Clinical trial NCT04309656
Conditions: Multi-drug Resistant Tuberculosis
Keywords: MDR-TB (multi-drug resistant tuberculosis) Extensively Resistant Pulmonary Tuberculosis XDR-TB (extensively drug resistant tuberculosis) pretomanid PA-824
Sponsor: Global Alliance for TB Drug Development
Start date: 2020-01-14; Completion date: 2020-02-28
Enrollment: 48 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This is a single-dose, open-label, randomized, four-period, four-treatment, crossover study in healthy adult subjects.

Detailed description:
This is a single-dose, open-label, randomized, four-period, four-treatment, crossover study in healthy adult subjects. Each panel of 24 subjects will be randomized according to the same 4-sequence, 4- period Williams design, in which each participant will receive four single-dose treatments. Subjects in Panel 1 will receive all treatments after consuming an FDA standard high-fat, high-calorie breakfast following an overnight fast of at least 10 hours. Subjects in Panel 2 will receive all treatments directly following an overnight fast of at least 10 hours. The two panels will be investigated concurrently.

Arms: arm 1: Each participant will receive four single-dose treatments with a 7-day washout period between each dose. Panel 1 will receive a meal before dosing. arm 2: Each participant will receive four single-dose treatments with a 7-day washout period between each dose. Panel 2 will fast before dosing.
Interventions: intervention 1: Pretomanid
Intervention descriptions: intervention 1: 1. Treatment A (reference) = 200 mg given as a single 200 mg tablet (using the immediate release formulation), orally administered.
2. Treatment B (test) = 200 mg given as four 50-mg tablets (using the dispersible pediatric formulation), orally administered.
3. Treatment C (test) = single 50-mg dispersible tablet, orally administered.
4. Treatment D (test) = single 10-mg dispersible tablet, orally administered.

Protocol documents:
Prot_000.pdf: 
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Appendix 16.1.1 - Page 4


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Global Alliance for TB Drug Development, Protocol Pa-824-CL-011 
Appendix 16.1.1 - Page 5


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Global Alliance for TB Drug Development, Protocol Pa-824-CL-011 
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Global Alliance for TB Drug Development, Protocol Pa-824-CL-011 
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 6DIHW\± (OHFWURFDUGLRJUDPV 
 2WKHU6DIHW\0HDVXUHV 
 
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$WWULEXWLRQ&DXVDOLW\ 
Global Alliance for TB Drug Development, Protocol Pa-824-CL-011 
Appendix 16.1.1 - Page 8


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Global Alliance for TB Drug Development, Protocol Pa-824-CL-011 
Appendix 16.1.1 - Page 9


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Appendix 16.1.1 - Page 10


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Global Alliance for TB Drug Development, Protocol Pa-824-CL-011 
Appendix 16.1.1 - Page 11


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Global Alliance for TB Drug Development, Protocol Pa-824-CL-011 
Appendix 16.1.1 - Page 12


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Global Alliance for TB Drug Development, Protocol Pa-824-CL-011 
Appendix 16.1.1 - Page 13


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Global Alliance for TB Drug Development, Protocol Pa-824-CL-011 
Appendix 16.1.1 - Page 14


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Appendix 16.1.1 - Page 15


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Appendix 16.1.1 - Page 16


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Appendix 16.1.1 - Page 17


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Global Alliance for TB Drug Development, Protocol Pa-824-CL-011 
Appendix 16.1.1 - Page 18


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Global Alliance for TB Drug Development, Protocol Pa-824-CL-011 
Appendix 16.1.1 - Page 19


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Global Alliance for TB Drug Development, Protocol Pa-824-CL-011 
Appendix 16.1.1 - Page 20


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Global Alliance for TB Drug Development, Protocol Pa-824-CL-011 
Appendix 16.1.1 - Page 21


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Global Alliance for TB Drug Development, Protocol Pa-824-CL-011 
Appendix 16.1.1 - Page 22


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Global Alliance for TB Drug Development, Protocol Pa-824-CL-011 
Appendix 16.1.1 - Page 23


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Global Alliance for TB Drug Development, Protocol Pa-824-CL-011 
Appendix 16.1.1 - Page 24


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Appendix 16.1.1 - Page 26


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Appendix 16.1.1 - Page 27


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Appendix 16.1.1 - Page 28


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Appendix 16.1.1 - Page 29


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Appendix 16.1.1 - Page 30


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Appendix 16.1.1 - Page 31


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Global Alliance for TB Drug Development, Protocol Pa-824-CL-011 
Appendix 16.1.1 - Page 32


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Global Alliance for TB Drug Development, Protocol Pa-824-CL-011 
Appendix 16.1.1 - Page 33


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Global Alliance for TB Drug Development, Protocol Pa-824-CL-011 
Appendix 16.1.1 - Page 34


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Appendix 16.1.1 - Page 35


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Appendix 16.1.1 - Page 36


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Appendix 16.1.1 - Page 37


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Appendix 16.1.1 - Page 38


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Global Alliance for TB Drug Development, Protocol Pa-824-CL-011 
Appendix 16.1.1 - Page 39


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Appendix 16.1.1 - Page 40


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Appendix 16.1.1 - Page 41


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Appendix 16.1.1 - Page 42


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Appendix 16.1.1 - Page 43


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Appendix 16.1.1 - Page 44


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Appendix 16.1.1 - Page 45


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Appendix 16.1.1 - Page 46


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Appendix 16.1.1 - Page 47


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Appendix 16.1.1 - Page 48


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Appendix 16.1.1 - Page 49


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Appendix 16.1.1 - Page 50


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Global Alliance for TB Drug Development, Protocol Pa-824-CL-011 
Appendix 16.1.1 - Page 51


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Global Alliance for TB Drug Development, Protocol Pa-824-CL-011 
Appendix 16.1.1 - Page 52


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Global Alliance for TB Drug Development, Protocol Pa-824-CL-011 
Appendix 16.1.1 - Page 53


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Global Alliance for TB Drug Development, Protocol Pa-824-CL-011 
Appendix 16.1.1 - Page 54


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Appendix 16.1.1 - Page 55


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Global Alliance for TB Drug Development, Protocol Pa-824-CL-011 
Appendix 16.1.1 - Page 56


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Global Alliance for TB Drug Development, Protocol Pa-824-CL-011 
Appendix 16.1.1 - Page 57

SAP_001.pdf: 
Worldwide Clinical Trials Controlled Quality Management Document
Sponsor:
TB Alliance
Protocol Number:
Pa-824-CL-011
STATISTICAL ANALYSIS PLAN – PHASE 1
QMD Ref: Worldwide-TMP-ST-006-4.0 Effective: 12Aug2019
Governing QMD: Worldwide-SOP-ST-001
Confidentiality Statement
This document is the property of Worldwide Clinical Trials Inc. and may not be duplicated, copied, altered or removed from company without 
prior approval from Worldwide Quality Assurance or in compliance with Worldwide Standard Operating Procedures.
REF: Worldwide-TMP-QA-001f-1.3
Page 1 of 26
Statistical Analysis Plan
An Open-label, Randomized, Four-period Crossover Study in Two Panels of 
Healthy Adult Participants to Assess the Relative Bioavailability, Food Effect, and 
Dose-dependence of Single-Dose Immediate-Release and Single-dose Dispersible 
Formulations of Pretomanid
Protocol Number: Pa-824-CL-011
Protocol Version: 1.0, dated 06-Dec-2019
SAP Version 1.0
SAP Issue Date: 09-March-2020
SAP Authors: Aimie Nunn, MSc,
Kathryn Roupe, PhD
Previous SAP Versions
Not Applicable
Global Alliance for TB Drug Development, Protocol Pa-824-CL-011
Appendix 16.1.9 - Page 3


Worldwide Clinical Trials Controlled Quality Management Document
Sponsor:
TB Alliance
Protocol Number:
Pa-824-CL-011
STATISTICAL ANALYSIS PLAN – PHASE 1
QMD Ref: Worldwide-TMP-ST-006-4.0 Effective: 12Aug2019
Governing QMD: Worldwide-SOP-ST-001
Confidentiality Statement
This document is the property of Worldwide Clinical Trials Inc. and may not be duplicated, copied, altered or removed from company without 
prior approval from Worldwide Quality Assurance or in compliance with Worldwide Standard Operating Procedures.
REF: Worldwide-TMP-QA-001f-1.3
Page 2 of 26
SAP Amendments Before Database Lock
Version 
Issue Date
Section
Revision / Addition
Rationale
Not Applicable
Global Alliance for TB Drug Development, Protocol Pa-824-CL-011
Appendix 16.1.9 - Page 4


Worldwide Clinical Trials Controlled Quality Management Document
Sponsor:
TB Alliance
Protocol Number:
Pa-824-CL-011
STATISTICAL ANALYSIS PLAN – PHASE 1
QMD Ref: Worldwide-TMP-ST-006-4.0 Effective: 12Aug2019
Governing QMD: Worldwide-SOP-ST-001
Confidentiality Statement
This document is the property of Worldwide Clinical Trials Inc. and may not be duplicated, copied, altered or removed from company without 
prior approval from Worldwide Quality Assurance or in compliance with Worldwide Standard Operating Procedures.
REF: Worldwide-TMP-QA-001f-1.3
Page 3 of 26
Table of Contents
1
INTRODUCTION...............................................................................................5
2
STUDY OBJECTIVES .......................................................................................5
2.1
Primary Objective ........................................................................................................... 5
2.2
Secondary Objectives...................................................................................................... 5
3
ENDPOINTS.......................................................................................................6
3.1
Safety Endpoints............................................................................................................. 6
3.2
Pharmacokinetic Endpoints ............................................................................................ 6
4
SAMPLE SIZE....................................................................................................6
5
RANDOMIZATION ...........................................................................................6
6
PLANNED ANALYSES.....................................................................................7
6.1
Analysis Sets................................................................................................................... 7
6.1.1
Randomized Set ........................................................................................................ 7
6.1.2
Safety Analysis Set ................................................................................................... 7
6.1.3
Pharmacokinetic Analysis Set................................................................................... 7
6.2
Derived Data................................................................................................................... 8
6.2.1
Race........................................................................................................................... 8
6.2.2
Baseline..................................................................................................................... 8
6.2.3
Early Terminations Assessments.............................................................................. 8
6.2.4
Duration / Study Day / Time..................................................................................... 8
6.2.5
Conventions for Missing and Partial Dates .............................................................. 8
6.2.6
Inexact Values........................................................................................................... 9
6.2.7
Unscheduled Visits ................................................................................................... 9
6.2.8
PK Parameters........................................................................................................... 9
6.3
Conventions .................................................................................................................. 12
6.3.1
Decimal Places........................................................................................................ 13
6.4
Subject Disposition....................................................................................................... 14
6.5
Protocol Deviations....................................................................................................... 14
6.6
Baseline Comparability................................................................................................. 14
6.6.1
Demographic Data .................................................................................................. 14
6.7
Medical History ............................................................................................................ 15
6.8
Prior and Concomitant Medications ............................................................................. 15
6.9
Exposure to Study Drug................................................................................................ 15
Global Alliance for TB Drug Development, Protocol Pa-824-CL-011
Appendix 16.1.9 - Page 5


Worldwide Clinical Trials Controlled Quality Management Document
Sponsor:
TB Alliance
Protocol Number:
Pa-824-CL-011
STATISTICAL ANALYSIS PLAN – PHASE 1
QMD Ref: Worldwide-TMP-ST-006-4.0 Effective: 12Aug2019
Governing QMD: Worldwide-SOP-ST-001
Confidentiality Statement
This document is the property of Worldwide Clinical Trials Inc. and may not be duplicated, copied, altered or removed from company without 
prior approval from Worldwide Quality Assurance or in compliance with Worldwide Standard Operating Procedures.
REF: Worldwide-TMP-QA-001f-1.3
Page 4 of 26
6.10
Statistical Analyses of Pharmacokinetic Data .............................................................. 15
6.10.1
Relative Bioavailability .......................................................................................... 15
6.10.2
Food Effect.............................................................................................................. 16
6.11
Safety Analyses............................................................................................................. 17
6.11.1
Adverse Events ....................................................................................................... 17
6.11.2
Laboratory Data ...................................................................................................... 18
6.11.3
Vital Signs............................................................................................................... 18
6.11.4
Electrocardiogram Data .......................................................................................... 19
6.11.5
Physical Examination.............................................................................................. 19
6.11.6
Taste Evaluation...................................................................................................... 19
7
CHANGES TO PLANNED PROTOCOL ANALYSIS ...................................20
8
REFERENCES..................................................................................................20
9
LIST OF TABLES, FIGURES AND LISTINGS .............................................21
Global Alliance for TB Drug Development, Protocol Pa-824-CL-011
Appendix 16.1.9 - Page 6


Worldwide Clinical Trials Controlled Quality Management Document
Sponsor:
TB Alliance
Protocol Number:
Pa-824-CL-011
STATISTICAL ANALYSIS PLAN – PHASE 1
QMD Ref: Worldwide-TMP-ST-006-4.0 Effective: 12Aug2019
Governing QMD: Worldwide-SOP-ST-001
Confidentiality Statement
This document is the property of Worldwide Clinical Trials Inc. and may not be duplicated, copied, altered or removed from company without 
prior approval from Worldwide Quality Assurance or in compliance with Worldwide Standard Operating Procedures.
REF: Worldwide-TMP-QA-001f-1.3
Page 5 of 26
1
INTRODUCTION
This document details the planned statistical analyses for TB Alliance, protocol “Pa-824-CL-011” 
study titled “An Open-label, Randomized, Four-period Crossover Study in Two Panels of Healthy 
Adult Participants to Assess the Relative Bioavailability, Food Effect, and Dose-dependence of 
Single-Dose Immediate-Release and Single-dose Dispersible Formulations of Pretomanid”. The 
proposed analyses are based on the contents of the final version of the protocol (dated
06-Dec-2019).
This is a single-dose, open-label, randomized, four-period, four-treatment, crossover study in
healthy adult subjects. Each panel of 24 subjects will be randomized according to the same 4-
sequence, 4-period Williams design, in which each participant will receive four single-dose 
treatments. Subjects in Panel 1 will receive all treatments after consuming an FDA standard high-
fat, high-calorie breakfast following an overnight fast of at least 10 hours. Subjects in Panel 2 will 
receive all treatments directly following an overnight fast of at least 10 hours. The two panels will 
be investigated concurrently. The maximum duration of the study from screening to study exit will 
be approximately 54 days. 
2
STUDY OBJECTIVES
2.1
Primary Objective
The primary objective of the study is to assess the relative bioavailability of the single-dose 
dispersible formulation intended for pediatric treatment, using the 200-mg single-dose immediate-
release formulation as the reference.  
2.2
Secondary Objectives
The secondary objectives of the study are as follows: 
x
To determine the food effect for each of the formulations. 
x
To assess the effect of dose on the bioavailability of the dispersible pediatric formulation 
under fed and fasted conditions.
x
To evaluate the taste perception of the dispersible pediatric formulation under fed and 
fasted conditions.
x
To evaluate the short-term safety and tolerability for each of the formulations under fed 
and fasted conditions.
Global Alliance for TB Drug Development, Protocol Pa-824-CL-011
Appendix 16.1.9 - Page 7


Worldwide Clinical Trials Controlled Quality Management Document
Sponsor:
TB Alliance
Protocol Number:
Pa-824-CL-011
STATISTICAL ANALYSIS PLAN – PHASE 1
QMD Ref: Worldwide-TMP-ST-006-4.0 Effective: 12Aug2019
Governing QMD: Worldwide-SOP-ST-001
Confidentiality Statement
This document is the property of Worldwide Clinical Trials Inc. and may not be duplicated, copied, altered or removed from company without 
prior approval from Worldwide Quality Assurance or in compliance with Worldwide Standard Operating Procedures.
REF: Worldwide-TMP-QA-001f-1.3
Page 6 of 26
3
ENDPOINTS
3.1
Safety Endpoints
Safety assessments will include physical examinations, vital sign measurements, clinical 
laboratory evaluations, electrocardiograms (ECGs), and reported or observed adverse events 
(AEs). Subjects will be monitored continuously for any AEs from the signing of the informed 
consent through the end of the study. 
3.2
Pharmacokinetic Endpoints
Full pharmacokinetic (PK) profiles of pretomanid will be determined up to 96 hours after each 
intake of pretomanid. Blood samples for analysis of pretomanid concentrations will be drawn just 
before drug intake (pre-dose), and at 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72, and 96 hours post 
dose (15 samples per dose). 
Primary PK measures include Tmax, Cmax, AUC0-t, and AUC0-inf. Secondary PK measures include 
the ratio of AUC0-t to AUC0-inf, T1/2, Kel, Cl/F and Vd/F.
4
SAMPLE SIZE
Two panels of healthy male and female subjects (24 subjects per panel) will be dosed in this study. 
The sample size is not based on statistical considerations. The number of subjects planned for 
enrollment is considered sufficient to achieve the study objectives. 
5
RANDOMIZATION
This is an open-label study without treatment blinding. Subjects will be randomly allocated to a 
panel by clinic staff, and the two panels will be investigated concurrently. Subjects in each panel 
(Panel 1 = Fed, Panel 2 = Fasted) will be randomized to a treatment sequence based on a 4-
sequence, 4-period Williams design prepared by the independent statistician.
Global Alliance for TB Drug Development, Protocol Pa-824-CL-011
Appendix 16.1.9 - Page 8


Worldwide Clinical Trials Controlled Quality Management Document
Sponsor:
TB Alliance
Protocol Number:
Pa-824-CL-011
STATISTICAL ANALYSIS PLAN – PHASE 1
QMD Ref: Worldwide-TMP-ST-006-4.0 Effective: 12Aug2019
Governing QMD: Worldwide-SOP-ST-001
Confidentiality Statement
This document is the property of Worldwide Clinical Trials Inc. and may not be duplicated, copied, altered or removed from company without 
prior approval from Worldwide Quality Assurance or in compliance with Worldwide Standard Operating Procedures.
REF: Worldwide-TMP-QA-001f-1.3
Page 7 of 26
Table 1: Treatment Schedule
Sequence (n=24
subjects per panel)
Treatment Periods
Period 1
Period 2
Period 3
Period 4
ABCD
A
B
C
D
BDAC
B
D
A
C
CADB
C
A
D
B
DCBA
D
C
B
A
Treatment A (reference) = 200 mg given as a single 200 mg tablet (using the immediate release 
formulation), orally administered.  
Treatment B (test) = 200 mg given as four 50-mg tablets (using the dispersible pediatric formulation), orally 
administered.  
Treatment C (test) = single 50-mg dispersible tablet, orally administered. 
Treatment D (test) = single 10-mg dispersible tablet, orally administered. 
6
PLANNED ANALYSES 
No statistical analysis plan (SAP) prepared in advance of the data can be absolutely definitive and 
the final Clinical Study Report (CSR) may contain additional tables or statistical tests if warranted 
by the data obtained. The justification for any such additional analyses will be fully documented 
in the final CSR. 
6.1
Analysis Sets 
Subjects excluded from the analysis sets and the reason for their exclusion will be listed 
in Appendix 16.2 of the CSR.
6.1.1
Randomized Set 
The Randomized Set includes all subjects to whom a treatment was randomly assigned.  
6.1.2
Safety Analysis Set
The Safety Analysis Set includes all subjects who received any dose of study drug.   
6.1.3
Pharmacokinetic Analysis Set
All evaluable subjects completing at least one treatment period will be included in the 
PK analysis set.   
Global Alliance for TB Drug Development, Protocol Pa-824-CL-011
Appendix 16.1.9 - Page 9


Worldwide Clinical Trials Controlled Quality Management Document
Sponsor:
TB Alliance
Protocol Number:
Pa-824-CL-011
STATISTICAL ANALYSIS PLAN – PHASE 1
QMD Ref: Worldwide-TMP-ST-006-4.0 Effective: 12Aug2019
Governing QMD: Worldwide-SOP-ST-001
Confidentiality Statement
This document is the property of Worldwide Clinical Trials Inc. and may not be duplicated, copied, altered or removed from company without 
prior approval from Worldwide Quality Assurance or in compliance with Worldwide Standard Operating Procedures.
REF: Worldwide-TMP-QA-001f-1.3
Page 8 of 26
6.2
Derived Data
This section describes the derivations required for statistical analysis. Unless otherwise stated,
variables derived in the source data will not be re-calculated.
6.2.1
Race
Where more than one race category has been selected for a subject, these race categories will be 
combined into a single category labeled “Multiple Race” in the summary tables. The listings will 
reflect the original selected categories. 
6.2.2
Baseline
For variables that will be summarized by treatment, the baseline for each period is defined as the 
last non-missing value (either scheduled, unscheduled or repeat) that is collected before dosing, 
but after check-in for the relevant period. 
For variables that will be summarized overall, baseline is defined as the last non-missing value 
(either scheduled, unscheduled or repeat) that is collected before the subject receives the first dose 
of study drug. 
6.2.3
Early Terminations Assessments
Early withdrawal (EW) assessments will be tabulated with End of Study (EOS). 
6.2.4
Duration / Study Day / Time 
Study day will be calculated as the number of days from first dose of study drug. 
x
date of event – date of first dose of study drug + 1, for events on or after first dose
x
date of event – date of first dose of study drug, for events before first dose.
6.2.5
Conventions for Missing and Partial Dates
It is not expected that there will be any missing dates, however in the rare case that an Adverse 
Event (AE) start date or time is missing and it is unclear whether the AE is treatment emergent or 
not then a conservative approach will be taken and it will be assumed that the AE occurred after 
first dosing. 
All dates presented in the individual subject listings will be as recorded on the Electronic Case 
Report Form (eCRF).
Global Alliance for TB Drug Development, Protocol Pa-824-CL-011
Appendix 16.1.9 - Page 10


Worldwide Clinical Trials Controlled Quality Management Document
Sponsor:
TB Alliance
Protocol Number:
Pa-824-CL-011
STATISTICAL ANALYSIS PLAN – PHASE 1
QMD Ref: Worldwide-TMP-ST-006-4.0 Effective: 12Aug2019
Governing QMD: Worldwide-SOP-ST-001
Confidentiality Statement
This document is the property of Worldwide Clinical Trials Inc. and may not be duplicated, copied, altered or removed from company without 
prior approval from Worldwide Quality Assurance or in compliance with Worldwide Standard Operating Procedures.
REF: Worldwide-TMP-QA-001f-1.3
Page 9 of 26
6.2.6
Inexact Values
In the case where a safety laboratory variable is recorded as “> x”, “≥ x”, “< x” or “≤ x”, a value 
of x will be taken for analysis purposes.
6.2.7
Unscheduled Visits
Only scheduled post-baseline assessments will be tabulated. Post-baseline repeat / unscheduled 
assessments will not be summarized but will be listed in the relevant appendices to the CSR.
6.2.8
PK Parameters
6.2.8.1
Concentration-Time Data
Blood samples for analysis of pretomanid concentrations for each panel (Panel 1=Fed; Panel 
2=Fasted) will be drawn just before drug intake (pre-dose), and at 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 
36, 48, 72, and 96 hours post dose (15 samples per dose).
Concentration-time data will be tabulated by panel, treatment, and nominal time using descriptive 
statistics including: sample size (n), arithmetic mean (mean), standard deviation (SD), percentage 
coefficient of variation (% CV), geometric mean, median, minimum (min), and maximum (max). 
For presentation of the individual data and summary statistics, concentrations below the limit of 
quantitation (BLQ) will be set to zero. Geometric means will be presented as NC (not calculated) 
if BLQ values are present in the concentration-time dataset. 
Individual subject and mean plasma concentration-time data will be presented graphically on linear 
and semi-logarithmic scales by panel. Mean data will be plotted using nominal sample times, and 
individual data will be plotted using actual times.
6.2.8.2
PK Parameters
Concentration-time data for pretomanid will be analyzed by noncompartmental methods using 
Phoenix™ WinNonlin® (Version 8.1, Certara, L.P.) in conjunction with the internet-accessible 
implementation of Pharsight® Knowledgebase ServerTM (PKSO; Version 4.0.4, Certara, L.P.).
During the pharmacokinetic analysis, concentrations below the limit of quantitation (BLQ) up to 
the time of the first quantifiable concentration will be treated as zero. Embedded (values between 
2 quantifiable concentrations) and terminal BLQ concentrations will be treated as “missing”. 
Actual sample times relative to the time of dose administration will be used in the PK analysis. If 
actual times are missing, nominal times may be used.
Global Alliance for TB Drug Development, Protocol Pa-824-CL-011
Appendix 16.1.9 - Page 11


Worldwide Clinical Trials Controlled Quality Management Document
Sponsor:
TB Alliance
Protocol Number:
Pa-824-CL-011
STATISTICAL ANALYSIS PLAN – PHASE 1
QMD Ref: Worldwide-TMP-ST-006-4.0 Effective: 12Aug2019
Governing QMD: Worldwide-SOP-ST-001
Confidentiality Statement
This document is the property of Worldwide Clinical Trials Inc. and may not be duplicated, copied, altered or removed from company without 
prior approval from Worldwide Quality Assurance or in compliance with Worldwide Standard Operating Procedures.
REF: Worldwide-TMP-QA-001f-1.3
Page 10 of 26
The following PK parameters will be calculated for pretomanid for each panel:
Parameter
Definition
Cmax
Maximum plasma concentration, determined directly from individual 
concentration-time- data
Tmax
Time of the maximum plasma concentrations
Clast
Last quantifiable plasma concentration determined directly from individual 
concentration-time data
Tlast
Time of the last quantifiable plasma concentration
AUC0-t
Area under the plasma concentration-time curve from time-zero to the time 
of the last quantifiable concentration (Clast), as calculated by the linear 
trapezoidal rule
AUC0-inf
Area under the plasma concentration-time curve from the time of dosing 
extrapolated to infinity, calculated as: 
AUC0-inf = AUC0-t + Clast/λz, where λz is the apparent terminal elimination rate 
constant calculated by linear regression of the terminal linear portion of the 
log concentration versus time curve
AUCExtrap
The percentage of AUC0-inf based on extrapolation, calculated as:
[1 - (AUC0-t/AUC0-inf)]* 100
λz (Kel,
Lambda z)
The apparent elimination rate constant λz will be calculated as the negative of 
the slope of the linear regression through the terminal log-linear segment of 
the plasma concentration-time curve
(additional criteria are summarized below)
T½
The observed terminal elimination half-life, calculated as: 
T½ = ln(2)/λz
Global Alliance for TB Drug Development, Protocol Pa-824-CL-011
Appendix 16.1.9 - Page 12


Worldwide Clinical Trials Controlled Quality Management Document
Sponsor:
TB Alliance
Protocol Number:
Pa-824-CL-011
STATISTICAL ANALYSIS PLAN – PHASE 1
QMD Ref: Worldwide-TMP-ST-006-4.0 Effective: 12Aug2019
Governing QMD: Worldwide-SOP-ST-001
Confidentiality Statement
This document is the property of Worldwide Clinical Trials Inc. and may not be duplicated, copied, altered or removed from company without 
prior approval from Worldwide Quality Assurance or in compliance with Worldwide Standard Operating Procedures.
REF: Worldwide-TMP-QA-001f-1.3
Page 11 of 26
Parameter
Definition
CL/F
The apparent total plasma clearance after an oral dose, calculated as:
CL/F=Dose/AUC0-inf, where F is the bioavailability,
Vz/F
The apparent volume of distribution after an oral dose, calculated as: 
Vz/F=Dose/(AUC0-inf x Oz), where F is the bioavailability,
Lambda-z (λz) Acceptance Criteria
The following criteria will be used to report lambda-z and related parameters:
x
At least 3 quantifiable concentration-time points should be used in the regression
x
Cmax or data prior to Cmax should not be included in the regression
x
Adjusted R2 should be ≥ 0.8000
If these acceptance criteria are not met, lambda-z and descriptive parameters such as the time range 
for the regression, adjusted R2, etc. will be retained in a parameter listing for informational 
purposes. Lambda-z will be excluded from summary statistics and from subsequent PK 
calculations; parameters calculated using lambda-z (e.g. t1/2, AUC0-inf, CL/F, and Vz/F) will be 
reported as ND (not determinable).
If lambda-z acceptance criteria are met and AUC0-inf is estimable, the following criteria are used 
to report AUC0-inf:
• The percentage of AUC0-inf based on extrapolation should be <30.0%.
If the percentage of AUC0-inf based on extrapolation is 30.0% or greater, AUC0-inf and AUCExtrap 
will be retained in a PK parameter listing for informational purposes; these parameters will be 
excluded from summary statistics, subsequent PK calculations (e.g. CL/F, Vz/F), and statistical 
analysis (e.g. ANOVA).
PK parameters will be summarized separately for each panel by treatment using the following 
descriptive statistics: n, mean, SD, median, min, max, CV%, geometric mean, and geometric mean 
CV%. 
6.2.8.3
Emesis
Subjects that experience emesis within 4 hours of dosing will be excluded from the PK analysis 
for the period during which the emesis occurred.
Global Alliance for TB Drug Development, Protocol Pa-824-CL-011
Appendix 16.1.9 - Page 13


Worldwide Clinical Trials Controlled Quality Management Document
Sponsor:
TB Alliance
Protocol Number:
Pa-824-CL-011
STATISTICAL ANALYSIS PLAN – PHASE 1
QMD Ref: Worldwide-TMP-ST-006-4.0 Effective: 12Aug2019
Governing QMD: Worldwide-SOP-ST-001
Confidentiality Statement
This document is the property of Worldwide Clinical Trials Inc. and may not be duplicated, copied, altered or removed from company without 
prior approval from Worldwide Quality Assurance or in compliance with Worldwide Standard Operating Procedures.
REF: Worldwide-TMP-QA-001f-1.3
Page 12 of 26
6.2.8.4
Unable to Complete FDA Standard Breakfast
Subjects in Panel 1 that are unable to complete the high-calorie, high-fat FDA breakfast will be 
excluded from PK analysis during which the incomplete breakfast occurred.
6.2.8.5
Quantifiable Predose Concentrations
If a quantifiable predose plasma concentration is identified, the following procedures will be 
followed: 
x
If the quantifiable predose concentration is less than 5% of the respective Cmax, the value 
will be included in the concentration-time, PK, and statistical analysis without adjustment,
x
If the predose concentration is greater than 5% of the respective Cmax, the concentration-
time data for the subject in question will be excluded from concentration-time analysis 
(mean and individual plots; concentration time tables), PK and statistical analyses. 
Quantifiable predose concentrations that are greater than 5% of the respective Cmax will be 
retained in the concentration-time listing. If there are several instances of predose 
concentrations being greater than 5% of the respective Cmax value, additional tables or
statistical tests may be warranted and will be discussed with the Sponsor prior to final PK 
analysis. 
6.3
Conventions
All clinical data listings, summaries, figures and statistical analyses will be generated using SAS 
(Version 9.4 or higher)1.
Summaries of the clinical data will be presented by treatment panel and treatment group or overall. 
PK data listings, summaries, figures, and statistical analyses will be generated using Phoenix™ 
WinNonlin® (Version 8.1 or higher)2 or SAS (Version 9.4 or higher)1. PK concentration data will 
be summarized by panel and treatment at each nominal sample time. PK parameter data will be 
summarized by panel and treatment.
Treatment panel labels will be displayed as follows:
Panel 1
(Fed)
Panel 2
(Fasted)
Global Alliance for TB Drug Development, Protocol Pa-824-CL-011
Appendix 16.1.9 - Page 14


Worldwide Clinical Trials Controlled Quality Management Document
Sponsor:
TB Alliance
Protocol Number:
Pa-824-CL-011
STATISTICAL ANALYSIS PLAN – PHASE 1
QMD Ref: Worldwide-TMP-ST-006-4.0 Effective: 12Aug2019
Governing QMD: Worldwide-SOP-ST-001
Confidentiality Statement
This document is the property of Worldwide Clinical Trials Inc. and may not be duplicated, copied, altered or removed from company without 
prior approval from Worldwide Quality Assurance or in compliance with Worldwide Standard Operating Procedures.
REF: Worldwide-TMP-QA-001f-1.3
Page 13 of 26
Treatment group labels will be displayed as follows:
Pretomanid 
200 mg IR Tablet
Pretomanid
4 x 50-mg Dispersible 
Tablets*
Pretomanid
50-mg Dispersible 
Tablet
Pretomanid
10-mg Dispersible 
Tablet
IR = Immediate Release; *Dispersible Pediatric Formulation.
Listings will be sorted in the following order: subject number, treatment panel, treatment sequence
parameter, and visit unless otherwise stated. All data will be listed.
For clinical data, continuous variables will be summarized by the number of non-missing 
observations, mean, median, standard deviation, and minimum and maximum. 
PK data (concentration-time data and PK parameters) will be summarized by the number of non-
missing observations (n), mean, standard deviation (SD), median, minimum (min), maximum
(max), and coefficient of variation (CV%), calculated as (SD/Mean)*100.  In addition, the 
geometric mean and geometric CV%, calculated as SQRT[exp(SD2 of log transformed data)-
1]*100, will be reported for Cmax and AUCs. 
Categorical variables will be summarized by presenting the frequency and percent. Percentages 
will be based on the number of non-missing observations or the analysis set unless otherwise 
specified. For each variable, all categories will be shown. Zero frequencies (but not the percent) 
within a category will be presented. 
6.3.1
Decimal Places
Means, medians and percentiles will be displayed to one more decimal place than the data,
dispersion statistics (e.g. standard deviation) will have two more decimal places, and the minimum 
and maximum will be displayed to the same number of decimal places as reported in the raw data. 
Percentages will be displayed with one decimal place. 
For PK data, individual concentrations and PK parameters will be reported to 3 significant figures. 
Nominal and relative times will be presented to 3 significant figures. For summary statistics, n will 
be reported as a whole number; mean, standard deviation, median, minimum, maximum, CV%, 
geometric mean, and geometric mean CV% will be reported to the same precision as for individual 
data. For results from the statistical comparisons, least squares (LS) means and geometric LS 
means will be presented to 3 significant figures, p-values will be reported to 4 decimal places, 
percent ratios of the geometric LS means and associated 90% confidence intervals will be reported 
to 2 decimal places.
Global Alliance for TB Drug Development, Protocol Pa-824-CL-011
Appendix 16.1.9 - Page 15


Worldwide Clinical Trials Controlled Quality Management Document
Sponsor:
TB Alliance
Protocol Number:
Pa-824-CL-011
STATISTICAL ANALYSIS PLAN – PHASE 1
QMD Ref: Worldwide-TMP-ST-006-4.0 Effective: 12Aug2019
Governing QMD: Worldwide-SOP-ST-001
Confidentiality Statement
This document is the property of Worldwide Clinical Trials Inc. and may not be duplicated, copied, altered or removed from company without 
prior approval from Worldwide Quality Assurance or in compliance with Worldwide Standard Operating Procedures.
REF: Worldwide-TMP-QA-001f-1.3
Page 14 of 26
6.4
Subject Disposition
Subject disposition will be summarized as follows:
x
The number of subjects completing the study and the number in each analysis set will be
summarized by treatment panel and overall for the Randomized set.
x
The number of subjects completing each treatment period will be summarized by treatment
panel and overall for the Randomized set.
x
The number of early withdrawals and the reasons for withdrawals will be tabulated by
treatment panel and overall for the Randomized set.
6.5
Protocol Deviations 
A listing of protocol deviations will be provided within Appendix 16.2 of the CSR.
6.6
Baseline Comparability 
The comparability of treatment panels (Fed/Fasted) with respect to subject demographics and 
baseline characteristics will be assessed in a descriptive manner, but no formal statistical testing 
will be performed. 
6.6.1
Demographic Data 
Standard continuous or categorical variable summaries will be presented by treatment panel and 
overall for the following variables based on the Safety Analysis Set. 
x
Sex (Male, Female)
x
Age at Informed Consent (years)
x
Ethnicity (Hispanic or Latino, Non-Hispanic or Latino)
x
Race (White, Black or African American, Asian, American Indian or Alaska Native,
Native Hawaiian or Other Pacific Islander, Multiple Race)
x
Height at Screening (cm)
x
Weight at Screening (kg)
x
Body Mass Index at Screening (kg/m2)
All demographic data will be listed. 
Global Alliance for TB Drug Development, Protocol Pa-824-CL-011
Appendix 16.1.9 - Page 16


Worldwide Clinical Trials Controlled Quality Management Document
Sponsor:
TB Alliance
Protocol Number:
Pa-824-CL-011
STATISTICAL ANALYSIS PLAN – PHASE 1
QMD Ref: Worldwide-TMP-ST-006-4.0 Effective: 12Aug2019
Governing QMD: Worldwide-SOP-ST-001
Confidentiality Statement
This document is the property of Worldwide Clinical Trials Inc. and may not be duplicated, copied, altered or removed from company without 
prior approval from Worldwide Quality Assurance or in compliance with Worldwide Standard Operating Procedures.
REF: Worldwide-TMP-QA-001f-1.3
Page 15 of 26
6.7
Medical History
A listing of previous and ongoing conditions at Screening will be presented for the Safety Analysis 
Set. Conditions will be coded using the Medical Dictionary of Regulated Activities (MedDRA 
version 22.0 or higher) primary system organ class and preferred term. 
6.8
Prior and Concomitant Medications
A listing of prior and concomitant medications will be provided. Prior medications are defined as 
all medications starting and stopping before the date of first dose of study drug. Concomitant 
medications are defined as medications taken on or after the date of first dose of study drug. Each 
concomitant medication will be assigned to the last study drug taken prior to starting the 
concomitant medication. Concomitant medications taken before the first dose of study drug will 
be assigned to ‘No Treatment’. Prior and concomitant medications will be coded using the World 
Health Organization (WHO) Drug Dictionary B3 – September 2019 version. 
6.9
Exposure to Study Drug
Exposure to study medication will be tabulated by treatment panel and treatment group.  All dosing 
information will be listed. 
6.10 Statistical Analyses of Pharmacokinetic Data
6.10.1
Relative Bioavailability
The bioavailability of 4 x 50 mg dispersible tablets (Treatment B) relative to the 200-mg reference 
tablet (Treatment A) will be determined separately for each panel using a mixed model with log 
transformed PK parameters (Cmax, AUC0-t, and AUC0-inf) as response variable; sequence, period, 
and treatment as fixed effects; and subject as random effect. The effect of dose on the relative 
Global Alliance for TB Drug Development, Protocol Pa-824-CL-011
Appendix 16.1.9 - Page 17


Worldwide Clinical Trials Controlled Quality Management Document
Sponsor:
TB Alliance
Protocol Number:
Pa-824-CL-011
STATISTICAL ANALYSIS PLAN – PHASE 1
QMD Ref: Worldwide-TMP-ST-006-4.0 Effective: 12Aug2019
Governing QMD: Worldwide-SOP-ST-001
Confidentiality Statement
This document is the property of Worldwide Clinical Trials Inc. and may not be duplicated, copied, altered or removed from company without 
prior approval from Worldwide Quality Assurance or in compliance with Worldwide Standard Operating Procedures.
REF: Worldwide-TMP-QA-001f-1.3
Page 16 of 26
bioavailability of the dispersible tablets (Treatments B, C, and D) will be determined separately 
for each panel using a power model (Smith, 2000) of the following general form, 
ln(PK) = ln(β0) + β1·ln(Dose) + ε,
Where
PK is the pharmacokinetic parameter tested (e.g. Cmax or AUC)
ln(β0) is the y-intercept,
β1 is the slope (a value of β1 | 1 indicates linearity), and
ε is an error term 
The estimate of β1 with the 90% CIs will be reported along with the dose range for proportionality. 
6.10.2
Food Effect
The effect of food on the relative bioavailability of pretomanid will be determined by comparing 
Panel 1 (Fed) to Panel 2 (Fasted) for each treatment using an ANOVA model with panel as the 
fixed effect.  For informational purposes, the food effect will also be evaluated using the following 
ANOVA models:
1) Using data from the 4 x 50 mg dispersible tablets (Treatment B) and the 200-mg reference
tablet (Treatment A) from both panels the ANOVA model will include panel, treatment,
and the panel by treatment interaction term as fixed effects to determine if the food effect
differs across the two treatments.  A p-value equal to or smaller than 0.05 for the panel by
treatment interaction term indicates that the food effect differs between the treatments.  If
the p-value is greater than 0.05 an ANOVA model with panel and treatment as the fixed
effects will be used to determine the common food effect for Treatments A and B (Panel 1
vs Panel 2).
2) Using data from the dispersible tablets (Treatments B, C, and D) from both panels the
ANOVA model will include panel, treatment, and the panel by treatment interaction term
as fixed effects to determine if the food effect differs across the dispersible tablets.  A p-
value equal to or smaller than 0.05 for the panel by treatment interaction term indicates that
the food effect differs among the dispersible tablets.  If the p-value is greater than 0.05 an
ANOVA model with panel and treatment as the fixed effects will be used to determine the
common food effect for the dispersible tablets (Panel 1 vs Panel 2).
Global Alliance for TB Drug Development, Protocol Pa-824-CL-011
Appendix 16.1.9 - Page 18


Worldwide Clinical Trials Controlled Quality Management Document
Sponsor:
TB Alliance
Protocol Number:
Pa-824-CL-011
STATISTICAL ANALYSIS PLAN – PHASE 1
QMD Ref: Worldwide-TMP-ST-006-4.0 Effective: 12Aug2019
Governing QMD: Worldwide-SOP-ST-001
Confidentiality Statement
This document is the property of Worldwide Clinical Trials Inc. and may not be duplicated, copied, altered or removed from company without 
prior approval from Worldwide Quality Assurance or in compliance with Worldwide Standard Operating Procedures.
REF: Worldwide-TMP-QA-001f-1.3
Page 17 of 26
6.11 Safety Analyses
The safety analyses will be presented by the treatment received for the Safety Analysis Set.
6.11.1
Adverse Events
Subjects will be monitored continuously for any AEs from the time of informed consent through 
the end of the study.  Only treatment emergent adverse events (TEAE) will be summarized.  All 
AEs will be listed.  TEAEs will be presented by treatment panel (Fed/Fasted) and overall.  
A TEAE is defined as:
x
Any AE that has an onset on or after the first dose of study drug through the EOS/EW
follow-up visit.
x
Any pre-existing AE that has worsened in severity on or after the first dose through the
EOS/EW follow-up visit.
Relatedness of an AE to treatment can be classified as Not Related, Unlikely, Possible, Probable 
or Certain.  A treatment-related AE is defined as any AE classified as possibly, probably or 
certainly related to the study drug.  If an AE has missing relationship it is assumed to be related to 
the study drug for analysis purposes. 
Severity of AEs will be graded using the Division of Microbiology and Infectious Disease (DMID) 
Toxicity Grade November 2007 version: Grade 1 (Mild), Grade 2 (Moderate), Grade 3 (Severe), 
Grade 4 (Potentially Life-Threatening).  Maximum grade will be assumed for an AE with missing 
grade.
The following tables will be presented for AEs:
x
Overall incidence and number of TEAEs, Treatment-related TEAEs, SAEs, Treatment-
related SAEs, TEAEs leading to Early Withdrawal and TEAEs leading to Death.
x
TEAEs by system organ class and preferred term, incidence and number of events
x
Treatment-related TEAEs by system organ class and preferred term, incidence and number
of events
x
TEAEs by system organ class, preferred term and maximum grade, incidence
x
TEAEs by system organ class, preferred term and relationship, incidence
x
Listing of AEs Leading to Early Withdrawal (presented in the Table section of the
appendices)
x
Listing of Serious AEs (presented in the Table section of the appendices)
Global Alliance for TB Drug Development, Protocol Pa-824-CL-011
Appendix 16.1.9 - Page 19


Worldwide Clinical Trials Controlled Quality Management Document
Sponsor:
TB Alliance
Protocol Number:
Pa-824-CL-011
STATISTICAL ANALYSIS PLAN – PHASE 1
QMD Ref: Worldwide-TMP-ST-006-4.0 Effective: 12Aug2019
Governing QMD: Worldwide-SOP-ST-001
Confidentiality Statement
This document is the property of Worldwide Clinical Trials Inc. and may not be duplicated, copied, altered or removed from company without 
prior approval from Worldwide Quality Assurance or in compliance with Worldwide Standard Operating Procedures.
REF: Worldwide-TMP-QA-001f-1.3
Page 18 of 26
x
Listing of Deaths (presented in the Table section of the appendices)
System organ class will be presented in descending order of overall frequency and then 
alphabetically.  Preferred terms will be displayed in descending order of overall frequency and 
then alphabetically. 
In counting the number of AEs reported, a continuous event (i.e. reported more than once and 
which did not cease), will be counted only once; non-continuous AE reported several times by the 
same subject will be counted as multiple events.
Where a subject reports more than one AE per system organ class and preferred term they will 
only be counted once for the most severe event or the most related event.
6.11.2
Laboratory Data
Descriptive statistics of the observed values and change from baseline in Period 1 to end of each 
treatment period (continuous data) will be presented by treatment panel and treatment group for 
each hematology, urinalysis and serum chemistry parameter. Each measurement (continuous data)
will be classed as below, within, or above normal range, based on ranges supplied by the laboratory 
used. Shift tables in relation to the normal range from baseline in Period 1 to the end of each 
treatment period will be presented. Descriptive statistics and normal range shift tables from 
baseline in Period 1 to EOS/EW will also be presented overall for each treatment panel.  Values 
will be summarized using the original units as provided by the analytical laboratory.  
A listing of any clinically significant laboratory measurements recorded throughout the study will 
also be presented. Other laboratory data including serology, urine drug, cotinine and alcohol 
screening and pregnancy test data will be listed.  
6.11.3
Vital Signs
Descriptive statistics for observed values and change from baseline within the relevant treatment 
period will be presented by treatment panel and treatment group for all scheduled measurements 
of the following vital signs:
x
Systolic blood pressure (mmHg)
x
Diastolic blood pressure (mmHg)
x
Pulse rate (bpm)
x
Respiration rate (breath/min)
x
Body temperature (degrees Celsius)
Global Alliance for TB Drug Development, Protocol Pa-824-CL-011
Appendix 16.1.9 - Page 20


Worldwide Clinical Trials Controlled Quality Management Document
Sponsor:
TB Alliance
Protocol Number:
Pa-824-CL-011
STATISTICAL ANALYSIS PLAN – PHASE 1
QMD Ref: Worldwide-TMP-ST-006-4.0 Effective: 12Aug2019
Governing QMD: Worldwide-SOP-ST-001
Confidentiality Statement
This document is the property of Worldwide Clinical Trials Inc. and may not be duplicated, copied, altered or removed from company without 
prior approval from Worldwide Quality Assurance or in compliance with Worldwide Standard Operating Procedures.
REF: Worldwide-TMP-QA-001f-1.3
Page 19 of 26
x
Body weight (kg)
x
Pulse oximetry (%)
The change from baseline in Period 1 to EOS/EW will also be summarized overall. All vital sign 
data will be listed.
6.11.4
Electrocardiogram Data
Descriptive statistics for ECG data obtained at baseline for each treatment period will be tabulated 
by treatment panel and treatment group for the following variables:
x
Heart Rate (bpm)
x
PR Interval (ms)
x
RR Interval (ms)
x
QRS Complex (ms)  
x
QT Interval (ms)
x
QTc Interval (ms) [Bazett’s formula - QTcB] 
x
QTc Interval (ms) [Fridericia’s formula - QTcF] 
x
Overall Interpretation
Descriptive statistics and change from baseline in Period 1 to EOS/EW will also be tabulated 
overall for each treatment panel.  
Shift tables in relation to the overall interpretation i.e. Normal, Abnormal NCS (Not Clinically 
Significant), and Abnormal CS (Clinically Significant), from baseline in Period 1 to EOS/EW will 
be also presented overall for each treatment panel.  
All ECG data, including details of any abnormalities, will be listed.
6.11.5
Physical Examination
Shift tables for the observed status of each of the body systems (Normal, Abnormal NCS, and 
Abnormal CS) from baseline in Period 1 to EOS/EW will be presented overall for each treatment 
panel.  
All data, including details of clinically significant findings will be listed. 
6.11.6
Taste Evaluation
Taste, Mouthfeel and Smell will be evaluated using the following categories: 1 - Like extremely, 
2 - Like moderately, 3 - Neither like nor dislike, 4 - Dislike moderately and6 5 - Dislike extremely.  
Global Alliance for TB Drug Development, Protocol Pa-824-CL-011
Appendix 16.1.9 - Page 21


Worldwide Clinical Trials Controlled Quality Management Document
Sponsor:
TB Alliance
Protocol Number:
Pa-824-CL-011
STATISTICAL ANALYSIS PLAN – PHASE 1
QMD Ref: Worldwide-TMP-ST-006-4.0 Effective: 12Aug2019
Governing QMD: Worldwide-SOP-ST-001
Confidentiality Statement
This document is the property of Worldwide Clinical Trials Inc. and may not be duplicated, copied, altered or removed from company without 
prior approval from Worldwide Quality Assurance or in compliance with Worldwide Standard Operating Procedures.
REF: Worldwide-TMP-QA-001f-1.3
Page 20 of 26
Taste evaluation will be summarized at each timepoint by treatment panel and treatment group.  
All data will be listed. 
7
CHANGES TO PLANNED PROTOCOL ANALYSIS
No changes to the planned analyses have been identified. 
8
REFERENCES
1. SAS Institute Inc., Cary, NC, 27513, USA
2. Phoenix™ WinNonlin® (Version 8.1, Certara L.P.)
Global Alliance for TB Drug Development, Protocol Pa-824-CL-011
Appendix 16.1.9 - Page 22


Worldwide Clinical Trials Controlled Quality Management Document
Sponsor:
TB Alliance
Protocol Number:
Pa-824-CL-011
STATISTICAL ANALYSIS PLAN – PHASE 1
QMD Ref: Worldwide-TMP-ST-006-4.0 Effective: 12Aug2019
Governing QMD: Worldwide-SOP-ST-001
Confidentiality Statement
This document is the property of Worldwide Clinical Trials Inc. and may not be duplicated, copied, altered or removed from company without 
prior approval from Worldwide Quality Assurance or in compliance with Worldwide Standard Operating Procedures.
REF: Worldwide-TMP-QA-001f-1.3
Page 21 of 26
9
LIST OF TABLES, FIGURES AND LISTINGS
The following table includes details of the tables, figures and listings to be included within each 
section of the electronic common technical document (eCTD). The eCTD section is shown in bold. 
The following validation methods maybe used:
x
Independent programming of numbers and manual review of format (IP)
x
Independent programming by statistician of numbers and manual review of format (Stat IP)
x
Manual review (MR)
x
Code review (CR)
Table 
Number
Table Title
Validation 
Method
Shell 
Number 
(if repeat)
Items in bold are not table titles but references to the section headings within eCTD.
14.1
Demographics Data
14.1.1
Disposition
14.1.1.1
Subject Disposition, Early Withdrawals - Randomized 
Set
IP
14.1.2
Demographics
14.1.2.1
Demographics, Safety Analysis Set
IP
14.1.3
Baseline Characteristics
Not Applicable
14.2
Efficacy Data
Not Applicable
14.3
Safety Data
14.3.1
Displays of Adverse Events
14.3.1.1
Adverse Events, Overall Summary of Treatment-
Emergent Adverse Events (TEAEs) - Safety Analysis Set
IP
14.3.1.2
Adverse Events, TEAEs by Primary System Organ Class 
and Preferred Term - Safety Analysis Set
IP
14.3.1.3
Adverse Events, Treatment-Related TEAEs by Primary 
System Organ Class and Preferred Term - Safety Analysis 
Set
IP
14.3.1.2
14.3.1.4
Adverse Events, TEAEs by Primary System Organ Class 
Preferred Term and Maximum Toxicity Grade - Safety 
Analysis Set
IP
Global Alliance for TB Drug Development, Protocol Pa-824-CL-011
Appendix 16.1.9 - Page 23


Worldwide Clinical Trials Controlled Quality Management Document
Sponsor:
TB Alliance
Protocol Number:
Pa-824-CL-011
STATISTICAL ANALYSIS PLAN – PHASE 1
QMD Ref: Worldwide-TMP-ST-006-4.0 Effective: 12Aug2019
Governing QMD: Worldwide-SOP-ST-001
Confidentiality Statement
This document is the property of Worldwide Clinical Trials Inc. and may not be duplicated, copied, altered or removed from company without 
prior approval from Worldwide Quality Assurance or in compliance with Worldwide Standard Operating Procedures.
REF: Worldwide-TMP-QA-001f-1.3
Page 22 of 26
Table 
Number
Table Title
Validation 
Method
Shell 
Number 
(if repeat)
14.3.1.5
Adverse Events, TEAEs by Primary System Organ Class 
Preferred Term and Nearest Relationship - Safety 
Analysis Set
IP
14.3.2
Listings of Deaths, Other Serious and Significant 
Adverse Events
14.3.2.1
TEAEs Leading to Early Withdrawal, Listing - Safety 
Analysis Set
IP
14.3.2.2
Serious TEAEs, Listing - Safety Analysis Set
IP
14.3.2.3
Deaths, Listing - Safety Analysis Set
IP
14.3.3
Narratives of Deaths, Other Serious and Certain Other 
Significant Adverse Events
14.3.4
Abnormal Laboratory Values
14.3.4.1
Listing of Clinically Significant Laboratory Values -
Safety Analysis Set
IP
14.3.5
Extent of
Exposure,
Dosage Information, And 
Compliance
14.3.5.1
Summary of Exposure - Safety Analysis Set
IP
14.3.6
Vital Signs and Physical Examination
14.3.6.1
Vital Signs, Descriptive Statistics - Safety Analysis Set
IP
14.3.6.2
Physical Examination, Descriptive Statistics - Safety 
Analysis Set
IP
14.3.7
Other Safety
14.3.7.1
Hematology Data, Descriptive Statistics - Safety Analysis 
Set
IP
14.3.7.2
Hematology Data, Normal Range Shifts - Safety Analysis 
Set
IP
14.3.7.3
Serum Chemistry Data, Descriptive Statistics - Safety 
Analysis Set
IP
14.3.7.1
14.3.7.4
Serum Chemistry Data, Normal Range Shifts - Safety 
Analysis Set
IP
14.3.7.2
14.3.7.5
Urinalysis Data, Descriptive Statistics - Safety Analysis 
Set
IP
14.3.7.1
14.3.7.6
Urinalysis Data, Normal Range Shifts - Safety Analysis 
Set
IP
14.3.7.2
14.3.7.7
ECG Data, Change from Baseline - Safety Analysis Set
IP
Global Alliance for TB Drug Development, Protocol Pa-824-CL-011
Appendix 16.1.9 - Page 24


Worldwide Clinical Trials Controlled Quality Management Document
Sponsor:
TB Alliance
Protocol Number:
Pa-824-CL-011
STATISTICAL ANALYSIS PLAN – PHASE 1
QMD Ref: Worldwide-TMP-ST-006-4.0 Effective: 12Aug2019
Governing QMD: Worldwide-SOP-ST-001
Confidentiality Statement
This document is the property of Worldwide Clinical Trials Inc. and may not be duplicated, copied, altered or removed from company without 
prior approval from Worldwide Quality Assurance or in compliance with Worldwide Standard Operating Procedures.
REF: Worldwide-TMP-QA-001f-1.3
Page 23 of 26
Table 
Number
Table Title
Validation 
Method
Shell 
Number 
(if repeat)
14.3.7.8
ECG 
Data, 
Change 
from 
Baseline 
in 
Overall 
Interpretation - Safety Analysis Set
IP
14.3.7.9
Taste Evaluation Data, Descriptive Statistics - Safety 
Analysis Set
IP
14.3.8
Concomitant Medication
Not Applicable
14.4
PK Tables
14.4.1
Descriptive Statistics for Plasma Concentration-Time
Data of Pretomanid by Panel 
14.4.2
Plasma Pharmacokinetic Parameters of Pretomanid by
Panel 
14.4.3
Statistical Analysis of the Natural Log-
Transformed Systemic Exposure of Pretomanid
Comparing Test Treatment of Dispersible Tablet 
(Treatment B) to the Reference 200 mg Immediate 
Release Tablet (Panel 1)
14.4.4
Statistical Analysis of the Natural Log-
Transformed Systemic Exposure of Pretomanid
Comparing Test Treatment of Dispersible Tablet 
(Treatment B) to the Reference 200 mg Immediate 
Release Tablet (Panel 2)
14.4.5
Statistical Analysis of the Natural Log-
Transformed Systemic Exposure of Pretomanid Among 
Treatments  Comparing Panel 1 vs. Panel 2
14.4.6
Assessment of Dose Effect on Relative Bioavailability of 
Dispersible Tablets  (Treatments B, C, and D) (Panel 1)
14.4.7
Assessment of Dose Effect on Relative Bioavailability of 
Dispersible Tablets  (Treatments B, C, and D) (Panel 2)
14.4.8
Assessment of Food Effect Across 200 mg Treatments (A 
and B) on Log-Transformed PK Parameters
14.4.9
Assessment of Food Effect Across Dispersible-Tablet 
Treatments (B, C, and D) on Log-Transformed PK 
Parameters
Global Alliance for TB Drug Development, Protocol Pa-824-CL-011
Appendix 16.1.9 - Page 25


Worldwide Clinical Trials Controlled Quality Management Document
Sponsor:
TB Alliance
Protocol Number:
Pa-824-CL-011
STATISTICAL ANALYSIS PLAN – PHASE 1
QMD Ref: Worldwide-TMP-ST-006-4.0 Effective: 12Aug2019
Governing QMD: Worldwide-SOP-ST-001
Confidentiality Statement
This document is the property of Worldwide Clinical Trials Inc. and may not be duplicated, copied, altered or removed from company without 
prior approval from Worldwide Quality Assurance or in compliance with Worldwide Standard Operating Procedures.
REF: Worldwide-TMP-QA-001f-1.3
Page 24 of 26
Figure 
Number
Figure Title
Validation 
Method
Shell 
Number (if 
repeat)
14.4.1
Mean 
Plasma 
Concentration-Time 
Profiles 
of 
Pretomanid for Panel 1 on Linear and Semi Logarithmic 
Scales
14.4.2
Mean 
Plasma 
Concentration-Time 
Profiles 
of 
Pretomanid for Panel 2 on Linear and Semi Logarithmic 
Scales
14.4.3
Mean 
Plasma 
Concentration-Time 
Profiles 
of 
Pretomanid for Treatment A (Panel 1 vs Panel 2) on 
Linear and Semi Logarithmic Scales
14.4.4
Mean 
Plasma 
Concentration-Time 
Profiles 
of 
Pretomanid for Treatment B (Panel 1 vs Panel 2) on 
Linear and Semi Logarithmic Scales
14.4.5
Mean 
Plasma 
Concentration-Time 
Profiles 
of 
Pretomanid for Treatment C (Panel 1 vs Panel 2) on 
Linear and Semi Logarithmic Scales
14.4.6
Mean 
Plasma 
Concentration-Time 
Profiles 
of 
Pretomanid for Treatment D (Panel 1 vs Panel 2) on 
Linear and Semi Logarithmic Scales
14.4.7
All Subject Plasma Concentration-Time Profiles of 
Pretomanid by Treatment for Panel 1 on Linear and Semi 
Logarithmic Scales
14.4.8
All Subject Plasma Concentration-Time Profiles of 
Pretomanid by Treatment for Panel 2 on Linear and Semi 
Logarithmic Scales
14.4.9
Individual Subject Plasma Concentration-Time Profiles 
of Pretomanid for Panel 1 on Linear and Semi 
Logarithmic Scales
14.4.10
Individual Subject Plasma Concentration-Time Profiles 
of Pretomanid for Panel 2 on Linear and Semi 
Logarithmic Scales
14.4.11
Concentration-Time Profiles for Pretomanid with Linear 
Regression for Estimating the Terminal Elimination 
Rate
Global Alliance for TB Drug Development, Protocol Pa-824-CL-011
Appendix 16.1.9 - Page 26


Worldwide Clinical Trials Controlled Quality Management Document
Sponsor:
TB Alliance
Protocol Number:
Pa-824-CL-011
STATISTICAL ANALYSIS PLAN – PHASE 1
QMD Ref: Worldwide-TMP-ST-006-4.0 Effective: 12Aug2019
Governing QMD: Worldwide-SOP-ST-001
Confidentiality Statement
This document is the property of Worldwide Clinical Trials Inc. and may not be duplicated, copied, altered or removed from company without 
prior approval from Worldwide Quality Assurance or in compliance with Worldwide Standard Operating Procedures.
REF: Worldwide-TMP-QA-001f-1.3
Page 25 of 26
Listing 
Number
Listing Title
Validation 
Method
Shell 
Number 
(if repeat)
16.2
Subject Data Listings
16.2.1
Discontinued Subjects
16.2.1.1
Subject Disposition, Early Withdrawals - All Enrolled 
Subjects
IP
16.2.2
Protocol Deviations
16.2.2.1
Protocol Deviations – Safety Analysis Set
IP
16.2.3
Subjects Excluded from the Efficacy Analyses
16.2.3.1
Analysis Sets
IP
16.2.4
Demographic Data
16.2.4.1
Demographic Data - Safety Analysis Set
IP
16.2.4.2
Previous and Ongoing Medical History - Safety Analysis 
Set
IP
16.2.4.3
Substance Use History - Safety Analysis Set
IP
16.2.5
Compliance and / or Drug Concentration Data
16.2.5.1
PK Sampling Information - Safety Analysis Set
IP
16.2.5.2
Dosing Information - Safety Analysis Set
IP
16.2.5.3
Prior and Concomitant Medications - Safety Analysis Set
IP
16.2.6
Individual Efficacy Response Data
16.2.6.1
Plasma Pretomanid Concentration Listing by Subject
16.2.6.2
Terminal Elimination Rate of Pretomanid in Plasma for 
Individual Subjects (Panel 1)
16.2.6.3
Terminal Elimination Rate of Pretomanid in Plasma for 
Individual Subjects (Panel 2)
16.2.6.4
PK Output Text (WinNonlin Text File)
16.2.6.5
SAS Output Text (Panel 1) Treatment B vs Treatment A
16.2.6.6
SAS Output Text (Panel 2) Treatment B vs Treatment A
16.2.6.7
SAS Output Text (Food Effect) Panel 1 vs. Panel 2
16.2.6.8
SAS Output Text (Dose Effect) Power Model
16.2.6.9
SAS Output Text (Panel by Treatment Interaction) 
16.2.7
Adverse Event Listings
16.2.7.1
Adverse Event Data – Safety Analysis Set
IP
16.2.8
Individual Laboratory Measurements and Other 
Safety
16.2.8.1
Vital Signs Data - Safety Analysis Set
IP
16.2.8.2
Physical Examination Data - Safety Analysis Set
IP
Global Alliance for TB Drug Development, Protocol Pa-824-CL-011
Appendix 16.1.9 - Page 27


Worldwide Clinical Trials Controlled Quality Management Document
Sponsor:
TB Alliance
Protocol Number:
Pa-824-CL-011
STATISTICAL ANALYSIS PLAN – PHASE 1
QMD Ref: Worldwide-TMP-ST-006-4.0 Effective: 12Aug2019
Governing QMD: Worldwide-SOP-ST-001
Confidentiality Statement
This document is the property of Worldwide Clinical Trials Inc. and may not be duplicated, copied, altered or removed from company without 
prior approval from Worldwide Quality Assurance or in compliance with Worldwide Standard Operating Procedures.
REF: Worldwide-TMP-QA-001f-1.3
Page 26 of 26
Listing 
Number
Listing Title
Validation 
Method
Shell 
Number 
(if repeat)
16.2.8.3
Taste Evaluation Data - Safety Analysis Set
IP
16.2.8.4
12-Lead ECG Data - Safety Analysis Set
IP
16.2.8.5
Hematology Data - Safety Analysis Set
IP
16.2.8.6
Serum Chemistry Data - Safety Analysis Set
IP
16.2.8.7
Urinalysis Data - Safety Analysis Set
IP
16.2.8.8
Urine Drug, Alcohol and Cotinine Screen Data - Safety 
Analysis Set
IP
16.2.8.9
Serology Data - Safety Analysis Set
IP
16.2.8.10
Pregnancy and FSH Test Data - Safety Analysis Set
IP
16.2.8.11
Meal Data - Safety Analysis Set
IP
Global Alliance for TB Drug Development, Protocol Pa-824-CL-011
Appendix 16.1.9 - Page 28


Worldwide Clinical Trials Controlled Quality Management Document 
Sponsor: 
TB Alliance 
Protocol Number: 
Pa-824-CL-011 
STATISTICAL ANALYSIS PLAN - TABLES, FIGURES AND LISTINGS SHELL APPROVAL
QMD Ref: Worldwide-TMP-ST-037-2.0 Effective: 12Aug2019
Governing QMD: Worldwide-SOP-ST-001
Confidentiality Statement 
This document is the property of Worldwide Clinical Trials Inc. and may not be duplicated, copied, altered or removed from company
without prior approval from Worldwide Quality Assurance or in compliance with Worldwide Standard Operating Procedures. 
REF: Worldwide-TMP-QA-001f-1.3 
Page 1 of 2
Study name: An Open-label, Randomized, Four-period Crossover Study in 
Two Panels of Healthy Adult Participants to Assess the Relative 
Bioavailability, Food Effect, and Dose-dependence of Single-
Dose 
Immediate-Release 
and 
Single-dose 
Dispersible 
Formulations of Pretomanid 
Protocol Number: Pa-824-CL-011 
Statistical Analysis Plan (SAP) 
Version being approved: 
SAP Version 1.0, dated 09-Mar-2020 
Tables, Figures and Listings 
(TFL) Shell version being 
approved: 
Table shells v1.0, dated 09-Mar-2020 
Listing shells v1.0, dated 09-Mar-2020 
The above SAP / TFL Shell has been reviewed and approved by Worldwide:
Name of Author: 
Aimie Nunn 
Position: 
Senior Statistician 
Signature: 
Date: 
Author: 
Kathryn Roupe Ph.D. 
Position: 
Principal Research Scientist, Pharmacokinetics 
Signature: 
Date: 
Global Alliance for TB Drug Development, Protocol Pa-824-CL-011
Appendix 16.1.9 - Page 29


Worldwide Clinical Trials Controlled Quality Management Document 
Sponsor: 
TB Alliance 
Protocol Number: 
Pa-824-CL-011 
STATISTICAL ANALYSIS PLAN - TABLES, FIGURES AND LISTINGS SHELL APPROVAL
QMD Ref: Worldwide-TMP-ST-037-2.0 Effective: 12Aug2019
Governing QMD: Worldwide-SOP-ST-001
Confidentiality Statement 
This document is the property of Worldwide Clinical Trials Inc. and may not be duplicated, copied, altered or removed from company
without prior approval from Worldwide Quality Assurance or in compliance with Worldwide Standard Operating Procedures. 
REF: Worldwide-TMP-QA-001f-1.3 
Page 2 of 2
The above SAP / TFL Shell has been reviewed and approved by Worldwide: 
Name of Reviewer: 
Michael Jones 
Position: 
Statistician 
Signature: 
Date: 
The above SAP / TFL Shell has been reviewed and approved by the Sponsor: 
Name of Sponsor Clinical 
Lead:
Jerry Nedelman 
Position: 
Senior Director Pharmacometrics 
Signature: 
Date: 
Global Alliance for TB Drug Development, Protocol Pa-824-CL-011
Appendix 16.1.9 - Page 30


Worldwide Clinical Trials Controlled Quality Management Document 
Sponsor: 
TB Alliance 
Protocol Number: 
Pa-824-CL-011 
STATISTICAL ANALYSIS PLAN SUPPLEMENT
 
QMD Ref: Worldwide-TMP-ST-050-2.0 Effective: 12Aug2019
Governing QMD: Worldwide-SOP-ST-001
Confidentiality Statement 
This document is the property of Worldwide Clinical Trials Inc. and may not be duplicated, copied, altered or removed from company
without prior approval from Worldwide Quality Assurance or in compliance with Worldwide Standard Operating Procedures. 
REF: Worldwide-TMP-QA-001f-1.3  
Page 1 of 3
Statistical Analysis Plan 
Supplement
An Open-label, Randomized, Four-period Crossover Study in Two Panels of 
Healthy Adult Participants to Assess the Relative Bioavailability, Food Effect, and 
Dose-dependence of Single-Dose Immediate-Release and Single-dose Dispersible 
Formulations of Pretomanid
Protocol Number: Pa-824-CL-011 
Protocol Version: 1.0, dated 06-Dec-2019 
SAP Version: 1.0, dated 09-March-2020
Supplement Version: 1.0
Supplement Issue Date:  07-Jul-2020
Previous Supplements  
Not Applicable 
Global Alliance for TB Drug Development, Protocol Pa-824-CL-011
Appendix 16.1.9 - Page 31


Worldwide Clinical Trials Controlled Quality Management Document 
Sponsor: 
TB Alliance 
Protocol Number: 
Pa-824-CL-011 
STATISTICAL ANALYSIS PLAN SUPPLEMENT
 
QMD Ref: Worldwide-TMP-ST-050-2.0 Effective: 12Aug2019
Governing QMD: Worldwide-SOP-ST-001
Confidentiality Statement 
This document is the property of Worldwide Clinical Trials Inc. and may not be duplicated, copied, altered or removed from company
without prior approval from Worldwide Quality Assurance or in compliance with Worldwide Standard Operating Procedures. 
REF: Worldwide-TMP-QA-001f-1.3  
Page 2 of 3
1.
BACKGROUND
This document details cosmetic / typographical changes only, which have no bearing or 
impact on the analysis or interpretation of results for TB Alliance, protocol “Pa-824-CL-
011” study previously described in Version 1.0 of the Statistical Analysis Plan dated 09-
March-2020. These amendments were made post database lock; however, the study was 
open label.   
2.
CHANGES TO EXISTING SAP
No changes to existing text. 
3.
ADDITIONS TO EXISTING SAP
No additions to existing text. 
4.
CHANGES TO TABLES, FIGURES AND LISTINGS (TFL) SHELL 
TABLE OF CONTENT (TOC) WITHIN SAP
For the following Listing, the Analysis Set was amended in the final output:  
Described in the SAP  
16.2.1.1 
Subject Disposition, Early Withdrawals - All Enrolled Subjects 
Presented in the final Listing 
16.2.1.1 
Subject Disposition, Early Withdrawals – Randomized Set 
New TOC attached: 
 yes 
 no 
5.
CHANGES TO TFL SHELL
No TFL changes. 
Global Alliance for TB Drug Development, Protocol Pa-824-CL-011
Appendix 16.1.9 - Page 32


Worldwide Clinical Trials Controlled Quality Management Document 
Sponsor: 
TB Alliance 
Protocol Number: 
Pa-824-CL-011 
STATISTICAL ANALYSIS PLAN SUPPLEMENT
 
QMD Ref: Worldwide-TMP-ST-050-2.0 Effective: 12Aug2019
Governing QMD: Worldwide-SOP-ST-001
Confidentiality Statement 
This document is the property of Worldwide Clinical Trials Inc. and may not be duplicated, copied, altered or removed from company
without prior approval from Worldwide Quality Assurance or in compliance with Worldwide Standard Operating Procedures. 
REF: Worldwide-TMP-QA-001f-1.3  
Page 3 of 3
Approval for Implementation of
Statistical Analysis Plan Supplement
The changes detailed above are purely cosmetic and have no impact on the planned analysis or interpretation 
of results:
Name of Author: 
Aimie Nunn
Position: 
Senior Statistician
Signature: 
Date: 
Name of Reviewer: 
Michael Jones
Position: 
Statistician
Signature: 
Date: 
Global Alliance for TB Drug Development, Protocol Pa-824-CL-011
Appendix 16.1.9 - Page 33