe 
 Mean 
 
 
 
 
 
90% CI of Mean 
 
 
 
 
 
Fold Changea 
 
 
 
 
 
90% CI of Mean 
 
 
 
 
Matched Controls 
Mean 
 
 
 
 
 
90% CI of Mean 
 
 
 
Saint Louis 
Mild 
 Mean 
 
 
 
 
 
90% CI of Mean 
 
 
 
 
 
Fold Changea 
 
 
 
 
 
90% CI of Mean 
 
 
 
 
Moderate 
 Mean 
 
 
 
 
 
90% CI of Mean 
 
 
 
 
 
Fold Changea 
 
 
 
 
 
90% CI of Mean 
 
 
 
 
Severe 
 Mean 
 
 
 
 
 
90% CI of Mean 
 
 
 
 
 
Fold Changea 
 
 
 
 
 
90% CI of Mean 
 
 
 
 
Matched Controls 
Mean 
 
 
 
 
 
90% CI of Mean 
 
 
 
Overall 
Mild 
 Mean 
 
 
 
 
 
90% CI of Mean 
 
 
 
 
 
Fold Changea 
 
 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 1: Table Mock-Ups 
08 May 2024 
 
Table 156: 
Estimated Impairment Group Fold Change for Noncompartmental PK Parameters 
(continued) 
- 156 - 
RESTRICTED 
 
Site 
Impairment Group 
Statistic 
AUC0-last  
(ng·hr/mL) 
AUC0-∞ 
(ng·hr/mL) 
Cmax 
(ng/mL) 
 
 
90% CI of Mean 
 
 
 
 
Moderate 
 Mean 
 
 
 
 
 
90% CI of Mean 
 
 
 
 
 
Fold Changea 
 
 
 
 
 
90% CI of Mean 
 
 
 
 
Severe 
 Mean 
 
 
 
 
 
90% CI of Mean 
 
 
 
 
 
Fold Changea 
 
 
 
 
 
90% CI of Mean 
 
 
 
 
Matched Controls 
Mean 
 
 
 
 
 
90% CI of Mean 
 
 
 
a Comparison is to matched controls 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 1: Table Mock-Ups 
08 May 2024 
 
- 157 - 
RESTRICTED 
Table 157: 
Estimated Impairment Group Shift for Noncompartmental PK Parameters 
[Implementation Note: Site column will only be included if confidence intervals between sites do not 
overlap.] 
 
Site 
Impairment Group 
Statistic 
Tmax 
(h) 
Duke 
Mild 
Median 
 
90% CIa 
 
 
Shiftb 
 
 
90% CIa 
 
Moderate 
Median 
 
 
90% CIa 
 
 
Shiftb 
 
90% CIa 
 
Severe 
Median 
 
 
 
90% CIa 
 
 
 
Shiftb 
 
 
 
90% CIa 
 
 
Matched Controls 
Median 
 
 
 
90% CIa 
 
Saint Louis 
Mild 
Median 
 
 
 
90% CIa 
 
 
 
Shiftb 
 
 
 
90% CIa 
 
 
Moderate 
Median 
 
 
 
90% CIa 
 
 
 
Shiftb 
 
 
 
90% CIa 
 
 
Severe 
Median 
 
 
 
90% CIa 
 
 
 
Shiftb 
 
 
 
90% CIa 
 
 
Matched Controls 
Median 
 
 
 
90% CIa 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 1: Table Mock-Ups 
08 May 2024 
 
Table 157: 
Estimated Impairment Group Shift for Noncompartmental PK Parameters (continued) 
- 158 - 
RESTRICTED 
 
Site 
Impairment Group 
Statistic 
Tmax 
(h) 
Overall 
Mild 
Median 
 
 
 
90% CIa 
 
 
 
Shiftb 
 
 
 
90% CIa 
 
 
Moderate 
Median 
 
 
 
90% CIa 
 
 
 
Shiftb 
 
 
 
90% CIa 
 
 
Severe 
Median 
 
 
 
90% CIa 
 
 
 
Shiftb 
 
 
 
90% CIa 
 
 
Matched Controls 
Median 
 
 
 
90% CIa 
 
a Confidence limits will be estimated using the inverted rank score method. 
b Comparison is to matched controls 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 2: Figure Mock-Ups 
08 May 2024 
 
- 159 - 
RESTRICTED 
APPENDIX 2. FIGURE MOCK-UPS 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 2: Figure Mock-Ups 
08 May 2024 
 
- 160 - 
RESTRICTED 
LIST OF FIGURES 
Figure 1: 
CONSORT Flow Diagram .......................................................................................163 
Figure 2: 
Schematic of Study Design .......................................................................................164 
Figure 3: 
Frequency of Related Adverse Events by MedDRA System Organ Class, Severity, and 
Impairment Group ....................................................................................................165 
Figure 4: 
Incidence of Related Adverse Events by MedDRA® System Organ Class, Maximum 
Severity, and Impairment Group ..............................................................................166 
Figure 5: 
Chemistry Laboratory Results by Scheduled Visits: Mean Changes from Baseline by 
Impairment Group – Total Bilirubin .........................................................................167 
Figure 6: 
Chemistry Laboratory Results by Scheduled Visits: Mean Changes from Baseline by 
Impairment Group – Serum Albumin .......................................................................167 
Figure 7 
Chemistry Laboratory Results by Scheduled Visits: Mean Changes from Baseline by 
Impairment Group – Potassium ................................................................................167 
Figure 8: 
Chemistry Laboratory Results by Scheduled Visits: Mean Changes from Baseline by 
Impairment Group – Magnesium ..............................................................................167 
Figure 9: 
Chemistry Laboratory Results by Scheduled Visits: Mean Changes from Baseline by 
Impairment Group – Calcium ...................................................................................167 
Figure 10: Chemistry Laboratory Results by Scheduled Visits: Mean Changes from Baseline by Sex 
and Impairment Group – Serum Creatinine ..............................................................168 
Figure 11: Chemistry Laboratory Results by Scheduled Visits: Mean Changes from Baseline by 
Impairment Group – BUN ........................................................................................169 
Figure 12: Chemistry Laboratory Results by Scheduled Visits: Mean Changes from Baseline by Sex 
and Impairment Group – Alkaline Phosphatase .......................................................170 
Figure 13: Chemistry Laboratory Results by Scheduled Visits: Mean Changes from Baseline by Sex 
and Impairment Group – ALT ..................................................................................170 
Figure 14: Chemistry Laboratory Results by Scheduled Visits: Mean Changes from Baseline by 
Impairment Group – AST .........................................................................................171 
Figure 15: Hematology Laboratory Results by Scheduled Visits: Mean Changes from Baseline by 
Sex and Impairment Group – Hematocrit .................................................................172 
Figure 16: Hematology Laboratory Results by Scheduled Visits: Mean Changes from Baseline by 
Sex and Impairment Group – Hemoglobin ...............................................................172 
Figure 17: Hematology Laboratory Results by Scheduled Visits: Mean Changes from Baseline by 
Sex and Impairment Group – Red Blood Cell Count ...............................................172 
Figure 18: Hematology Laboratory Results by Scheduled Visits: Mean Changes from Baseline by 
and Impairment Group – White Blood Cell Count ...................................................173 
Figure 19: Hematology Laboratory Results by Scheduled Visits: Mean Changes from Baseline by 
and Impairment Group – Neutrophils .......................................................................173 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 2: Figure Mock-Ups 
08 May 2024 
 
LIST OF FIGURES (continued) 
- 161 - 
RESTRICTED 
Figure 20: Hematology Laboratory Results by Scheduled Visits: Mean Changes from Baseline by 
and Impairment Group – Eosinophils .......................................................................173 
Figure 21: Hematology Laboratory Results by Scheduled Visits: Mean Changes from Baseline by 
and Impairment Group – Basophils ..........................................................................173 
Figure 22: Hematology Laboratory Results by Scheduled Visits: Mean Changes from Baseline by 
and Impairment Group – Lymphocytes ....................................................................173 
Figure 23: Hematology Laboratory Results by Scheduled Visits: Mean Changes from Baseline by 
and Impairment Group – Monocytes ........................................................................173 
Figure 24: Hematology Laboratory Results by Scheduled Visits: Mean Changes from Baseline by 
and Impairment Group – Platelets ............................................................................173 
Figure 25: Coagulation Laboratory Results by Scheduled Visits: Mean Changes from Baseline by 
and Impairment Group – INR ...................................................................................174 
Figure 26: Linear Plot of Pretomanid Concentration Profiles by Nominal Time – Mild Hepatic 
Impairment ................................................................................................................175 
Figure 27 Linear Plot of Pretomanid Concentration Profiles by Nominal Time – Moderate Hepatic 
Impairment ................................................................................................................175 
Figure 28: Linear Plot of Pretomanid Concentration Profiles by Nominal Time – Severe Hepatic 
Impairment ................................................................................................................175 
Figure 29: Linear Plot of Pretomanid Concentration Profiles by Nominal Time – Matched Controls
 ..................................................................................................................................175 
Figure 30: Linear Plot of Pretomanid Concentration Profiles by Nominal Time for Subjects with 
Mild Hepatic Impairment and Their Matched Controls ...........................................176 
Figure 31: Linear Plot of Pretomanid Concentration Profiles by Nominal Time for Subjects with 
Moderate Hepatic Impairment and Their Matched Controls ....................................176 
Figure 32: Linear Plot of Pretomanid Concentration Profiles by Nominal Time for Subjects with 
Severe Hepatic Impairment and Their Matched Controls ........................................176 
Figure 33: Semilogarithmic Plot of Pretomanid Concentration Profiles by Nominal Time – Mild 
Hepatic Impairment ..................................................................................................177 
Figure 34: Semilogarithmic Plot of Pretomanid Concentration Profiles by Nominal Time – Moderate 
Hepatic Impairment ..................................................................................................177 
Figure 35: Semilogarithmic Plot of Pretomanid Concentration Profiles by Nominal Time – Severe 
Hepatic Impairment ..................................................................................................177 
Figure 36: Semilogarithmic Plot of Pretomanid Concentration Profiles by Nominal Time – Matched 
Controls.....................................................................................................................177 
Figure 37: Linear Plots of Mean Pretomanid Plasma Concentration by Nominal Time ...........178 
Figure 38: Semilogarithmic Plots of Mean Pretomanid Plasma Concentration by Nominal Time179 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 2: Figure Mock-Ups 
08 May 2024 
 
LIST OF FIGURES (continued) 
- 162 - 
RESTRICTED 
Figure 39: Impairment Group Summary for Noncompartmental PK Parameters – Cmax ..........180 
Figure 40: Impairment Group Summary for Noncompartmental PK Parameters – Tmax ..........180 
Figure 41: Impairment Group Summary for Noncompartmental PK Parameters – AUC(0-∞) ..180 
Figure 42: Impairment Group Summary for Noncompartmental PK Parameters –AUC(0-last) ..180 
Figure 43: Impairment Group Summary for Noncompartmental PK Parameters – CL/F .........180 
Figure 44: Impairment Group Summary for Noncompartmental PK Parameters – Vd/F ..........180 
 


Statistical A nal ysis Pla n - D MI D Pr ot oc ol: 1 3- 0 0 5 3 
Versi o n 2. 0 
A p pe n di x 2: Fi g ure M o c k- U ps  
0 8 Ma y 2 0 2 4 
 
- 1 6 3  - 
R E S T RI C T E D  
1 0. 1 
Dis p ositi o n of S u bjects  
Fi g ure  1: 
C O N S O R T Fl o w Di a gr a m  
 
 
 
Mil d H e p ati c I m p air m e nt ( n = x)  
R e c ei v e d Pr et o m a ni d ( n = x)  
  
E arl y T er mi n ati o n ( n = x)  
[ R e a s o n 1] ( x), [ R e a s o n 2] ( x) 
A n al y s e d f or p h ar m a c o ki n eti c s ( n = x)  
E x cl u d e d fr o m p h ar m a c o ki n eti c s 
a n al y s e s ( n = x)  
[ R e a s o n 1] ( x), [ R e a s o n 2] ( x) 
A n al y z e d f or s af et y ( n = x)  
E x cl u d e d fr o m s af et y a n al y s e s ( n = x)  
[ R e a s o n 1] ( x), [ R e a s o n 2] ( x) 
E x cl u d e d* ( n = x)  
   [ R e a s o n 1] ( n = x) 
E nr oll e d ( n = x)  
All o c ati o n  
  
A n al y si s  
F oll o w -U p  
E nr oll m e nt  
M o d er at e H e p ati c I m p air m e nt ( n = x)  
R e c ei v e d Pr et o m a ni d ( n = x)  
S e v er e H e p ati c I m p air m e nt ( n = x)  
R e c ei v e d Pr et o m a ni d ( n = x)  
E arl y T er mi n ati o n ( n = x)  
[ R e a s o n 1] ( x), [ R e a s o n 2] ( x) 
E arl y T er mi n ati o n ( n = x)  
[ R e a s o n 1] ( x), [ R e a s o n 2] ( x) 
A n al y s e d f or p h ar m a c o ki n eti c s ( n = x)  
E x cl u d e d fr o m p h ar m a c o ki n eti c s 
a n al y s e s ( n = x)  
[ R e a s o n 1] ( x), [ R e a s o n 2] ( x) 
A n al y z e d f or s af et y ( n = x)  
E x cl u d e d fr o m s af et y a n al y s e s ( n = x)  
[ R e a s o n 1] ( x), [ R e a s o n 2] ( x) 
A n al y s e d f or p h ar m a c o ki n eti c s ( n = x)  
E x cl u d e d fr o m p h ar m a c o ki n eti c s 
a n al y s e s ( n = x)  
[ R e a s o n 1] ( x), [ R e a s o n 2] ( x) 
A n al y z e d f or s af et y ( n = x)  
E x cl u d e d fr o m s af et y a n al y s e s ( n = x)  
[ R e a s o n 1] ( x), [ R e a s o n 2] ( x) 
A s s e s s e d f or Eli gi bilit y ( n = x)  
M at c h e d C o ntr ol s ( n = x)  
R e c ei v e d Pr et o m a ni d ( n = x) 
E arl y T er mi n ati o n ( n = x)  
[ R e a s o n 1] ( x), [ R e a s o n 2] ( x) 
A n al y s e d f or p h ar m a c o ki n eti c s ( n = x)  
E x cl u d e d fr o m p h ar m a c o ki n eti c s 
a n al y s e s ( n = x)  
[ R e a s o n 1] ( x), [ R e a s o n 2] ( x) 
A n al y z e d f or s af et y ( n = x)  
E x cl u d e d fr o m s af et y a n al y s e s ( n = x) 
[ R e a s o n 1] ( x), [ R e a s o n 2] ( x) 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 2: Figure Mock-Ups 
08 May 2024 
 
- 164 - 
RESTRICTED 
Figure 2: 
Schematic of Study Design 
 
1Group 4a is referring to the non-hepatically impaired controls matched with Group 1 
2Group 4b is referring to the non-hepatically impaired controls matched with Group 2 
3Group 4c is referring to the non-hepatically impaired controls matched with Group 3 
 
Task Order 
Initiation 
Meeting
Group 1 (Mild Disease) 
and Group 4a1 (Non-
hepatically Impaired 
Controls) Enrollment
6 subjects per group
Interim Safety 
Review
Data from first three 
Group 1 subjects
Group 2 (Moderate Disease) 
Enrollment and Group 
Group 4b2 (Non-hepatically 
Impaired Controls) 
Enrollment
6 subjects per group 
Group 3 (Severe Disease) 
Enrollment and Group 
4c3 (Non-hepatically 
Impaired Controls) 
Enrollment
6 subjects per group
Group 2 and 4b 
Follow-up
12 days
Group 3 and 4c 
Follow-up
12 days
PK Analysis


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 2: Figure Mock-Ups 
08 May 2024 
 
- 165 - 
RESTRICTED 
14.2.2 
Efficacy/Immunogenicity Response Figures by Measure, Treatment/Vaccination, and Time 
Point 
Not Applicable. 
 
14.3.1.2 Unsolicited Adverse Events 
Figure 3: 
Frequency of Related Adverse Events by MedDRA System Organ Class, Severity, and 
Impairment Group 
[Implementation Note: A sample figure is shown below. Separate panels will be displayed for each 
impairment group and matched controls and labeled “Mild Hepatic Impairment (N=X)”, “Moderate Hepatic 
Impairment (N=X)”, “Severe Hepatic Impairment (N=X)” and “Matched Controls (N=X)” The y-axis will be 
labeled “System Organ Class” and the x-axis will be labeled “Number of Events”] 
 
 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 2: Figure Mock-Ups 
08 May 2024 
 
- 166 - 
RESTRICTED 
Figure 4: 
Incidence of Related Adverse Events by MedDRA® System Organ Class, Maximum 
Severity, and Impairment Group 
[Implementation Note: A sample figure is shown below. Separate panels will be displayed for each 
impairment group and matched controls and labeled “Mild Hepatic Impairment (N=X)”, “Moderate Hepatic 
Impairment (N=X)”,  “Severe Hepatic Impairment (N=X)” and “Matched Controls (N=X)” The y-axis will be 
labeled “System Organ Class” and the x-axis will be labeled “Percent of Subjects (%)”] 
 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 2: Figure Mock-Ups 
08 May 2024 
 
- 167 - 
RESTRICTED 
14.3.5 
Displays of Laboratory Results 
Figure 5: 
Chemistry Laboratory Results by Scheduled Visits: Mean Changes from Baseline by 
Impairment Group – Total Bilirubin 
 
 
Figures with similar format: 
Figure 6: 
Chemistry Laboratory Results by Scheduled Visits: Mean Changes from Baseline by 
Impairment Group – Serum Albumin 
Figure 7 
Chemistry Laboratory Results by Scheduled Visits: Mean Changes from Baseline by 
Impairment Group – Potassium 
Figure 8: 
Chemistry Laboratory Results by Scheduled Visits: Mean Changes from Baseline by 
Impairment Group – Magnesium 
Figure 9: 
Chemistry Laboratory Results by Scheduled Visits: Mean Changes from Baseline by 
Impairment Group – Calcium 
 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 2: Figure Mock-Ups 
08 May 2024 
 
- 168 - 
RESTRICTED 
Figure 10: 
Chemistry Laboratory Results by Scheduled Visits: Mean Changes from Baseline by 
Sex and Impairment Group – Serum Creatinine 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 2: Figure Mock-Ups 
08 May 2024 
 
- 169 - 
RESTRICTED 
Figure 11: 
Chemistry Laboratory Results by Scheduled Visits: Mean Changes from Baseline by 
Impairment Group – BUN 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 2: Figure Mock-Ups 
08 May 2024 
 
- 170 - 
RESTRICTED 
Figure 12: 
Chemistry Laboratory Results by Scheduled Visits: Mean Changes from Baseline by 
Sex and Impairment Group – Alkaline Phosphatase 
 
 
Figure with Similar format: 
Figure 13: 
Chemistry Laboratory Results by Scheduled Visits: Mean Changes from Baseline by 
Sex and Impairment Group – ALT 
 
 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 2: Figure Mock-Ups 
08 May 2024 
 
- 171 - 
RESTRICTED 
Figure 14: 
Chemistry Laboratory Results by Scheduled Visits: Mean Changes from Baseline by 
Impairment Group – AST 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 2: Figure Mock-Ups 
08 May 2024 
 
- 172 - 
RESTRICTED 
Figure 15: 
Hematology Laboratory Results by Scheduled Visits: Mean Changes from Baseline by 
Sex and Impairment Group – Hematocrit 
 
 
Figures with Similar Format: 
Figure 16: 
Hematology Laboratory Results by Scheduled Visits: Mean Changes from Baseline by 
Sex and Impairment Group – Hemoglobin 
Figure 17: 
Hematology Laboratory Results by Scheduled Visits: Mean Changes from Baseline by 
Sex and Impairment Group – Red Blood Cell Count 
 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 2: Figure Mock-Ups 
08 May 2024 
 
- 173 - 
RESTRICTED 
Figure 18: 
Hematology Laboratory Results by Scheduled Visits: Mean Changes from Baseline by 
and Impairment Group – White Blood Cell Count 
 
Figures with Similar Format: 
Figure 19: 
Hematology Laboratory Results by Scheduled Visits: Mean Changes from Baseline by 
and Impairment Group – Neutrophils 
Figure 20: 
Hematology Laboratory Results by Scheduled Visits: Mean Changes from Baseline by 
and Impairment Group – Eosinophils 
Figure 21: 
Hematology Laboratory Results by Scheduled Visits: Mean Changes from Baseline by 
and Impairment Group – Basophils 
Figure 22: 
Hematology Laboratory Results by Scheduled Visits: Mean Changes from Baseline by 
and Impairment Group – Lymphocytes 
Figure 23: 
Hematology Laboratory Results by Scheduled Visits: Mean Changes from Baseline by 
and Impairment Group – Monocytes 
Figure 24: 
Hematology Laboratory Results by Scheduled Visits: Mean Changes from Baseline by 
and Impairment Group – Platelets 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 2: Figure Mock-Ups 
08 May 2024 
 
- 174 - 
RESTRICTED 
Figure 25: 
Coagulation Laboratory Results by Scheduled Visits: Mean Changes from Baseline by 
and Impairment Group – INR 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 2: Figure Mock-Ups 
08 May 2024 
 
- 175 - 
RESTRICTED 
14.6 
Pharmacokinetics 
Figure 26: 
Linear Plot of Pretomanid Concentration Profiles by Nominal Time – Mild Hepatic 
Impairment 
 
Note: Values below the lower limit of quantification (LLOQ) are plotted as LLOQ/2. 
 
Figures with Similar Format: 
Figure 27 
Linear Plot of Pretomanid Concentration Profiles by Nominal Time – Moderate Hepatic 
Impairment 
Figure 28: 
Linear Plot of Pretomanid Concentration Profiles by Nominal Time – Severe Hepatic 
Impairment 
Figure 29: 
Linear Plot of Pretomanid Concentration Profiles by Nominal Time – Matched Controls 
 
 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 2: Figure Mock-Ups 
08 May 2024 
 
- 176 - 
RESTRICTED 
Figure 30: 
Linear Plot of Pretomanid Concentration Profiles by Nominal Time for Subjects with 
Mild Hepatic Impairment and Their Matched Controls 
Concentration (ng/mL) 
 
Time Since Dose (h) 
 
Figures with Similar Format: 
Figure 31: 
Linear Plot of Pretomanid Concentration Profiles by Nominal Time for Subjects with 
Moderate Hepatic Impairment and Their Matched Controls 
Figure 32: 
Linear Plot of Pretomanid Concentration Profiles by Nominal Time for Subjects with 
Severe Hepatic Impairment and Their Matched Controls 
 
 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 2: Figure Mock-Ups 
08 May 2024 
 
- 177 - 
RESTRICTED 
Figure 33: 
Semilogarithmic Plot of Pretomanid Concentration Profiles by Nominal Time – Mild Hepatic 
Impairment 
 
 
Figures with Similar Format: 
Figure 34: 
Semilogarithmic Plot of Pretomanid Concentration Profiles by Nominal Time – Moderate 
Hepatic Impairment 
Figure 35: 
Semilogarithmic Plot of Pretomanid Concentration Profiles by Nominal Time – Severe Hepatic 
Impairment 
Figure 36: 
Semilogarithmic Plot of Pretomanid Concentration Profiles by Nominal Time – Matched 
Controls 
 
 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 2: Figure Mock-Ups 
08 May 2024 
 
- 178 - 
RESTRICTED 
Figure 37: 
Linear Plots of Mean Pretomanid Plasma Concentration by Nominal Time  
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 2: Figure Mock-Ups 
08 May 2024 
 
- 179 - 
RESTRICTED 
Figure 38: 
Semilogarithmic Plots of Mean Pretomanid Plasma Concentration by Nominal Time 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 2: Figure Mock-Ups 
08 May 2024 
 
- 180 - 
RESTRICTED 
Figure 39: 
Impairment Group Summary for Noncompartmental PK Parameters – Cmax  
[Implementation Note: Each boxplot may include panels by site if appropriate as described in Section 10.3] 
 
 
Figure 40: 
Impairment Group Summary for Noncompartmental PK Parameters – Tmax 
Figure 41: 
Impairment Group Summary for Noncompartmental PK Parameters – AUC(0-∞) 
Figure 42: 
Impairment Group Summary for Noncompartmental PK Parameters –AUC(0-last) 
Figure 43: 
Impairment Group Summary for Noncompartmental PK Parameters – CL/F 
Figure 44: 
Impairment Group Summary for Noncompartmental PK Parameters – Vd/F 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 3: Listings Mock-Ups 
08 May 2024 
 
- 181 - 
RESTRICTED 
APPENDIX 3. LISTINGS MOCK-UPS 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 3: Listings Mock-Ups 
08 May 2024 
 
- 182 - 
RESTRICTED 
LISTINGS 
Listing 1: 16.2.1 Early Terminations or Discontinued Subjects ...............................................184 
Listing 2: 16.2.2.1: Subject-Specific Protocol Deviations ........................................................185 
Listing 3: 16.2.2.2: Non-Subject-Specific Protocol Deviations ................................................186 
Listing 4: 16.2.3: Subjects Excluded from Analysis Populations .............................................187 
Listing 5: 16.2.4.1: Demographic Data .....................................................................................188 
Listing 6: 16.2.4.2: Pre-Existing and Concurrent Medical Conditions .....................................189 
Listing 7: 16.2.7.2: Unsolicited Adverse Events .......................................................................191 
Listing 8: 16.2.8.1: Clinical Laboratory Results – Chemistry ..................................................192 
Listing 9: 16.2.8.2: Clinical Laboratory Results – Hematology ...............................................193 
Listing 10: 16.2.8.3: Clinical Laboratory Results – Urinalysis...................................................194 
Listing 11: 16.2.8.3: Clinical Laboratory Results – Coagulation ...............................................195 
Listing 12: 16.2.9.1: Vital Signs .................................................................................................196 
Listing 13: 16.2.9.2: Physical Exam Findings ............................................................................197 
Listing 14: 16.2.10: Concomitant Medications ...........................................................................198 
Listing 15: 16.2.11.1: Pregnancy Reports – Maternal Information ............................................199 
Listing 16: 16.2.11.2: Pregnancy Reports – Gravida and Para ...................................................199 
Listing 17: 16.2.11.3: Pregnancy Reports – Live Birth Outcomes .............................................200 
Listing 18: 16.2.11.4: Pregnancy Reports – Still Birth Outcomes ..............................................200 
Listing 19: 16.2.11.5: Pregnancy Reports – Spontaneous, Elective, or Therapeutic Abortion 
Outcomes ..................................................................................................................200 
Listing 20: Listing of 12-Lead Standard ECG Overall Interpretation and Comments ...............201 
Listing 21: Listing of 12-Lead Standard ECG Interval Measurements ......................................202 
Listing 22: Subject Level Drug Concentrations ..........................................................................203 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 3: Listings Mock-Ups 
08 May 2024 
 
- 183 - 
RESTRICTED 
16.1.6 Listing of Subjects Receiving Investigational Product 
(not included in SAP, but this is a placeholder for the CSR) 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 3: Listings Mock-Ups 
08 May 2024 
 
- 184 - 
RESTRICTED 
16.2 
Database Listings by Subject 
16.2.1 Discontinued Subjects 
Listing 1: 
16.2.1 Early Terminations or Discontinued Subjects 
Impairment Group Subject ID 
Category 
Reason for Early Termination  
Study Day 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 3: Listings Mock-Ups 
08 May 2024 
 
- 185 - 
RESTRICTED 
16.2.2 Protocol Deviations 
Listing 2: 
16.2.2.1: Subject-Specific Protocol Deviations 
Impairment 
Group 
Subject ID DV Number 
Deviation 
Deviation 
Category 
Study Day 
Reason for 
Deviation 
Deviation 
Resulted 
in AE? 
Deviation Resulted 
in Subject 
Termination? 
Deviation 
Resolution 
Comments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 3: Listings Mock-Ups 
08 May 2024 
 
- 186 - 
RESTRICTED 
Listing 3: 
16.2.2.2: Non-Subject-Specific Protocol Deviations 
Site 
Start Date  Deviation 
End Date 
Reason for 
Deviation 
Deviation 
Resulted in 
Subject 
Termination? 
Deviation 
Affected 
Product 
Stability? 
Deviation 
Category 
Deviation 
Resolution 
Comments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 3: Listings Mock-Ups 
08 May 2024 
 
- 187 - 
RESTRICTED 
16.2.3 Subjects Excluded from the Efficacy Analysis 
Listing 4: 
16.2.3: Subjects Excluded from Analysis Populations 
Impairment Group 
Subject ID 
Analyses in which 
Subject is Included 
Analyses from which  
Subject is Excluded 
Results Available? 
Reason Subject Excluded 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: “Yes” in the “Results available” column indicates that available data were removed from the analysis. “No” indicates that no data were available for inclusion in the analysis. 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 3: Listings Mock-Ups 
08 May 2024 
 
- 188 - 
RESTRICTED 
16.2.4 Demographic Data 
Listing 5: 
16.2.4.1: Demographic Data 
Impairment 
Group 
 Subject ID 
Sex 
Age at Enrollment (years) 
Ethnicity 
Race 
Height at 
Screening (cm) 
Weight at 
Screening (kg) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 3: Listings Mock-Ups 
08 May 2024 
 
- 189 - 
RESTRICTED 
Listing 6: 
16.2.4.2: Pre-Existing and Concurrent Medical Conditions 
•  
Impairment 
Group 
Subject ID 
MedDRA 
System Organ 
Class 
MedDRA 
Preferred 
Term 
MH Number 
Medical History Term 
Condition Start Day  
Condition End Day 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 3: Listings Mock-Ups 
08 May 2024 
 
- 190 - 
RESTRICTED 
16.2.5 Compliance and/or Drug Concentration Data (if available) 
Not Applicable. 
 
16.2.6 Individual Efficacy/Immunogenicity Response Data 
Not Applicable. 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 3: Listings Mock-Ups 
08 May 2024 
 
- 191 - 
RESTRICTED 
16.2.7 Adverse Events 
Listing 7: 
16.2.7.2: Unsolicited Adverse Events 
Adverse 
Event 
MedDRA 
System Organ 
Class 
MedDRA 
Preferred 
Term 
No. of Days 
Post Dose 
(Duration) 
Severity 
SAE? 
Relationship to 
Study 
Treatment 
In Not 
Related, 
Alternative 
Etiology 
Action Taken 
with Study 
Treatment 
Subject 
Discontinued 
Due to AE 
Outcome 
 Impairment Group: , Subject ID: , AE Number:  
 
 
 
 
 
 
 
 
 
 
 
Comments: 
 
 
 
 
 
 
 
 
 
 
 
 Impairment Group: , Subject ID: , AE Number:  
 
 
 
 
 
 
 
 
 
 
 
Comments: 
Note: For additional details about SAEs, see Table 20. 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 3: Listings Mock-Ups 
08 May 2024 
 
- 192 - 
RESTRICTED 
16.2.8 Individual Laboratory Measurements 
Listing 8: 
16.2.8.1: Clinical Laboratory Results – Chemistry 
Impairment 
Group 
Subject ID 
Planned 
Time Point  
Actual 
Study Day  Sex  
Age (years) 
Laboratory 
Parameter (Units) 
Result (Severity 
Grade) 
Reference 
Range Low 
Reference Range 
High 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 3: Listings Mock-Ups 
08 May 2024 
 
- 193 - 
RESTRICTED 
Listing 9: 
16.2.8.2: Clinical Laboratory Results – Hematology 
Impairment 
Group 
Subject ID 
Planned Time 
Point  
Actual 
Study 
Day  
Sex  
Age 
(years) 
Laboratory Parameter 
(Units) 
Result (Severity 
Grade) 
Reference Range 
Low 
Reference Range 
High 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 3: Listings Mock-Ups 
08 May 2024 
 
- 194 - 
RESTRICTED 
Listing 10: 
16.2.8.3: Clinical Laboratory Results – Urinalysis 
Impairment 
Group 
Subject ID 
Planned Time 
Point  
Actual 
Study 
Day  
Sex  
Age 
(years) 
Laboratory Parameter 
(Units) 
Result (Severity 
Grade) 
Reference Range 
Low 
Reference Range High 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 3: Listings Mock-Ups 
08 May 2024 
 
- 195 - 
RESTRICTED 
Listing 11: 
16.2.8.3: Clinical Laboratory Results – Coagulation 
Impairment 
Group 
Subject ID 
Planned Time 
Point  
Actual 
Study 
Day  
Sex  
Age 
(years) 
Laboratory Parameter 
(Units) 
Result (Severity 
Grade) 
Reference Range 
Low 
Reference Range High 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 3: Listings Mock-Ups 
08 May 2024 
 
- 196 - 
RESTRICTED 
16.2.9 Vital Signs and Physical Exam Findings 
Listing 12: 
16.2.9.1: Vital Signs 
Impairment 
Group 
Subject ID 
Planned 
Time Point 
Actual 
Study Time 
Point 
Temperature 
(°C) 
Systolic Blood 
Pressure 
(mmHg) 
Diastolic Blood 
Pressure 
(mmHg) 
Heart Rate 
(beats/min) 
Weight 
(kg) 
Height 
(cm) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 3: Listings Mock-Ups 
08 May 2024 
 
- 197 - 
RESTRICTED 
Listing 13: 
16.2.9.2: Physical Exam Findings 
Impairment 
Group 
Subject ID 
Planned Time 
Point 
Actual Study 
Day 
Body System 
Abnormal Finding 
Reported as an AE? 
(AE Description; Number) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 3: Listings Mock-Ups 
08 May 2024 
 
- 198 - 
RESTRICTED 
16.2.10 Concomitant Medications 
Listing 14: 
16.2.10: Concomitant Medications 
Impairment 
Group 
Subject ID 
CM 
Number 
Medication 
Medication Start 
Day 
Medication End 
Day 
Indication 
Taken for an AE? 
(AE Description; 
Number) 
Taken for a condition 
on Medical History? 
(MH Description; 
Number) 
ATC Level 1  
(ATC Level 2) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 3: Listings Mock-Ups 
08 May 2024 
 
- 199 - 
RESTRICTED 
16.2.11 Pregnancy Reports 
Listing 15: 
16.2.11.1: Pregnancy Reports – Maternal Information 
Impairment 
Group 
Subject 
ID  
Pregnancy 
Number 
Study Day 
Corresponding 
to Estimated 
Date of 
Conception 
Source of 
Maternal 
Information 
Pregnancy 
Status 
Mother’s 
Pre-
Pregnancy 
BMI 
Mother’s 
Weight 
Gain 
During 
Pregnancy 
Tobacco, 
Alcohol, or 
Drug Use 
During 
Pregnancy? 
Medications 
During 
Pregnancy? 
Maternal 
Complications 
During 
Pregnancy? 
Maternal 
Complications 
During Labor, 
Delivery, or 
Post-Partum? 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Maternal Complications are included in the Adverse Event listing. Medications taken during pregnancy are included in the Concomitant Medications Listing. 
 
Listing 16: 
16.2.11.2: Pregnancy Reports – Gravida and Para 
 
 
 
Live Births 
 
 
 
 
 
Subject 
ID 
Pregnancy 
Number 
Gravida 
Extremely 
PBa 
Very 
Early 
PBa 
Early 
PBa 
Late 
PBa 
Early 
TBb 
Full 
TBb 
Late 
TBb 
Post 
TBb 
Still 
Births 
Spontaneous 
Abortion/ 
Miscarriage 
Elective 
Abortions 
Therapeutic 
Abortions 
Major 
Congenital 
Anomaly 
with 
Previous 
Pregnancy? 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Gravida includes the current pregnancy, para events do not. 
a Preterm Birth 
b Term Birth 
 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 3: Listings Mock-Ups 
08 May 2024 
 
- 200 - 
RESTRICTED 
Listing 17: 
16.2.11.3: Pregnancy Reports – Live Birth Outcomes 
Subject 
ID 
Pregnancy 
Number 
Fetus 
Number 
Pregnancy 
Outcome 
(for this 
Fetus) 
Fetal 
Distress 
During 
Labor and 
Delivery? 
Delivery 
Method 
Gestational 
Age at Live 
Birth  
Size for 
Gestational 
Age 
Apgar 
Score, 1 
minute 
Apgar 
Score, 5 
minutes 
Cord pH 
Congenital 
Anomalies? 
Illnesses/ 
Hospitalizations 
within 1 Month of 
Birth? 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Congenital Anomalies are included in the Adverse Event listing. 
 
Listing 18: 
16.2.11.4: Pregnancy Reports – Still Birth Outcomes 
Subject 
ID 
Date of 
Initial 
Report 
Fetus 
Number 
Pregnancy 
Outcome 
(for this 
Fetus) 
Fetal Distress 
During 
Labor and 
Delivery? 
Delivery 
Method 
Gestational 
Age at Still 
Birth 
Size for 
Gestational 
Age 
Cord pH 
Congenital 
Anomalies? 
Autopsy 
Performed? 
If Autopsy, Etiology 
for Still Birth 
Identified? 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Listing 19: 
16.2.11.5: Pregnancy Reports – Spontaneous, Elective, or Therapeutic Abortion Outcomes 
Subject 
ID 
Date of Initial 
Report 
Fetus Number 
Pregnancy Outcome 
(for this Fetus) 
Gestational Age at 
Termination 
Abnormality in Product of Conception? 
Reason for Therapeutic 
Abortion 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 3: Listings Mock-Ups 
08 May 2024 
 
- 201 - 
RESTRICTED 
Listing 20: 
Listing of 12-Lead Standard ECG Overall Interpretation and Comments 
Impairment 
Group 
Subject ID 
Planned 
Time Point 
Actual Study 
Time Point 
Interpretation 
Abnormal Finding 
Comments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 3: Listings Mock-Ups 
08 May 2024 
 
- 202 - 
RESTRICTED 
Listing 21: 
Listing of 12-Lead Standard ECG Interval Measurements 
Impairment 
Group 
Subject ID 
Planned 
Time Point 
Actual Study 
Time Point 
Parameter (units) 
Result (Severity) 
Change from Baseline 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 13-0053 
Version 2.0 
Appendix 3: Listings Mock-Ups 
08 May 2024 
 
- 203 - 
RESTRICTED 
Listing 22: 
Subject Level Drug Concentrations 
Impairment 
Group 
Subject ID 
Nominal Timea (hr) 
Actual Timea (hr) 
Drug Concentration 
(ng/mL) 
Sample Within 
Time Window 
Used in λz 
Calculations 
Excluded from 
NCA 
Reason for 
Exclusion from 
NCA 
 
 
yes/no 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
a Times are relative to time of first dose. For actual time, out of window times are indicated by an asterisk.