Clinical trial NCT03557281
Conditions: Tuberculosis
Keywords: Early bactericidal activity Mycobacterium Tuberculosis GSK3036656 Pulmonary tuberculosis Colony forming units
Sponsor: GlaxoSmithKline
Start date: 2019-03-22; Completion date: 2021-12-14
Enrollment: 76 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
Tuberculosis remains a concerning health problem, with Mycobacterium Tuberculosis (MTB) now causing more deaths than acquired immune deficiency syndrome (AIDS). GSK3036656 is a compound with a novel mechanism of action under development for the treatment of tuberculosis. It suppresses protein synthesis in MTB by selectively inhibiting the enzyme Leucyl t-ribose nucleic acid (RNA) synthetase. Thus, this study will investigate the early bactericidal activity, safety and tolerability of GSK3036656 in up to four sequential cohorts of subjects with rifampicin-susceptible tuberculosis. The primary objective of this dose-escalation study is to establish the anti-tuberculosis effect of GSK3036656 on serial colony forming units (CFU) counts of MTB in sputum over 14 days of therapy. Subjects in each cohort will be randomized in 3:1 ratio to one of two treatments: either GSK3036656 or standard-of-care (RIFAFOUR® e-275) regimen. The approximate duration of the study for an individual subject will be 5 weeks, including 1 week of screening, 2 weeks of treatment period and another 2 weeks of final follow-up visit. RIFAFOUR e-275 is a registered trademark of Sanofi-Aventis.

Detailed description:

Arms: arm 1: All participants will receive a standard-of-care therapy (rifafour e-275) tablet, orally, once daily from Day 1 to Day 14. Participants will receive the standard treatment for tuberculosis (i.e. rifafour e-275 or equivalent generic alternative) once the study treatment (Day 1 to Day 14) is completed. arm 2: Participants will receive a loading dose of GSK3036656 3 milligram (mg), capsule, orally on Day 1, followed by maintenance dose of GSK3036656 1 mg, orally, once daily from Day 2 to Day 14. arm 3: Participants will receive a loading dose of GSK3036656 15 mg, capsule, orally on Day 1, followed by maintenance dose of GSK3036656 5 mg, orally, once daily from Day 2 to Day 14. arm 4: Participants will receive a loading dose of GSK3036656 30 mg, capsule, orally on Day 1, followed by maintenance dose of GSK3036656 15 mg, orally, once daily from Day 2 to Day 14. arm 5: Participants will receive a loading dose of GSK3036656 75 mg, capsule, orally on Day 1, followed by maintenance dose of GSK3036656 30 mg, orally, once daily from Day 2 to Day 14.
Interventions: intervention 1: GSK3036656 intervention 2: Rifafour e-275
Intervention descriptions: intervention 1: GSK3036656 will be administered intervention 2: Rifafour e-275 will be administered

Protocol documents:
Prot_000.pdf: 
TMF-13331420  
CONFIDENTIAL 
 
GlaxoSmithKline group of companies 
 
201214 
 
1 
 
TITLE PAGE 
Protocol Title: A Phase IIa open-label trial to investigate the early bactericidal activity, 
safety and tolerability of GSK3036656 in participants with drug-sensitive pulmonary 
tuberculosis. 
Protocol Number: 201214 / Amendment 05  
Short Title: GSK3036656 EBA Study 
Compound 
Number: 
GSK3036656  
 
Sponsor Name and Legal Registered Address:  
GlaxoSmithKline Research & Development Limited 
980 Great West Road 
Brentford 
Middlesex, TW8 9GS 
UK 
Medical Monitor Name and Contact Information can be found in the Study Reference 
Manual 
Approval Date: 12-MAY-2021 
 
 
 
 
 
 
 
 
 
 
Copyright 2021 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.


TMF-13331420 
CONFIDENTIAL 
 
 
 
201214 
 
2 
 
SPONSOR SIGNATORY: 
Protocol Title: A Phase IIa open-label trial to investigate the early bactericidal activity, 
safety and tolerability of GSK3036656 in participants with drug-sensitive pulmonary 
tuberculosis. 
Protocol Number: 201214 /Amendment 05  
Compound 
Number: 
GSK3036656  
 
 
 
 
 
Dr Alison Webster 
Head, Global Health Clinical 
 
Date 
The signed page is a separate document. 
 
 
 
 
 
 
Medical Monitor Name and Contact Information [can be found in the Study 
Reference Manual] 
 
 


TMF-13331420 
CONFIDENTIAL 
 
 
 
201214 
 
3 
 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
DOCUMENT HISTORY 
Document 
Date 
DNG Number 
Amendment 5 
12-MAY-2021 
TMF-13331420 
Amendment 4 
17-FEB-2021 
TMF-11820616 
Amendment 3 
24-JUL-2019 
2017N332005_03 
Amendment 2 
24-SEP-2018 
2017N332005_02 
Amendment 1 
20-FEB-2018 
2017N332005_01 
Original Protocol 
09-FEB-2018 
2017N332005_00 
 
Amendment 5: 12-MAY-2021  
Overall Rationale for the Amendment:  
Variability in the rate of change of log10CFU observed in the trial to-date is lower than 
anticipated. Due to this, and slower than anticipated recruitment, the study sample size 
has been re-calculated. The potential to modify the haemoglobin exclusion and stopping 
criteria in subsequent cohorts investigating lower doses of GSK3036656 has been added. 
Further changes made to the protocol are detailed in the table below. 


TMF-13331420 
CONFIDENTIAL 
 
 
 
201214 
 
4 
 
Section # 
Description of Change 
Brief Rationale 
Section 1 
Synopsis 
Changed from: 
“Up to 5 cohorts; 20 participants in each cohort 
(15 participants will receive GSK3036656, and 5 
participants will receive SoC in each cohort).” 
 
To: 
“Up to 5 cohorts; 12-20 participants in each 
cohort (9-15 participants will receive 
GSK3036656, and 3-5 participants will receive 
SoC in each cohort).” 
Updated to reflect changes in 
number of participants due to 
sample size re-calculations 
 
 
Section 3.3.1 
Risk 
Assessment  
 
 
Changed from: 
“Participants whose haemoglobin drops below 
pre-specified limits (<8.0 g/dL) will be withdrawn 
from the study (Section 8.1.3).” 
 
To: 
“Participants whose haemoglobin drops below 
pre-specified limits will be withdrawn from the 
study (Section 8.1.3).” 
Removed specific value 
(<8.0 g/dL) as cross reference to 
Section 8.1.3 provides further 
information 
Section 5.1 
Overall Design 
Changed from: 
"The study will comprise up to 5 cohorts of 
participants. It is intended that 15 participants 
in each cohort will receive GSK3036656 and 5 
will receive standard-of-care regimen for 
DS-TB (i.e. Rifafour e-275 or equivalent generic 
alternative)." 
 
To: 
"The study will comprise up to 5 cohorts of 
participants. It is intended that 9-15 participants 
in each cohort (dependent on the cohort) will 
receive GSK3036656 and 3-5 will receive 
standard-of-care regimen for DS-TB (i.e. Rifafour 
e-275 or equivalent generic alternative), with a 
randomisation ratio of 3:1" 
Updated to reflect changes in 
number of participants due to 
sample size re-calculations 
Section 5.1 
Overall Design 
Changed from: 
"Cohorts will proceed sequentially starting A 
through D" 
 
To: 
"Cohorts will proceed sequentially starting A 
through E" 
Corrected to align with study 
design of up to 5 cohorts 


TMF-13331420 
CONFIDENTIAL 
 
 
 
201214 
 
5 
 
Section # 
Description of Change 
Brief Rationale 
Section 5.1 
Overall Design 
Changed from: 
"It is anticipated that it may be necessary to 
administer a dose of GSK3036656 the same or 
lower than in a previous cohort, dependent on 
preliminary safety, tolerability and 
pharmacokinetic data" 
 
To: 
"It is anticipated that it may be necessary to 
administer a dose of GSK3036656 the same or 
lower than in a previous cohort, dependent on 
preliminary safety, tolerability, pharmacokinetic 
or efficacy data" 
Corrected to align with text in 
Section 11, Dose Escalation. 
Section 5.3 
Number of 
Participants  
Changed from: 
"Up to 20 participants will be enrolled into each 
cohort." 
 
To: 
"It is intended that 12- 20 participants will be 
enrolled into each cohort, dependent on the 
cohort." 
Updated to reflect changes in 
number of participants due to 
sample size re-calculations 
Section 5.3 
Number of 
Participants 
Changed from: 
"If participants prematurely discontinue the study, 
additional replacement participants may be 
recruited at the discretion of the Sponsor in 
consultation with the Investigator." 
 
To: 
"If participants prematurely discontinue the study, 
or if their respiratory sputum cultures are 
contaminated, additional replacement 
participants may be recruited at the discretion of 
the Sponsor in consultation with the 
Investigator." 
 
The primary endpoint for this 
study is derived from respiratory 
sputum cultures. If sputum 
cultures are contaminated, 
critical data for study analysis 
could be lost  


TMF-13331420 
CONFIDENTIAL 
 
 
 
201214 
 
6 
 
Section # 
Description of Change 
Brief Rationale 
Section 6.1 
Inclusion Criteria 
Changed from: 
"6. Ability to produce an adequate volume of 
sputum as estimated from an overnight sputum 
collection sample (estimated 10 ml or more). 
(Estimated from a spot sputum sample and 
confirmed with the first overnight collection. If 
less than 10 ml is collected overnight this may be 
repeated once)." 
 
To: 
"6. Ability to produce an adequate volume of 
sputum as estimated from an overnight sputum 
collection sample (estimated 10 mL or more). (If 
less than 10 mL is collected overnight this may 
be repeated once)." 
A random spot sputum sample 
does not provide a good 
estimation of a participant’s 
ability to produce at least 10 mL 
sputum compared to a 16-hour 
overnight collection period, thus 
this sentence has been removed 
Section 6.2 
Exclusion 
Criteria  
Changed from: 
"13. Participants with the following abnormal 
laboratory values at screening as graded by 
the enhanced Common Terminology Criteria for 
Adverse Events (CTCAE v 5 2017): 
 
a. haemoglobin <10.0 g/dL;" 
 
 
To: 
"13. Participants with the following abnormal 
laboratory values at screening as graded by the 
enhanced Common Terminology Criteria for 
Adverse Events (CTCAE v 5 2017): 
 
a. haemoglobin <10.0 g/dL; this criterion may be 
adjusted following DEC review (see Section 11).”  
Cross reference to Section 11 
has been added and provides 
further details that the Dose 
Escalation Committee are 
empowered to make regarding 
haemoglobin exclusion criteria 
Section 8.1.3 
Haematology 
Stopping Criteria 
Changed from: 
"A reduction in haemoglobin to below 8.0 g/dL" 
 
 
To: 
"A reduction in haemoglobin to below 8.0 g/dL; 
this criterion may be adjusted following DEC 
review (see Section 11)." 
Cross reference to Section 11 
has been added and provides 
further details that the Dose 
Escalation Committee are 
empowered to make regarding 
haemoglobin stopping criteria 


TMF-13331420 
CONFIDENTIAL 
 
 
 
201214 
 
7 
 
Section # 
Description of Change 
Brief Rationale 
Section 9.1 
Microbiological 
Efficacy/Activity 
Assessments 
The following text was added: 
"MIC data reporting will likely occur after the 
clinical database has been authorised for the 
primary and secondary efficacy and safety 
endpoints at the end of the study (i.e. after 
Database Freeze [DBF]). The report detailing the 
data will remain as a separate report and will not 
be included in the GSK clinical study report." 
The lab conducting microbiology 
assessments are in the process 
of validating the EUCAST liquid 
MIC protocol which will be used 
to determine the MIC. The lab 
will require additional time to 
validate the EUCAST MIC 
protocol, so the MIC data will be 
reported outside of the clinical 
study report 
Section 9.4 Vital 
Signs 
Changed from: 
"Vital signs (to be taken before blood collection 
for laboratory tests) will consist of at least 1 pulse 
and blood pressure measurement. Where a 
measurement is abnormal or significantly 
different from previous measurements, this will 
be repeated. Where BP and pulse is repeated 
above, a further 2 readings recorded at least 1 
min apart will be obtained for confirmation and 
recorded in the CRF." 
 
To: 
"Vital signs (to be taken before blood collection 
for laboratory tests) will consist of at least 1 pulse 
and blood pressure measurement. Where a 
measurement is abnormal or significantly 
different from previous measurements, a further 
2 readings will be taken. When vital signs are 
measured in triplicate, values should be taken at 
least 1 minute but not more than 5 minutes apart 
and recorded in the CRF." 
Updated to specify window for 
repeat vital signs, as 
documented in the Study 
Reference Manual 
Section 10.1 
Sample Size 
Determination 
Details of Sample Size Re-estimation added 
(Section 10.1.2) and separated from Original 
Sample Size Calculations (Section 10.1.1) 
Variability in the rate of change 
of log10CFU observed in the trial 
to-date is lower than anticipated. 
Due to this, and slower than 
anticipated recruitment, the study 
sample size has been re-
calculated. 


TMF-13331420 
CONFIDENTIAL 
 
 
 
201214 
 
8 
 
Section # 
Description of Change 
Brief Rationale 
Section 10.3.1 
Activity/ 
Pharmacokinetic 
Analyses 
For the analysis of the primary endpoint, EBA 
CFU0−14, and the secondary endpoints, EBA 
CFU0−2, EBA CFU2−14, EBA TTP0−14, EBA TTP0−2 
and EBA TTP2−14, the covariates to be included 
in the mixed model have been changed from 
dose and baseline value, to treatment, day, BMI 
and treatment-by-day     
A repeated measures analysis, 
including day as a covariate is 
more appropriate for measuring 
the rate of change over the 
treatment period. Dose has been 
replaced by treatment, with data 
for participants receiving 
standard-of-care included, and 
BMI has been added due to it’s 
potential influence on the EBA 
endpoints. 
Section 11 Dose 
Escalation  
Changed from: 
"PK data in at least 10 subjects receiving 
GSK3036656 and selected safety data from all 
subjects in a cohort." 
 
 
To: 
"PK data in at least 7 subjects receiving 
GSK3036656 and selected safety data from all 
subjects in a cohort" 
Based on the PK variability 
observed in the first two Cohorts, 
a sample size of 7 will give at 
least 80% power in the derivation 
of key PK parameters with an 
acceptable precision. 
Section 11 Dose 
Escalation 
Changed from: 
"The primary endpoint may be analysed for all 
available cohorts after the final visit of the last 
subject on the second consecutive cohort that 
reaches or exceeds the target PK plasma 
exposure for efficacy (based on the murine 
infection model), and subsequent cohorts." 
 
 
To: 
"The primary endpoint may be analysed once 
data is available for 12 evaluable subjects, as per 
the sample size re-estimation calculations, on the 
second consecutive cohort that reaches or 
exceeds the target PK plasma exposure for 
efficacy (based on the murine infection model), 
and subsequent cohorts." 
Updated to reflect changes in 
number of participants due to 
sample size re-calculations 


TMF-13331420 
CONFIDENTIAL 
 
 
 
201214 
 
9 
 
Section # 
Description of Change 
Brief Rationale 
Section 11 Dose 
Escalation  
The following text was added: 
"To adjust the haemoglobin exclusion and 
stopping criteria if no haematological 
abnormalities are observed in the review of 
safety data from the highest dose cohort (Cohort 
3).  For the subsequent cohort(s) receiving a 
lower dose of GSK3036656, the haemoglobin 
exclusion criterion will be lowered to <8.0g/dL, 
and the haemoglobin stopping criterion will be 
lowered to <6.0g/dL. Patients with a confirmed 
haemoglobin <8.0g/dL after randomisation will 
require enhanced observations, with a repeat 
haemoglobin level and discussion of patient 
status with the GSK medical monitor." 
A high number of screen fails 
have occurred due to 
haemoglobin levels being slightly 
lower than the current exclusion 
criteria (<10.0 g/dL), which is a 
common characteristic in this 
study population.  


TMF-13331420  
CONFIDENTIAL 
 
 
 
201214 
 
10 
 
TABLE OF CONTENTS 
PAGE 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ..................................... 3 
1. 
SYNOPSIS ............................................................................................................. 12 
2. 
SCHEDULE OF ACTIVITIES (SOA) ....................................................................... 15 
3. 
INTRODUCTION .................................................................................................... 19 
3.1. 
Study Rationale .......................................................................................... 19 
3.2. 
Background ................................................................................................ 19 
3.3. 
Benefit/Risk Assessment ............................................................................ 20 
3.3.1. 
Risk Assessment ......................................................................... 21 
3.3.2. 
Benefit Assessment ..................................................................... 30 
3.3.3. 
Overall Benefit:Risk Conclusion ................................................... 30 
4. 
OBJECTIVES AND ENDPOINTS ........................................................................... 31 
5. 
STUDY DESIGN .................................................................................................... 32 
5.1. 
Overall Design ............................................................................................ 32 
5.2. 
Study Schematic ......................................................................................... 33 
5.3. 
Number of Participants ............................................................................... 33 
5.4. 
Participant and Study Completion ............................................................... 33 
5.5. 
Scientific Rationale for Study Design .......................................................... 34 
5.6. 
Dose Justification ........................................................................................ 34 
6. 
STUDY POPULATION ........................................................................................... 36 
6.1. 
Inclusion Criteria ......................................................................................... 36 
6.2. 
Exclusion Criteria ........................................................................................ 37 
6.3. 
Lifestyle Restrictions ................................................................................... 38 
6.3.1. 
Meals and Dietary Restrictions .................................................... 38 
6.3.2. 
Caffeine, Alcohol, and Tobacco ................................................... 38 
6.3.3. 
Activity ......................................................................................... 39 
6.4. 
Screen Failures........................................................................................... 39 
7. 
TREATMENTS ....................................................................................................... 39 
7.1. 
Treatments Administered ............................................................................ 40 
7.2. 
Method of Treatment Assignment ............................................................... 41 
7.3. 
Preparation/Handling/Storage/Accountability .............................................. 41 
7.4. 
Treatment Compliance ................................................................................ 42 
7.5. 
Concomitant Therapy.................................................................................. 42 
8. 
DISCONTINUATION CRITERIA ............................................................................. 42 
8.1. 
Discontinuation of Study Treatment ............................................................ 43 
8.1.1. 
Liver Chemistry Stopping Criteria ................................................ 43 
8.1.2. 
QTc Stopping Criteria .................................................................. 44 
8.1.3. 
Haematology Stopping Criteria .................................................... 44 
8.2. 
Individual/Cohort Stopping Criteria.............................................................. 44 
8.3. 
Trial Stopping Criteria ................................................................................. 45 
8.4. 
Withdrawal from the Study .......................................................................... 45 
8.5. 
Lost to Follow Up ........................................................................................ 45 


T M F -1 3 3 3 1 4 2 0  
C O N FI D E N TI A L  
 
 
 
2 0 1 2 1 4  
 
1 1  
 
9.  
S T U D Y A S S E S S M E N T S A N D P R O C E D U R E S  ..................................................... 4 6  
9. 1.  
Mi cr o bi ol o gi c al Effi c a c y/ A cti vit y A s s e s s m e nt s  ............................................ 4 6  
9. 2.  
A d v er s e E v e nt s ........................................................................................... 4 7  
9. 2. 1.  
Ti m e P eri o d a n d Fr e q u e n c y f or C oll e cti n g A E a n d S A E 
I nf or m ati o n ................................................................................... 4 8  
9. 2. 2.  
M et h o d of D et e cti n g A E s a n d S A E s  ............................................. 4 8  
9. 2. 3.  
F oll o w -u p  of A E s a n d S A E s  ......................................................... 4 8  
9. 2. 4.  
R e g ul at or y R e p orti n g R e q uir e m e nt s f or S A E s  ............................. 4 8  
9. 2. 5.  
C ar di o v a s c ul ar a n d D e at h E v e nt s  ................................................ 4 9  
9. 2. 6.  
Pr e g n a n c y  ................................................................................... 4 9  
9. 3.  
Tr e at m e nt of O v er d o s e  ............................................................................... 4 9  
9. 4.  
S af et y A s s e s s m e nt s  ................................................................................... 5 0  
9. 4. 1.  
P h y si c al E x a mi n ati o n s  ................................................................. 5 0  
9. 4. 2.  
Vit al Si g n s  .................................................................................... 5 0  
9. 4. 3.  
El e ctr o c ar di o gr a m s  ...................................................................... 5 0  
9. 4. 4.  
E c h o c ar di o gr a m s  ......................................................................... 5 1  
9. 4. 5.  
Cli ni c al S af et y L a b or at or y A s s e s s m e nt s  ...................................... 5 1  
9. 5.  
P h ar m a c o ki n eti c s  ....................................................................................... 5 2  
9. 6.  
P ot e nti al S urr o g at e Di s e a s e/ Bi o m ar k er s  .................................................... 5 2  
..................................... 5 2  
..................................... 5 3  
9. 7.  
I n ci d e nt al fi n di n g s ....................................................................................... 5 4  
1 0.  S T A TI S TI C A L C O N SI D E R A TI O N S  ........................................................................ 5 4  
1 0. 1.  S a m pl e Si z e D et er mi n ati o n  ........................................................................ 5 4  
1 0. 1. 1.  
Ori gi n al S a m pl e Si z e C al c ul ati o n  ................................................. 5 4  
1 0. 1. 2.  
S a m pl e Si z e R e -e sti m ati o n  .......................................................... 5 6  
1 0. 2.  P o p ul ati o n s f or A n al y s e s  ............................................................................ 5 8  
1 0. 3.  St ati sti c al A n al y s e s  ..................................................................................... 5 8  
1 0. 3. 1.  
A cti vit y/ P h ar m a c o ki n eti c A n al y s e s  ............................................... 5 8  
1 0. 3. 2.  
S af et y A n al y s e s  ........................................................................... 6 0  
1 0. 3. 3.  
Ot h er A n al y s e s  ............................................................................ 6 1  
1 0. 3. 4.  
Effi c a c y A n al y s e s  ......................................................................... 6 1  
1 1.  D O S E E S C A L A TI O N  ............................................................................................. 6 1  
1 2.  R E F E R E N C E S  ....................................................................................................... 6 3  
1 3.  A P P E N DI C E S  ........................................................................................................ 6 5  
1 3. 1.  A p p e n di x 1: A b br e vi ati o n s a n d Tr a d e m ar k s  ................................................ 6 5  
1 3. 2.  A p p e n di x 2: E B A d efi niti o n s  ........................................................................ 6 7  
1 3. 3.  A p p e n di x  3: Cli ni c al L a b or at or y T e st s  ......................................................... 6 8  
1 3. 4.  A p p e n di x 4: St u d y G o v er n a n c e C o n si d er ati o n s  .......................................... 7 0  
1 3. 5.  A p p e n di x 5: A d v er s e E v e nt s: D efi niti o n s a n d Pr o c e d ur e s f or 
R e c or di n g, E v al u ati n g, F oll o w -u p, a n d R e p orti n g  ....................................... 7 4  
1 3. 6.  A p p e n di x  6: C o ntr a c e pti v e G ui d a n c e a n d C oll e cti o n of Pr e g n a n c y 
I nf or m ati o n .................................................................................................. 8 0  
1 3. 7.  A p p e n di x 7: Li v er S af et y: R e q uir e d A cti o n s a n d F oll o w -u p 
A s s e s s m e nt s  .............................................................................................. 8 3  
1 3. 8.  A p p e n di x 8: R A DI A TI O N D O S E  ................................................................. 8 7  
1 3. 9.  A p p e n di x 9: Pr ot o c ol A m e n d m e nt Hi st or y  ................................................... 8 8  
 
C CI


TMF-13331420  
CONFIDENTIAL 
 
 
 
201214 
 
12 
 
1. 
SYNOPSIS 
Protocol Title: A Phase IIa open-label trial to investigate the early bactericidal activity, 
safety and tolerability of GSK3036656 in participants with drug-sensitive pulmonary 
tuberculosis. 
Short Title: GSK3036656 EBA Study 
Objectives and Endpoints: 
Objectives 
Endpoints 
Primary 
• 
To determine the early bactericidal 
activity of GSK3036656 over 14 days 
of once daily repeat dosing. 
 
• Rate of change in log10CFU per mL direct 
respiratory sputum samples over the 
period baseline to Day 14 (EBA CFU0–14). 
Secondary 
• To assess the safety and tolerability of 
GSK3036656 administered once daily 
over 14 days to participants with 
tuberculosis. 
 
• To characterise the pharmacokinetics 
of 14-day once daily dosing of 
GSK3036656 in tuberculosis 
participants. 
 
 
 
 
• To determine the early bactericidal 
activity of GSK3036656 over the first 2 
days and the last 12 days with 14 
days of once daily repeat dosing. 
 
 
• Adverse events (AE), clinical laboratory 
values, vital signs, electrocardiogram 
(ECG) parameters. 
 
 
• Derived pharmacokinetic parameters for 
GSK3036656 including area under the 
plasma drug concentration versus time 
curve (AUC0–t, AUC0–24), maximum 
observed plasma drug concentration 
(Cmax), and time to maximum observed 
plasma drug concentration (tmax), as 
appropriate.  
 
 
• Rate of change in log10CFU per mL direct 
respiratory sputum samples over the 
period baseline to Day 2 (EBA CFU0-2). 
• Rate of change in log10CFU per mL direct 
respiratory sputum samples over the 
period Day 2 to Day 14 (EBA CFU2-14). 
• Rate of change in time to sputum culture 
positivity (TTP) over the time period 
baseline to Day 14 (EBA TTP0-14). 
 


T M F -1 3 3 3 1 4 2 0  
C O N FI D E N TI A L  
 
 
 
2 0 1 2 1 4  
 
1 3  
 
O bj e cti ve s  
E n d p oi nt s  
•  R at e of c ha n ge i n ti me t o sput u m c ultur e 
p osit ivity ov er t h e ti me p erio d b aseli n e to 
D ay 2 ( E B A T T P 0 -2). 
•  R at e of c ha n ge i n ti me t o sput u m c ultur e 
p ositivity ov er t h e  ti m e p erio d Day 2 t o 
D ay 1 4  (E B A T T P 2 -14). 
 
E x pl or at or y  
 
 
 
  
F or t he p ur p os e of ass ess me nt of bacterial  
 e n d p oi nts, t he pre -tr eat me nt 
baseli ne will be defi n e d as t he mea n of Da y – 2 a n d Da y – 1 ; if data is a v aila ble at o nl y 
Da y – 2 or Da y – 1  t he n t h at val ue will be use d as b aseli ne. F or E C G e n d p oi nts, baseli ne is 
scree ni n g. 
 
 
O ver all Desi g n:  
A si n gle -ce ntr e, o pe n-l a b elle d, cli nical trial i n u p t o fi ve se q ue ntial c o h orts of par tici pa nts 
wit h rifa m pici n-s usce pti ble t u berc ul osis ( D S-T B) . Eac h c o h ort will i n v ol ve partici pa nts  
bei n g ra n d o mise d t o o ne of t w o p ossi ble treat me nt s: eit her G S K 3 0 3 6 6 5 6 or Sta n dar d-of -
care ( S o C) re gi me n f or D S -T B ( i.e. Rifaf o ur  e-2 7 5  or e q ui vale nt ge n eric a lter nati ve). T h e 
rati o of partici pa nts  assi g ne d t o G S K 3 0 3 6 6 5 6 vs Rifaf o ur e-2 7 5 ( or e q ui vale nt ge neri c 
alter nati ve) will be 3: 1.  
T he starti n g d os e is set at 5  m g o nce dail y  ( wit h a 1 5 m g l oa di n g d ose o n da y 1) gi ve n 
orall y  a n d the st u d y will e m pl o y d ose escal ati o n, w here t he d os e f or eac h c o h ort will be 
deci de d bas e d o n re vi e ws of preli mi nar y safet y, t olera bilit y a n d p h ar mac o ki netic data.  
T h is i ncl u des t he p ossi bilit y of s u bse q u e nt  d ose s b ei n g less t ha n or t he sa m e as a 
prece di n g d os e, if a p pr o priate.   
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After the initial dose of GSK3036656, the decision to proceed to each subsequent dose 
level will be made by the Dose Escalation Committee (DEC) based on safety, tolerability 
and preliminary pharmacokinetic data from the prior cohort. The DEC may also include 
efficacy data in their deliberations, if that is available. 
Number of Participants: up to approximately 100 participants will be enrolled. 
Treatment Groups and Duration: Up to 5 cohorts; 12-20 participants in each cohort 
(9-15 participants will receive GSK3036656, and 3-5 participants will receive SoC in 
each cohort). 
The approximate duration of the study for an individual participant is anticipated to be 5 
weeks to include a maximum of 1 week for screening, 2 days of baseline sputum sample 
collection, 2 weeks for the treatment period and another 2 weeks for the final follow-up 
visit.


TMF-13331420  
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15 
 
2. 
SCHEDULE OF ACTIVITIES (SOA) 
Period 
Screening 
Dosing 
Follow-up 
Visit 
1 
2 
3 
4 
5 to 10 
11 
12 to 16 
17 
18 
Early 
Withdrawal 
19 
Day 
(-9 to -
3) A 
-2B 
-1 
1 
2 to 7C 
8 
9 to 13C 
14 
15 
28 
( 
7) 
Documentation of Positive GeneXpert and/or 
TB smear (TB clinic/site of initial diagnosis) 
X 
 
 
 
 
 
 
 
 
 
 
Written Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Demography (including smoking history) 
X 
 
 
 
 
 
 
 
 
 
 
Medical & Treatment History 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion/Eligibility Assessment 
X 
 
 
 
 
 
 
 
 
Chest X-ray 
X 
 
 
 
 
 
 
 
 
 
Physical ExaminationD 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs E 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-Lead ECG  
X 
 
 
 
 
 
 
X 
X 
X 
RandomisationM 
 
X 
 
 
 
 
 
 
 
 
Echocardiogram (may be conducted at any of 
the screening visits) 
X 
 
 
 
 
 
 
XS 
XS 
Blood PKF 
 
 
 
 
 
 
XF 
X 
X 
X 
 
Spot Sputum (confirm TB & adequate bacterial 
load) G 
X 
 
 
 
 
 
 
 
 
 
 
Rifampicin Resistance Test (rapid)G 
(microscopy and GeneXpert tests may be 
repeated on an overnight sputum sample if 
needed) 
X 
 
 
 
 
 
 
 
 
 
 
Haematology, Clinical Chemistry, Urinalysis H 
X 
 
 
X 
X 
X 
 
X 
 
X 
X 
Cardiac safety biomarkersT 
X 
X 
X 
 
 
X 
 
 
 
Urine Drug ScreenI 
X 
XI 
 
 
 
 
 
 
 
 
 


T M F -1 3 3 3 1 4 2 0  
C O N FI D E N TI A L  
 
 
 
2 0 1 2 1 4  
 
1 6  
 
P eri o d  
Scr e e ni n g  
D o si n g  
F oll o w -u p  
Vi sit  
1  
2  
3  
4  
5 t o 1 0  
1 1  
1 2 t o 1 6  
1 7  
1 8  
E arl y 
Wit h dra w al  
1 9  
D a y  
(-9 t o -
3) A  
-2 B  
-1  
1  
2 t o 7 C  
8  
9 t o 1 3 C  
1 4  
1 5  
2 8  
( 
7)  
 
 
 
 
 
 
 
 
 
 
HI V T est (a n d C D 4 C o u nt  if HI V c o nfir m e d) 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
X  
X  
 
 
X  
 
X  
 
 
 
 
X  
X  
 
 
X  
 
X  
 
 
X  
 
 
 
 
X  
 
 
H os pit al A d missi o n  
X B  
X B  
 
 
 
 
 
 
 
 
 
Ov er ni g ht S p ut u m L 
X  
X  
X  
X  
X  
X  
X  
X  
 
 
 
I P A d mi nistr ati o n a n d C o m pli a nc e C h eck N  
 
 
 
X  
X  
X  
X  
X  
 
 
 
Myc o b act eri ol o gy Ass ess m e nts O  
 
X  
X  
 
 
 
 
X  
 
 
 
H os pit al Disc h ar g e  
 
 
 
 
 
 
 
 
X  
X  
 
C o nc o mit a nt M e dic ati o n  
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
A dv ers e Ev e nts P  
 
 
 
X  
X  
X  
X  
X  
X  
X  
X  
P oi nt of C ar e Bl o o d Gl uc os e or H b A 1c Q  
 
X  
 
 
 
 
X  
 
 
A.  T h e Visit 1  ( d ay -9 t o -3) ti m e p eri o d will b e u p t o a m axi m u m of 7 d ays b ut will b e k e pt as s h ort as p ossi bl e.  
B.   P artici p a nts c a n pr oc e e d wit h t h e Visit 2 ( d ay -2) ass ess m e nts as s o o n as t h eir Visit 1 ( d ay -9 t o -3) ass ess m e nts h av e b e e n c o m pl et e d i. e. Visits 1 a n d 2  m ay occ ur o n t h e s a m e 
d ay as l o n g as t h e scr e e ni n g r es ults ar e av ail a bl e i n t i m e f or r a n d o misati o n . Partici p a nts m ay b e h os pit alis e d d uri n g t h e e ntir e pr e -tr e at m e nt p eri o d if t h e I nv esti g at or c o nsi d ers it 
a dvis a bl e f or r e as o ns of s af ety or c o m pli a nc e.  
C.  All  ev e nts list e d as occ urri n g o n Visit 5 ( d ay 2) t o Visit 1 0 ( d ay 7) a n d Visit 1 2 ( d ay 9) t o Visit 1 6 ( d ay 1 3) will b e c o n d uct e d  e ac h d ay d uri n g t h es e  visits.  
D.  H ei g ht ( m) will o nly b e c oll ect e d o nc e at Visit 1 ( d ay -9 t o -3). A f ull p hysic al ex a mi n ati o n will  b e p erf or m e d at Visit 1 ( d ay -9 t o -3), wit h sy m pt o m -dir ect e d p hysic al ex a mi n ati o ns at 
Visit 1 7 ( d ay 1 4), Visit 1 9 ( d ay 2 8) a n d E arly Wit h dr a w al  Visit ( E W V) .  Sy m pt o m dir ect e d p hysic al ex a mi n ati o ns m ay b e c o n d uct e d as r e q uir e d d uri n g t h e st u dy (visits 4 to 1 6).   
R e q uir e m e nts f or t h e p hysic al ex a mi n ati o n ar e s p ecifi e d i n t h e S R M.  
E.  Syst olic bl o o d pr ess ur e ( S B P) a n d di ast olic bl o o d pr ess ur e ( D B P) ( m m H g), h e art r at e ( b e ats p er mi nut e [ b p m]), b o dy t e m p er at ur e (° C) , r es pir at ory r at e ( br e at h es p er mi n ut e) a n d 
w ei g ht (k g). T o b e p erf or m e d wit hi n 4  h o urs pri or t o t h e first d aily d osi n g o n Visit 4 ( d ay 1) t hr o u g h t o Visit 1 7 ( d ay 1 4) a n d wit hi n 4  h o urs b ef or e t h e ti m e d osi n g w o ul d h av e 
occ urr e d o n Visit 1 8 ( d ay 1 5). O n d ays w h er e t h e f oll o wi n g ass ess m e nts ar e d o n e t h e or d er s h o ul d b e: vit al si g ns b ef or e bl o o d  dr a ws f or P K or s af ety ass ess m e nts.  
F.  P Ks will b e p erf or m e d as n ot e d i n t h e P K t a bl e. A si n gl e pr e -d os e P K s a m pl e will b e c oll ect e d o n e ac h of D ays 1 2 & 1 3, a n d s eri al P K bl o o d s a m pli n g will occ ur o n D ay 1 4 (s e e 
P K t a bl e b el o w). At E W V  a P K s a m pl e will b e t ak e n b ef or e  t h e ti m e of t h e pl a n n e d d aily d osi n g.  If t his is n ot p ossi bl e, a s p o nt a ne o us  P K s a m pl e will b e t ak e n. 
C CI


T M F -1 3 3 3 1 4 2 0  
C O N FI D E N TI A L  
 
 
 
2 0 1 2 1 4  
 
1 7  
 
G.  S p ut u m s m e ar m icr osc o py a n d m ol ec ul ar r a pi d t est f or c o nfir m ati o n of Myc o b act eri u m t u b erc ul osis a n d rif a m pici n s usc e pti bility ( G e n e X p ert). If t h e first s p ot s p ut u m or ov er ni g ht 
s p ut u m s a m pl e s h o ws a n u nf av o ur a bl e r es ult, t h e tests m ay b e r e p e at e d o n a fr es hly c oll ect e d s p ot s p ut u m or ov er ni g ht s p ut u m s a m pl e a n d t h at r es ult us e d  i nst e a d. 
H.  ). R ef er t o A p p e n dix  3  f or d et ails. 
I. 
Uri n e dr u g  scr e e n: c oc ai n e, a m p h et a mi n es a n d o pi at es. Uri n e dr u g scr e e n c a n b e r e p e at e d at Visit 2 ( d ay -2) f or p artici p a nts w h o w er e n ot h os pit aliz e d at Visit 1 ( d ay -9 t o -3). 
J. 
K.  
L.  
Ov er ni g ht s p ut u m s a m pli n g m ay st art at Scr e e ni n g visit ( d ay -9 t o -3)  or o n Visit 2 ( d ay – 2) a n d will c o nti n u e d aily u ntil Visi t 7 ( d ay 4). A d diti o n al s a m pli n g will b e c o n d uct e d at v isit 
9 ( d ay 6), Visit 1 1 ( d ay 8), Visit 1 3 ( d ay 1 0), Visit 1 5 ( d ay 1 2) a n d Visit 1 7 ( d ay 1 4). S p ut u m s a m pli n g will st o p o n t h e m or ni n g of Visit 1 8 ( d ay 1 5). S p ut u m c oll ecti o n will st art i n t h e 
aft er n o o n s at 1 5: 0 0  h o urs  (1 h o ur)  a n d c o nti n u e f or 1 6 h o urs ov er ni g ht. T h e 1 6 -h o ur s p ut u m s a m pli n g f or e ac h of t h e s a m pli n g d ays m ust b e fi nis h e d pri or t o t h e a d mi nistr ati o n 
of t h e n ext d ay’s I P.  
Ov er ni g ht s p ut u m c oll ecti o n m ay b e c oll ect e d as m a ny ti m es as r e q uir e d ov er t h e scr e e ni n g p eri o d u ntil a n eli gi bl e s a m pl e is o bt ai n e d . Of t h e pr e -tr e at m e nt p eri o d s a m pl es 
c oll ect e d, o nly t h e Visit 2 ( d ay -2) a n d Visit 3( d ay -1) ov er ni g ht s p ut u m s a m pl es will b e us e d f or t h e effic acy e n d p oi nt t ests.  
T h e d ay s p ut u m c oll ecti o n st arts r efl ects t h e d ay t o w hic h t h at s a m pl e a p pli es. e. g. a s a m pl e w h os e c oll ecti o n st arts o n d ay 1 a n d e n ds o n d ay 2, is  d esi g n at e d as t h e d ay 1 
ov er ni g ht s p ut u m s a m pl e ( a n d r es ults).  
M.  R a n d o miz ati o n m ay occ ur o nc e all t h e scr e e ni n g r es ults ar e av ail a b l e a n d t h e I nv esti g at or h as d et er mi n e d t h at t h e p artici p a nt is eli gi bl e f or t h e tri al.  
N.  Aft er t h e first d os e of I P, s u bs e q u e nt d os es of I P will b e a d mi nist er e d 2 3 t o 2 5 h o urs aft er t h e pr evi o us d os e.  
O.  Mi ni m u m i n hi bit ory c o nc e ntr ati o n ( MI C) a n d s p eci ati o n of  t h e i nf ecti n g or g a nis m by p oly m er as e c h ai n r e acti o n ( P C R) will b e esti m at e d fr o m a c ult ur e c oll ect e d o n a pr e-tr e at m e nt 
d ay ( d ay -1 or d ay -2) a n d f r om t h e l ast av ail a bl e c ult ur e o n a tr e at m e nt d ay ( d ay 1 4 or e arli er, b ut n ot e arli er t h a n d ay 8).  Dr u g s usc e pti bility t esti n g of M. t u b erc ul osis  f or s e nsitivity 
t o rif a m pici n wit h a m ol ec ul ar m et h o d will b e t est e d at Visit 1.  Susc e pti bility t o I N H, Rif, E M B a n d P Z A will b e t est e d o n a c ult ur e gr o w n fr o m a b as eli n e s a m pl e ( d ay -2 or d ay -1).  
T h e a n aly sis of a ny  b act eri al is ol at es  s e nt t o G S K, S p ai n f or f urt h er c h ar act eris ati o n i n t h e ev e nt of MI C c h a n g e will n ot b e r e p ort e d i n t h e cli nic al st u dy r e p ort  a n d  will b e r e p ort e d 
s e p ar at ely.  
P.  A dv ers e ev e nts ( A E) will b e c oll ect e d by t h e I nv esti g at or fr o m t h e ti m e a p artici p a nt r ec eiv es his/ h er first d os e of I P t hr o u g h t o t h e Visit 1 9 ( d ay 2 8) F oll o w u p Visit. 
Q.  
R.  [ n ot us e d] 
S.  O nly t o b e p erf or m e d o n p artici p a nts as d et er mi n e d by t h e  d os e esc al ati o n c o m mitt e e  (D E C ) or o n p artici p a nts wit h c h a n g es i n cli nic al st at us w arr a nti n g a f oll o w -u p ec h o i n t h e 
o pi ni o n of t h e i nv esti g at or . T h e D E C  m ay d eci d e t o p erf or m t his ass ess m e nt i n a d diti o n al c o h orts wit h i n t his st u dy. 
T.  S a m pl es will b e ass ay e d f or: Tr o p o ni n I . T h e first t w o s a m pl es at l e ast 2 4 h o urs a p art, o n e d uri n g t h e scr e e ni n g p h as e a n d o n e pri or t o t h e first d os e of st u dy tr e at m e nt. D ay 1 4 
s a m pl e wi n d o w is  ± 2 4 h o urs.  T hir d s a m pl e t o b e t ak e n o n D ay 3.  
 
C CI
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TMF-13331420  
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18 
 
PK sampling time and events table 
STUDY VISIT  
Visit 15 
Visit 16 
Visit 17 
Visit 18 
STUDY DAY 
Day 12 
Day 13 
Day 14 
Day 15 
STUDY HOURB  
 
 
0 
0.5 
1 
1.5 
2 
3 
4 
6 
8 
12 
24 
Pharmacokinetic 
samplingC 
XA 
XA 
XD 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
A.  Sample to be taken within 30 minutes pre-dose. 
B. All values are relative to the time of day that the study treatment is administered on Day 14. 
C. PK sampling is only to be performed on participants receiving GSK3036656. PK samples will not be taken from participants receiving Rifafour e-275 (or equivalent generic 
alternative). 
D. Sample to be taken within 10 minutes pre-dose 
 
PK Sample timing window allowances 
Sample timepoint 
Sample collection window allowed 
Pre dose  
Not applicable (see footnotes above) 
0h - 4h post  
  5 min 
> 4h – 12h post 
 15 min 
> 12h – 24h post 
 1 h 
 
 


TMF-13331420  
CONFIDENTIAL 
 
 
 
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19 
 
3. 
INTRODUCTION 
3.1. 
Study Rationale 
This trial seeks to establish the antituberculosis effect of GSK3036656 on serial CFU 
counts of Mycobacterium tuberculosis (Mtb) in sputum over 14 days of therapy. 
The assessment of the early bactericidal activity (EBA) of antituberculosis agents in 
sputum over the first 2 weeks of treatment is the established method for the early clinical 
evaluation of new antituberculosis agents and regimens [Jindani, 1980]. The primary 
endpoint of EBA studies is the daily rate of change in colony forming units (CFU) of Mtb 
in sputum (measured as log10CFU/mL sputum/day) or the prolongation of time to 
positivity (TTP) in liquid culture (measured in hours/day) in participants with smear-
positive pulmonary tuberculosis (TB). This approach potentially provides an indication 
whether a novel treatment has antituberculosis properties in humans and gives an early 
indication of the dosage required. Pharmacokinetic analyses offer the opportunity to 
study the relationship between dosages, serum drug levels, and efficacy. Preliminary 
safety and tolerability data can also be collected for the duration of the treatment 
[Donald, 2003; Diacon, 2011a]. 
Additional details related to rationale for the study design appears in Section 5.5. 
3.2. 
Background 
TB remains a concerning health problem, with Mtb now causing more deaths than 
HIV/AIDS. Six countries in Africa and Asia accounted for the majority of the 10.4 
million new TB cases reported in 2015 (WHO, 2016a). The current long-standing first-
line antituberculosis agents are relatively ineffective in controlling the TB epidemic in 
high-burden countries. Treatment takes 6-9 months to complete and is associated with 
side effects resulting in poor compliance which leads to treatment failure and an 
increased likelihood of developing drug-resistance.  
Drug-resistant TB poses a major threat to control of the TB epidemic. The prevalence of 
multi drug-resistant TB (MDR: resistance to at least isoniazid and rifampicin) and 
extensively drug-resistant (XDR: MDR plus resistance to at least a fluoroquinolone and 
an injectable antituberculosis drug) continues to increase. In 2015, an estimated 580 000 
new cases qualified for MDR-TB treatment and incident cases of XDR-TB, 
approximately 10% of patients with MDR-TB, were reported in more countries, 
including Eastern Europe and India (WHO, 2016a).  
The treatment of DR-TB remains sub-optimal due to constraints such as availability of 
drugs, duration (9−24 months, including a daily injectable in the initial phase), and 
significant toxicities leading to poor compliance and an increased risk of developing 
further drug-resistance. The new 9-month regimen for MDR-TB recently proposed by the 
WHO is optimising the use of currently known substances but only a minority of MDR 
cases are likely to qualify for it (WHO, 2016b). Despite the lengthy duration, DR-TB 
treatment is only successful in around half of MDR- and less than a third of XDR-TB 
cases, further escalating the threat to global health.  


TMF-13331420  
CONFIDENTIAL 
 
 
 
201214 
 
20 
 
The development of new drug combinations that are effective against drug-resistant 
strains of Mtb, and that have the potential to shorten the duration of TB treatments offers 
the hope of tackling the TB pandemic. The addition of promising new drugs such as 
moxifloxacin, bedaquiline [Rustomjee, 2008; Diacon, 2009; Diacon, 2013], delamanid 
[Diacon, 2011b], PA-824 [Diacon, 2010; Diacon, 2012], new oxazolidinone candidates 
[Wallis, 2014; Furin, 2016] for M/XDR-TB is an important step in that direction. 
However, questions remain related to their best possible use in combination regimens.  
A new treatment regimen requires at least three different drugs to which no clinical 
resistance exists. However, potential antagonism in humans between drugs [Mdluli, 
2009], for instance PA-824 and bedaquiline, and the additive potential for significant 
toxicity e.g. QTc prolongation of moxifloxacin [Bloomfield, 2008], bedaquiline 
[Matteelli, 2010], limit the number of possible combinations. This highlights the need for 
the development of additional new chemical entities that strike an appropriate balance 
between antituberculosis activity and safety profiles, a balance that will enable new 
future drug combinations that make the optimal use of previously-developed entities. 
GSK3036656 is a compound with a novel mechanism of action under development for 
the treatment of TB. It suppresses protein synthesis in Mtb by selectively inhibiting the 
enzyme Leucyl t-RNA synthetase. 
There is no known circulating resistance to GSK3036656, and GSK3036656 is active 
against both drug-sensitive and drug-resistant strains of Mtb when screened in a variety 
of in vitro and in vivo animal models. The MIC is low (MIC90 of 0.16 M against a 
panel of clinical isolates) and the drug shows potent activity in animal models, resulting 
in a very low predicted efficacious human dose for GSK3036656 (10 mg, Section 5.6). In 
vitro data show that the risk of drug-drug interactions with GSK3036656, either as 
perpetrator or victim, is low. These factors make GSK3036656 a very attractive candidate 
for the treatment of tuberculosis.  
A description of the chemistry, nonclinical and clinical data generated to date for 
GSK3036656 is provided in the Investigator’s Brochure (IB). 
3.3. 
Benefit/Risk Assessment 
Consistent with GlaxoSmithKline guidance for early phase studies, GSK3036656 will be 
administered in an in-patient setting (with sufficient overnight facilities) with appropriate 
monitoring. 
 
Summaries of findings from non-clinical and first time in human (FTIH) clinical studies 
conducted with GSK3036656 can be found in the IB. The following section outlines the 
risk assessment and mitigation strategy for this protocol. 
More detailed information about the known and expected benefits and risks and 
reasonably expected adverse events of GSK3036656 may be found in the IB. 
 


TMF-13331420  
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21 
 
3.3.1. 
Risk Assessment 
 
Potential Risk of Clinical Significance  
Summary of Data/Rationale for Risk 
Mitigation Strategy  
Investigational Product (IP) GSK3036656 
Reduction in red blood cell count 
Non-Clinical 
In a 4-week rat study (doses 3, 10 & 30 mg/kg/d) -  
dose-dependent decline in reticulocytes (by up to 
52% in males and 62% in females) at day 7 followed 
by normal levels by day 14 and increased levels by 
day 29/30 compared to controls. Hgb levels 
decreased by 10-13% compared to controls on day 
14 and day 29/30. 
In a 4 week dog study (doses 5, 10 & 20 mg/kg/d) -  
mild dose-dependent decrease in Hgb on day 14 (by 
about 10% compared to controls) with recovery by 
week 4. Reticulocyte counts unaffected. Dogs not 
bled on day 7. 
No histopathological changes in bone marrow or 
other relevant histopathology in the 4-week studies. 
Clinical 
In the 201040 study, a possible trend of decreased 
haemoglobin from baseline to follow-up was noted in 
aggregate haematology data.  The mean change 
 
Standard safety haematology and clinical 
chemistry assessments will be performed and 
both trends and changes outside normal range 
will be monitored as part of laboratory safety 
assessments. 
 
Participants whose haemoglobin drops below 
pre-specified limits will be withdrawn from the 
study (Section 8.1.3). 
 
 


TMF-13331420  
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Potential Risk of Clinical Significance  
Summary of Data/Rationale for Risk 
Mitigation Strategy  
from baseline to follow-up was -4.9 g/L in the 15 mg 
repeat dose cohort, compared to -1.5 g/L in the 
placebo group. None of the values hit potential 
clinical importance (PCI) criteria, and declines were 
not clinically relevant. 
No clinically significant trends in reticulocyte values 
were observed, and there were no values of potential 
clinical importance reported for reticulocytes. 
GSK3036656 is cleared through the 
kidneys 
The main route of clearance for GSK3036656 is 
renal and there is therefore a risk that participants 
with low creatinine clearance will accumulate 
GSK3036656 and exceed predefined exposure 
limits.  
Participants with a creatinine clearance less 
than 75 mL/min have been excluded.  
Reduction in white blood cell count 
Non-Clinical 
In the 4-week rat study, decrease of up to 37% in 
total leucocyte count on day 29/30 compared to 
controls. 
In the 4-week dog study, no reported effects on white 
blood cells. 
Clinical 
No clinically significant trends in leukocyte or 
neutrophil count values were observed. Two subjects 
White blood cell count will be monitored as part 
of laboratory safety assessments. Any clinically 
significant changes will be followed up until 
levels are not clinically significant. 
 
Participants developing neutrophil counts 
<500/mm3 (1.0x109/L) will be withdrawn from 
the study (Section 8.1.3). 


TMF-13331420  
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Potential Risk of Clinical Significance  
Summary of Data/Rationale for Risk 
Mitigation Strategy  
showed PCI values. One subject had low neutrophil 
count (normal range 1.57-6.81 × 10^9/L) from 
screening (1.38) until follow-up (1.41), and also 
showed low leukocyte count (normal range 3.3-9.8 × 
10^9/L) on Day 4 (2.5), Day 10 (2.6) and Day 14 
(2.9) and was within normal range at follow-up. Given 
the low screening values, this observation was 
considered likely related to the subject’s Black or 
African American race. A second subject had a 
single low neutrophil count at follow-up (1.48). 
 
Heart valvular and vascular pathology 
Non-Clinical 
In a 7-day dog dose range finding (DRF) study – 
minimal focal subendocardial hemorrhage on the 
atrial surface of the left atrioventricular valve 
observed in both animals at the top dose of 60 
mg/kg/d. 
In a 10-day dog investigative study at 65 mg/kg/d – 
vascular lesions (including minimal focal necrosis 
and inflammatory infiltrate) in 3 out of 8 dogs. 
In the 4-week dog GLP study - no heart or valve 
changes were observed up to the top dose of 20 
 
This pathology is not monitorable in humans. 
To avoid risk to study participants, dosing will be 
limited to doses at which individual exposures 
do not exceed AUC0-24 and Cmax to 
15µg.hr/mL and 1.5µg/mL respectively. 
These exposures are 10-fold below the lowest 
NOAEL achieved in the 17 week studies (rat)  
In addition, although the pathology is not 
monitorable in humans, echocardiograms will be 
performed for all participants at screening and, 
for subjects receiving the highest dose of 
GSK3036656 or whose clinical status warrants 


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Potential Risk of Clinical Significance  
Summary of Data/Rationale for Risk 
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mg/kg/day and there was no increase in 
inflammatory markers.  
In the 17 week GLP dog study there were no heart or 
valve changes up to the top dose of 45mg/kg/day. 
 
In the 17 week rat study there were no changes in 
cardiac pathology up to the top dose of 30mg/kg/day.  
 
Valvular or vascular pathology were not observed in 
rats. This pathological change is not commonly seen 
in animals, and its mechanism and significance to 
humans are not clear. A correlation between the 
presence of hemodynamic changes and the 
presence of this pathology is suspected, but currently 
unproven. 
Clinical 
Echocardiograms were performed at screening and 
follow up in the 201040 FTIH study in order to 
exclude participants with pre-existing valve or other 
cardiac abnormalities from the study, and to detect 
the presence of abnormalities after completion of the 
study.  No abnormalities were detected. 
No SAEs, or AEs of cardiovascular nature were 
reported.  There was no change from baseline in 
it, also at follow-up (or early withdrawal). 
Cardiac troponin will be measured. 
  


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Potential Risk of Clinical Significance  
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Mitigation Strategy  
heart rate observed at any dose.  No trends in blood 
pressure change were observed.  Cardiac telemetry 
and echocardiogram-related interpretations were 
within normal range.  There were no clinically 
significant ECG observations.  There were no 
troponin I abnormalities in participants after receiving 
study drug. 
 
Hemodynamic changes 
Non-Clinical 
Hemodynamic changes in several studies at ≥100 
mg/kg in rats and ≥20 mg/kg in dogs - increased 
heart rate (rats and dogs), increased (rats) or 
decreased (dogs) blood pressure. 
Clinical 
Data from the 201040 FTIH study showed no 
significant changes in vital signs assessments during 
the study, and no clinically significant changes in 
ECG or telemetry assessments including QTc and 
PR intervals. 
 
Vital signs monitoring will be implemented in 
this study. 


T M F -1 3 3 3 1 4 2 0  
C O N FI D E N TI A L  
 
 
 
2 0 1 2 1 4  
 
2 6  
 
P ot e nti al Ri sk of Cli ni c al Si g nifi c a n ce  
S u m m ar y of D ata/ R ati o n ale f or Ri s k  
Miti g ati o n Str at e g y  
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T M F -1 3 3 3 1 4 2 0  
C O N FI D E N TI A L  
 
 
 
2 0 1 2 1 4  
 
2 7  
 
 
D ev el o p m ent of b act eri al r esist a nc e to 
G S K 30 3 66 56 . 
A d mi nistr ati o n of G S K3 0 366 5 6 as a m o n ot h er apy 
c o ul d p ote nti ally l ea d to th e d ev el op m e nt of 
r esist a nc e t o th e co m p ou n d i n M . t u b erc ul osis d urin g  
t h e co urs e of th e stu dy. 
T h e risk of d ev elo p m e nt of r esist a nc e i n th e 
E B A m on oth er a py st udy is c o nsi d er ed to b e l o w 
b as ed o n i n -vitr o dat a with G S K 30 3 66 56 a n d 
hist oric al ex perie nc e wit h E B A st udi es i n 
g e ner al. Susc e ptibility t esti ng o n s a m pl es of M . 
t u b erc ulosis fr o m p articip a nts will b e c o nd ucte d 
a n d ass ess ed as p art of th e st u dy t o m onit or f or 
t h e d ev elo p m e nt of r esist a nc e t o G S K3 0 36 6 56. 
I n-vitr o d at a i ndic at es t hat resist a nc e t o 
G S K 30 3 66 56 d o es n ot co nfer a ny cli nic ally 
si g nific a nt cross r esist anc e t o S o C 
a ntit u b erc ul ar tre at m en t 
Ski n d epi g m e nt ati on  
N o n -Cli ni c al  
I n a 1 7 we ek  d o g t oxic ol ogy st u dy ( dos es 0, 6, 20 & 
4 5 m g/k g  / d ay): l oss of pig m e nt ati on o n th e ey eli ds, 
 
T h e d ur ati on of d osi ng i n t his st u dy ( 14 d ays) is 
s h ort er th a n th at use d i n t he d o g t oxic ol ogy 
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Mitigation Strategy  
nose or muzzle of all animals at 45 mg/kg/day group 
(week 17 AUC0–t mean 405 µg.h/mL) and most 
animals in the 20 mg/kg/day group (week 17 AUC0–t 
176 µg.h/mL). PNL-2 (a melanocyte marker) 
immunohistochemistry staining demonstrated 
moderate cytoplasmic positivity in a population of 
cells in the basal region of the epidermis (interpreted 
to be melanocytes). The decreased pigmentation 
was therefore not associated with a loss of 
melanocytes in affected animals on 
immunohistochemistry. Depigmentation was not 
observed in the 0 or 6 mg/kg/day group (59.4 
ug/h/mL). Depigmentation was not observed in the 
two previous 4 week dog toxicology studies up to 
45 mg/kg/day (week 4 AUC0-t. 388 ug.h/mL) 
Clinical 
No adverse events were reported in the 201040 FTIH 
study that would be considered consistent with 
depigmentation. 
study and the maximum exposure (AUC0-24) has 
been capped at 15 ug.h/mL (4-fold margin to the  
mg/kg/day dose).  
The physical examination of study participants 
will include visual examination of the skin. 
Participants with vitiligo will be excluded from 
the study to avoid confounding skin assessment 
at baseline and follow-up physical examinations. 
Teratogenicity of GSK3036656 
Non-clinical safety 
Preliminary results from the definitive rat embryo-
fetal toxicology are as follows: 
60mg/kg/day: Reductions in fetal viability and 
reduced fetal weights, with minimal reductions in 
 
Women will be excluded from recruitment to this 
study. 


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Mitigation Strategy  
body weight gains and malformations including 
ventricular septal defects (13 animals across 8 litters) 
and cleft palates (10 animals/6 litters). 
20mg/kg/day: Reduced fetal weights and incidences 
of ventricular septal defects (2 animals across 2 
litters) that were outside the historical control data in 
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3.3.2. 
Benefit Assessment 
Mouse models predict efficacy at human equivalent exposures consistent with the upper 
doses being tested. Nevertheless, efficacy of GSK3036656 has not been demonstrated in 
humans and no benefit can be expected from receiving the compound over the 2-week 
course of the study, and as monotherapy. A significant proportion of people with TB fail 
treatment (~15% with drug-sensitive up to ~80% with XDR). New effective compounds 
with novel mechanisms of action are urgently needed for TB, and it is recognised as a 
priority area by the WHO. The results of this study will establish whether GSK3036656 
has activity, tolerability and safety adequate to take into subsequent studies of longer 
duration with the intention of developing a medicine for TB with a novel mechanism of 
action that could form part of a new combination treatment regimen for TB. 
A delay of treatment with the full standard regimen of 14 days is not expected to have an 
adverse impact on the ultimate cure of TB in these participants, and this approach has 
been used as part of recent successful TB drug development programs (Diacon, 2011b, 
Diacon, 2013). Participants in this study will have their TB infection carefully 
characterized and drug sensitivity profiles established.  
Participants will remain under constant medical attention and will be housed and 
monitored in hospital from admission through the duration of the treatment period; this 
will allow the continuous monitoring of the health conditions of each participant, any of 
whom can be withdrawn at any stage of the trial and removed from study treatment 
should his/her condition suggest to the Investigator that this would be in his/her best 
interest. Multiple blood samples will be taken for safety laboratory studies. Upon 
discharge, the participants will be given the initial doses of standard TB treatment and 
immediately referred to the national TB treatment program local TB clinic where they 
will receive a full course of standard treatment. At the follow-up visit it will be confirmed 
that this treatment has been initiated and is being continued. The Investigators’ primary 
responsibility is to ensure participant safety. 
3.3.3. 
Overall Benefit:Risk Conclusion 
The overall benefit-risk balance is considered to be favourable in light of the safety data 
of GSK3036656 from the FTiH study, the mitigation strategies used and the potential 
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4. 
OBJECTIVES AND ENDPOINTS 
Objectives 
Endpoints 
Primary 
• 
To determine the early bactericidal 
activity of GSK3036656 over 14 days 
of once daily repeat dosing. 
 
• Rate of change in log10CFU per mL direct 
respiratory sputum samples over the 
period baseline to Day 14 (EBA CFU0-14). 
Secondary 
• To assess the safety & tolerability of 
GSK3036656 administered once daily 
over 14 days to participants with 
tuberculosis. 
 
• To characterise the pharmacokinetics 
of 14-day once daily dosing of 
GSK3036656 in tuberculosis 
participants. 
 
 
 
 
• To determine the early bactericidal 
activity of GSK3036656 over the first 2 
days and the last 12 days with 14 
days of once daily repeat dosing. 
 
 
 
 
 
 
 
 
 
 
 
  
 
• Adverse events (AE), clinical laboratory 
values, vital signs, electrocardiogram 
(ECG) parameters. 
 
 
• Derived pharmacokinetic parameters for 
GSK3036656 including area under the 
plasma drug concentration versus time 
curve (AUC0−t, AUC0−24), maximum 
observed plasma drug concentration 
(Cmax), and time to maximum observed 
plasma drug concentration (tmax), as 
appropriate. 
 
 
• Rate of change in log10CFU per mL direct 
respiratory sputum samples over the 
period baseline to Day 2 (EBA CFU0-2). 
• Rate of change in log10CFU per mL direct 
respiratory sputum samples over the 
period Day 2 to Day 14 (EBA CFU2-14). 
• Rate of change in time to sputum culture 
positivity (EBA TTP) over the time period 
baseline to Day 14 (EBA TTP0-14). 
• Rate of change in time to sputum culture 
positivity over the time period baseline to 
Day 2 (EBA TTP0-2). 
• Rate of change in time to sputum culture 
positivity over the time period Day 2 to 
Day 14 (EBA TTP2-14). 
 


T M F -1 3 3 3 1 4 2 0  
C O N FI D E N TI A L  
 
 
 
2 0 1 2 1 4  
 
3 2  
 
O bj e cti ve s  
E n d p oi nt s  
E x pl or at or y  
 
 
F or t he p ur p os e of ass ess me nt of bacterial 
e n d p oi nts, t he pre -tr eat me nt 
baseli ne will be defi n e d as  t he mea n of Da y – 2 a n d Da y – 1; if data is a v aila ble at o nl y 
Da y – 2 or Da y – 1,  t he n t hat val ue will be use d as baseli ne. F or E C G e n d p oi nts, baseli ne 
is scree ni n g. 
 
 
5.  
S T U D Y D E SI G N  
5. 1.  
O v er all D e si g n  
T he st u d y will c o m prise u p t o 5  c o h orts of partici pa nts . It is i nte n de d t hat 9 -1 5 
partici pa nts  i n eac h c o h ort ( de pe n d e nt o n t he c o h ort) will recei v e  G S K 3 0 3 6 6 5 6 a n d 3 -5 
will  recei ve sta n d ar d-of -care re gi me n  f or D S-T B ( i.e. Rifaf o ur  e-2 7 5  or e q ui vale nt 
ge n eric alter nati ve ), wit h a ra n d o misati o n rati o of 3: 1. T here will be n o pla ce b o i n t his 
st u d y. T he st u d y will be  ra n d o mize d, b ut n ot bli n de d (i.e., it will be ‘ o pe n-l a bel’) wit h  
neit her partici pa nt  n or In vesti gat or bli n de d t o treat me nt.  St u d y p artici pa nts will re vert t o 
t he sta n dar d treat me nt f or T B (i. e. Rifaf o ur  e-2 7 5 or e q ui vale nt ge n eric alter nati ve ) o nce 
t he st u d y treat me nt ( Da y 1 t o Da y 1 4) has bee n c o m plete d. All la b orat or y staff i n v ol ve d 
i n a nal ysi n g a n d re p orti n g t he pri mar y a n d sec o n d ar y c ha n ge i n l o g1 0C F U  c o u nts a n d 
T T P  e n d p oi nts  res ults will be bli n de d  t o treat ment all ocati o n. C o h orts will pr ocee d 
se q ue ntiall y starti n g A t hr o u g h E , wit h preli mi nar y safet y, t olera bilit y a n d 
p har mac o ki netic d ata fr o m t he pre vi o us c o h ort re vie we d pri or t o selecti n g t he d ose f or 
t he ne xt c o h ort. 
It is a ntici pate d t hat it ma y be n ecessar y t o a d mi nister a d ose of G S K 3 0 3 6 6 5 6 t he sa me or 
l o wer t ha n i n a pre vi o us c o h ort, de pe n d e nt o n preli mi nar y safet y, t olera bilit y , 
p har mac o ki netic  or efficac y  data . 
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5.2. 
Study Schematic 
 
 
 
 
 
 
5.3. 
Number of Participants 
It is intended that 12- 20 participants will be enrolled into each cohort, dependent on the 
cohort. 
If participants prematurely discontinue the study, or if their respiratory sputum cultures 
are contaminated, additional replacement participants may be recruited at the discretion 
of the Sponsor in consultation with the Investigator. 
5.4. 
Participant and Study Completion 
A participant is considered to have completed the study if he/she has completed all 
phases of the study including the last visit (the ‘follow-up’ visit). A participant is 
considered to have completed the study treatment phase once they have received the final 
dose of study treatment on Day 14. 
The end of the study is defined as the date of the last visit of the last participant in the 
study. 
Following completion of the study treatment phase and after discharge from hospital the 
participants will be provided with their first dose/s of standard TB therapy (i.e. Rifafour 
SCREENING 
from -9 days 
prior to first 
dose 
14-Day treatment period – 
GSK3036656 
Day 15 
start/continue 
Rifafour*
1 
14-Day treatment period – 
Rifafour
1 
 
Follow-up at 
Day 28 
*This is not part of the study but is the post-study definitive treatment of TB. 
1Rifafour e-275 or equivalent generic alternative. 
CCI


T M F -1 3 3 3 1 4 2 0  
C O N FI D E N TI A L  
 
 
 
2 0 1 2 1 4  
 
3 4  
 
e-2 7 5  or e q ui v ale nt ge neric alter nati ve ) wit h a p pr o priate c o u nselli n g.  All p artici pa nts will 
be referre d t o t he l ocal c o m m u nit y T B cli nics t o r ecei ve t h e re mai n d er of a f ull c o urse of 
sta n dar d a ntit u berc ul osis c he m ot hera p y acc or di n g t o nati o nal g ui deli nes. T he partici pa nts 
will be pr o vi de d wit h a referral letter t o ta k e wit h t he m t o t he T B cli nic. Wit hi n a wee k of 
t he partici pa nt’s disc h ar ge fr o m t he st u d y cli nic, a f oll o w-u p call will be ma de b y t h e 
st u d y site staff t o t he T B cli nic t o deter mi ne if t he partici pa nt atte n de d t h e cli nic.  
5. 5.  
S ci e ntifi c R ati o n al e f or St u d y D e si g n  
E B A st u dies are c urre ntl y t he o nl y a v aila ble wa y of  assessi n g dr u g acti vit y a gai nst T B 
earl y i n d r u g de v el o p me nt. E B A is a s urr o gate efficac y e n d p oi nt ( decli ne of s p ut u m 
bacterial c o u nts ) w hic h all o ws t he esti mati o n of earl y dr u g effects  i n st u dies t hat are 
si g nifica ntl y s h orter t ha n st u dies usi n g defi niti ve cli nical e n d p oi nts (e. g., rel a pse-free 
c ure).
E B A has a n u m ber of well -rec o g nise d li mitati o ns [B ur ma n , 2 0 0 3 ], a n d alter nati ve 
s urr o gate e n d p oi nts are ur ge ntl y n ee de d. St u dies e val uati n g t he Mt b res p o nse t o t hera p y 
i n D S-T B s u bjects b y  
 ha ve alrea d y bee n re p orte d, t h o u g h at later ti me p oi nts, a n d 
a f urt her st u d y re p orti n g t he da y 1 4 res p o ns e has rece ntl y c o m plete d recr uit me nt.
D ose ra n gi n g is ne cessar y t o i n vesti gate t he relati o ns hi p bet wee n d ose/e x p os ure a n d 
effic ac y, a n d t o sel ect a n o pti mal d ose f or f urt her pr o gressi o n i nt o t he cli nic. D ue t o 
fi n di n gs of car di o vas c ular t o xicit y i n d o gs, it is rec o m me n de d t hat s yste mic e x p os ures t o 
G S K 3 0 3 6 6 5 6 i n h u ma ns d o n ot e x cee d cert ai n pre defi ne d li mits (see S ecti o n  5. 6 ). T h e 
P K of G S K 3 0 3 6 6 5 6 ha s o nl y bee n st u die d i n healt h y v ol u nteers a n d its P K i n T B 
partici pa nts  is u n k n o w n. T heref ore, t o mi ni mize t he ris k of e x cee di n g t he pre defi n e d 
e x p os ure li mits, a d ose escalati o n a p pr o ac h will b e use d w here t he starti n g d ose i n t he 
st u d y is l o wer t ha n d os es pre vi o usl y a d mi nistere d safel y t o healt h y v ol u nteers wit h 
s u bse q ue nt selecti o n of d oses base d o n P K a n d safet y res ults.  
T he Rifaf o ur e-2 7 5 ( or e q ui vale nt ge neric alter nati ve) treat me nt gr o u p is i n cl u de d as a 
be nc h mar k f or t he E B A q ua ntitati ve m yc o b acteri ol o g y a n d t o e val uate w het her H R Z E i n 
t his p o p ulati o n gi ves si milar E B A res ults t o t hat de m o nstrate d i n pri or st u dies wit h t his 
c o m bi nati o n.  A ne gati ve c o ntr ol ar m, w here s u bjects are left u ntreate d, w o ul d be 
u net hical d ue t o t he a v aila bilit y of  effecti ve treat m e nt a n d t he c o nse q u e nces of n ot 
treati n g T B. 
5. 6.  
D o s e J u stifi c ati o n  
A p o p ulati o n p har mac o ki netic m o del was de v el o pe d base d o n preli mi nar y c o nce ntr ati o n -
ti me data o btai ne d i n t he F TI H st u d y. T he m o d el was use d t o si m ulate l oa di n g a n d 
mai nte na nce d os es f or G S K 3 0 3 6 6 5 6 base d o n t he E B A st u d y desi g n a n d acc o u nti n g f or 
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the effect of renal impairment on exposure (preliminary data suggest GSK303656 is > 
70% renally excreted). A target exposure for efficacy of 1.74 ug.h/mL was set based on 
the exposure associated with efficacy in a mouse infection model and the target 
attainment rate was defined as the percentage of participants with an AUC0–24 greater 
than this target exposure. Exposure limits of AUC0–24 of 15 μg.h/mL and Cmax of 1.5 
ug/mL were set, based on information in Section 3.3. 
A loading dose of GSK3036656 may be administered on the first day (or over multiple 
days where required in order to not exceed AUC and Cmax exposure limits) of study 
treatment administration in each cohort. The long half-life of GSK3036656 (45 hours) 
means that subjects will take up to 10 days to reach steady-state concentrations, which is 
not optimal for a 14-day treatment study. A loading dose will allow participants to reach 
steady-state concentrations in 2 to 3 days for a given maintenance dose regimen.  
The probability rates for individual participants to exceed GSK3036656 exposure limits 
and achieve the efficacy target for proposed loading and maintenance dose regimens are 
shown in Table 1. 
Table 1 
Probability rates of individual participants for proposed loading and 
maintenance doses 
Loading Dose 
(mg)a 
Probability 
Day 1 c 
Maintenance 
Dose (mg)b 
probability 
Day 14d 
Target 
Attainment Ratee 
15 
<1% 
5 
<1% 
<1% 
25 
<1% 
10 
<1% 
100% 
50 
<1% 
20 
<1% 
100% 
75 
6.90% 
30 
5.80% 
100% 
a Day 1 
  
  
  
  
b Day 2-14 
  
cper trial probability of an individual participant exceeding the exposure limits 
[AUC0–24 = 15 ug.h/mL or Cmax = 1.5 ug/mL] on Day 1 (simulations based on a 
lower limit of 75 mL/min for creatinine clearance) 
d per trial probability of an individual participant exceeding the exposure limits 
[AUC0–24 = 15 ug.h/mL or Cmax = 1.5 ug/mL] on Day 14 (simulations based on a 
lower limit of 75 mL/min for creatinine clearance) 
e per trial probability of >90% of participants exceeding the target exposure for 
efficacy 
The starting dose regimen for this study will be 15 mg loading dose on Day 1 and 5 mg 
maintenance dose on Day 2-14, based on the above information, with the option to 


T M F -1 3 3 3 1 4 2 0  
C O N FI D E N TI A L  
 
 
 
2 0 1 2 1 4  
 
3 6  
 
i n vesti gate a l o wer d os e i n s u bse q ue nt c o h orts s h o ul d t he preli mi nar y data i n dicate t his is 
a p pr o priate. 
T he l oa di n g  d os e (if a p plic a ble) a n d m ai nte na nce d ose f or eac h c o h ort will be c h ose n o n 
t he basis t hat it is n ot pre dicte d t o e xcee d t he pre-s pecifie d safet y ca p, a n d t he d ose use d 
will be deci de d b y t he D ose Escalati o n C o m mittee ( Secti o n 1 1 ). 
6.  
S T U D Y P O P U L A TI O N  
Pr os pecti ve a p pr o val of pr ot oc ol de viati o ns t o recr uit me nt a n d e nr ol me nt  criteria, als o 
k n o w n as pr ot oc ol wai v ers or e x e m pti o ns, is n ot per mitte d.  
6. 1.  
I n cl u si o n Crit eri a 
Partici pa nts are eli gi ble t o be i ncl u de d i n t he st u d y o nl y if all  t he f oll o wi n g criteria a p pl y: 
A ge  
1.  Partici pa nt m ust be 1 8  t o 6 5  years of a ge i ncl usi ve, at t he ti me of si g ni n g t h e 
i nf or me d c o nse nt.  
2.  
T y pe of P artici p a nt a n d Dise ase C h ar acteristi cs  
3.  Ne w e pis o de of  u ntreate d, rifa m pici n -s usce pti ble p ul m o nar y T B. 
4.  A c hest X -ra y pict ure w hic h i n t he o pi ni o n of t he I n vesti gat or is c o nsiste nt wit h T B.  
5.  At least o ne s p ut u m sa m ple p ositi ve o n direct micr osc o p y f or aci d -fast bacilli (at 
least 1 + o n t he I U A T L D/ W H O scale) or m olec ular test ( X pert M T B/ Rif) wit h res ult 
of eit her me di u m or hi g h p ositi ve f or M T B  
6.  A bilit y t o pr o d u ce a n a de q uate v ol u me of s p ut u m as esti mate d fr o m a n o ver ni g ht 
s p ut u m c ollecti o n sa m ple (esti mate d 1 0 m L or m ore). (If less t ha n 1 0 m L is c ollecte d 
o ver ni g ht t his ma y be re p eate d o nce).  
7.  N or mal ec h o car di o gra m or ec h ocar di o gra m wit h n or mal left ve ntr ic ular f u ncti o n 
wit h at m ost trace t o mil d val v ular re g ur gitati o n is all o we d a n d n o val v ular ste n osis.  
8.  Wit hi n t he n or mal ra n ge f or t he assa y f or tr o p o ni n at scree ni n g.  
9.  A creati ni ne cleara nce ≥7 5  m L/ mi n  ( C oc kr oft-Ga ult f or m ula) . 
 
Wei g ht  
1 0.  B o d y wei g ht (i n li g ht cl ot hi n g a n d wit h n o s h oes) bet wee n 4 0 a n d 9 0 k g, i ncl usi ve , 
at scree ni n g. 
Se x  
1 1.  Male  
a.  M ale p artici p a nts:  
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T M F -1 3 3 3 1 4 2 0  
C O N FI D E N TI A L  
 
 
 
2 0 1 2 1 4  
 
3 7  
 
A male partici pa nt wit h f e male part n ers of c hil d -beari n g p ote ntial m ust a gree t o use 
c o ntrace pti o n as detaile d i n  Secti o n  1 3. 6  (A p pe n di x  6 ). 
I nf or me d C o nse nt 
1 2.  C a pa ble of gi vi n g si g n e d i nf or me d c o nse nt as d es cri be d i n A p pe n di x  3  w hic h 
i ncl u des c o m plia nce wit h t he re q uire m e nts a n d restricti o ns liste d i n t he i nf or me d 
c o nse nt f or m (I C F) a n d i n t his pr ot oc ol.  
 
6. 2.  
E x cl u si o n Crit eri a  
Partici pa nts are e x cl u de d fr o m t he st u d y if a n y of t he f oll o wi n g criteria a p pl y:  
1.  E vi de nce of a cli nicall y si g nifica nt (as j u d ge d b y t he In vesti gat or) c o n diti o n or 
a b n or malit y ( ot her t ha n t he i n dicati o n bei n g st u die d) t hat mi g ht c o m pr o mise safet y or 
t he i nter pretati o n of trial effic ac y or safet y e n d p oi nts.   
2.  P o or ge n eral c o n diti o n w here a n y d ela y i n treat me nt ca n n ot be t olerat e d per 
discreti o n of t he I n v esti gat or.  
3.  Cli nicall y si g nifica nt e vi de nce of e xtrat h oracic T B ( miliar y T B, a b d o mi nal T B, 
ur o ge nital T B, oste o art hritic T B, T B m e ni n gitis), as j u d ge d b y t he I n vesti gat or.  
4.  Q Tc F > 4 5 0  msec.  
5.  Hist or y of aller g y t o a n y of t he trial I P/s or relat e d s u bsta nces as c o nfir me d b y t he 
cli nical j u d ge m e nt of t he I n v esti gat or.  
6.  Partici pa nts wit h vitili g o.  
7.  C urre nt  alc o h ol or dr u g a b use, t hat is, i n t he o pi ni o n of t he I n vesti gat or, s ufficie nt t o 
c o m pr o mise t he safet y or c o o perati o n of t h e partici pa nt.  
8.  HI V i nfecte d partici p a nts : 
a. ha vi n g a C D 4 + c o u nt < 3 5 0 cells/ µ L;  
b.  or ha vi n g recei ve d a ntiretr o viral t hera p y me di cati o n wit hi n t he last 3 0 da ys;  
c. or ha vi n g recei ve d oral or i ntra ve n o us a ntif u n gal me dicati o n wit hi n t he last 3 0 
da ys;  
d.  or wit h a n AI D S -defi ni n g o p p ort u nistic i nfecti o n or mali g na nci es  [C D C , 1 9 9 3]  
i n t he last 1 2 m o nt hs (e xce pt p ul m o nar y T B).  
9.  P artici pate d i n ot her cli ni cal st u dies wit h i n vesti gati o nal a ge nts wit hi n 8 wee ks pri or 
t o t he first d osi n g da y i n t he c urre nt st u d y. 
1 0.  P artici pa nts  wit h dia betes ( T y p e 1 or 2), p oi nt of care H b A 1c a b o ve 6. 5  % , or ra n d o m 
gl uc ose o ver 1 1. 1 m m ol/ L  will be e x cl u de d  fr o m c o h orts u n der g oi n g 
 
C CI
C CI


T M F -1 3 3 3 1 4 2 0  
C O N FI D E N TI A L  
 
 
 
2 0 1 2 1 4  
 
3 8  
 
1 1.  Treat me nt r ecei v e d wit h a n y dr u g acti ve a gai nst Mt b (i ncl u di n g b ut n ot li mite d t o 
is o niazi d, et ha m b ut ol, fl u or o q ui n ol o nes, rifa m pici n), or wit h i m m u n os u p pressi ve 
me dicati o ns s uc h as T N F -al p ha i n hi bit ors or s yst e mic or i n hale d c ortic oster oi ds  ( use d 
f or > 5 c o ns ec uti ve da ys), wit hi n 2 wee ks pri or t o scree ni n g. Refer t o t he S R M f or 
details.  
1 2.  U na v oi da ble treat me nt wit h pr o hi bite d c o nc o mita nt me dicati o ns (see S R M)  
1 3.  Partici pa nts wit h t he f oll o wi n g a b n or mal la b orat or y v al ues  at scree ni n g as gra de d b y 
t he e n ha nce d C o m m o n Ter mi n ol o g y Criteri a f or A d verse E v e nts ( C T C A E  v 5 2 0 1 7 ): 
a. h ae m o gl o bi n < 1 0 . 0 g/ d L;  t his criteri o n ma y b e a dj uste d f oll o wi n g D E C 
re vie w (s ee Secti o n 1 1 ).  
b.  t hr o m b oc yt o pe ni a gra d e 2 or great er ( u n d er 5 0  × 1 0 9 cells/ L);  
c. ser u m p otassi u m gra de 2 or great er ( < 3. 0 m E q/ L); 
d.  as partate a mi n otra nsfe ras e ( A S T) gra de 3 ( ≥3. 0 ×  U L N) ; 
e. ala ni ne a mi n otra nsf e ras e ( A L T) gra de 3 ( ≥3. 0 ×  U L N) ; 
f. A P T T gra de 3  ( ≥2. 5 ×  U L N)  
g.  I N R gra de 3 ( ≥2. 5 ×  U L N)  
h.  T otal w hite cell c o u nt gra de 3  ( < 2. 0 × 1 0 9 cells/ L) 
 
1 4.  
 
6. 3.  
Lif e st yl e R e stri cti o n s   
6. 3. 1.  
M e al s a n d Di et ar y R e stri cti o n s  
•  
Refrai n fr o m c o ns u m pti o n of re d wi ne, Se ville ora n ges, gra pefr uit or gra pefr uit 
j uice, fr o m t he da y of start of st u d y tr eat me nt u ntil after t he fi nal d ose. 
•  
W ater is all o we d a d li bit u m.  
6. 3. 2.  
C aff ei n e, Al c o h ol, a n d T o b a c c o  
•  
D uri n g eac h d osi n g s essi o n, partici pa nts will a bstai n fr o m i n gesti n g caffei ne- or 
x a nt hi ne -c o ntai ni n g pr o d ucts (e .g ., c offee, tea, c ola dri n ks, a n d c h o c olate) f or 2 4 
h o urs  bef ore t he start of d osi n g u ntil after c ollecti o n of t he fi nal p har m ac o ki netic 
( P K) a n d/ or p har mac o d y na mic sa m ple. 
C CI


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• 
During each dosing session, participants will abstain from alcohol for 24 hours 
before the start of dosing until after collection of the final PK and/or 
pharmacodynamic sample.  
• 
Use of tobacco products will be strongly discouraged from screening until after the 
final follow-up visit. 
6.3.3. 
Activity 
• 
Participants will abstain from strenuous exercise for 48 hours before each blood 
collection for clinical laboratory tests. Participants may participate in light 
recreational activities during the study (e.g., watching television, reading). 
6.4. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study 
but are not subsequently randomised. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes 
demography, screen failure details, eligibility criteria, and any serious adverse events 
(SAEs). 
7. 
TREATMENTS 
Study treatment is defined as any investigational treatment(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according 
to the study protocol. 


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7.1. 
Treatments Administered 
Study Treatment 
Name: 
 
GSK3036656 
Rifafour e-275 (or equivalent 
generic alternative) 
Dosage 
formulation: 
 
Capsule 
Tablet 
Unit dose 
strength(s)/Dosage 
level(s): 
1 mg or 5 mg or 25 mg GSK3036656 
capsules 
(as free base equivalent) 
Standard dose: 
150/75/400/275 mg of 
Rifampicin, Isoniazid, 
Pyrazinamide and Ethambutol 
respectively per tablet 
Route of 
Administration  
Oral 
Oral 
Dosing 
instructions: 
 
Refer to study reference manual 
Refer to South African National 
TB Treatment Guidelines 
(including pyridoxine as 
required) 
Packaging and 
Labelling 
 
Study Treatment will be provided in 
HDPE bottles. Each HDPE bottle will 
be labelled as required per country 
requirement.  
Will be provided by the 
manufacturer. 
Manufacturer 
WuXi AppTec (1 and 5 mg capsules) 
Aptuit (25 mg capsule) 
Rifafour e-275: Sanofi-Aventis 
or appropriate alternative 
Equivalent Generic 
alternative to Rifafour e-275: 
Appropriate suppliers 
 


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Rifafour e-275 (or equivalent generic alternative). 
Some participants will be treated with standard, intensive phase pulmonary TB treatment 
as recommended in the SA National TB Treatment Guidelines to verify that the 
laboratory assays used measure the expected magnitude of activity. This is HRZE 
(Rifafour e-275 or equivalent generic alternative) (HRZE: H=isoniazid: R=rifampicin: 
Z=pyrazinamide: E=ethambutol). The Rifafour e-275 (or equivalent generic alternative) 
treatment group is included as a benchmark for the EBA quantitative mycobacteriology 
and to evaluate whether HRZE in this population gives similar EBA results to that 
demonstrated in prior studies using this combination. 
Rifafour e-275 (or equivalent generic alternative) Package Insert contains its known and 
potential risks and benefits. 
7.2. 
Method of Treatment Assignment 
On or prior to day 1, eligible participants will be assigned a unique number 
(randomization number) in ascending numerical order at the study site. The 
randomization number encodes the participant’s assignment to one of the two arms of the 
study (GSK3036656 or standard-of-care), according to the randomization schedule 
generated prior to the study by the Statistics Department at GSK, using validated internal 
software. Once a participant number has been assigned to a subject, it cannot be re-
assigned to another subject.  
7.3. 
Preparation/Handling/Storage/Accountability 
1. The Investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study treatment received and any discrepancies 
are reported and resolved before use of the study treatment. 
2. Only participants enrolled in the study may receive study treatment and only 
authorized site staff may supply or administer study treatment. All study treatments 
must be stored in a secure, environmentally controlled, and monitored (manual or 
automated) area in accordance with the labeled storage conditions with access 
limited to the Investigator and authorized site staff. 
3. The Investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study treatment accountability, reconciliation, and record 
maintenance (i.e., receipt, reconciliation, and final disposition records). 
4. Further guidance and information for the final disposition of unused study treatment 
are provided in the Study Reference Manual. 
• 
Under normal conditions of handling and administration, study treatment is not 
expected to pose significant safety risks to site staff. 
Precaution will be taken to avoid direct contact with the study treatment.  A Material 
Safety Data Sheet (MSDS) describing occupational hazards and recommended handling 
precautions will be provided to the Investigator. In the case of unintentional occupational 
exposure notify the monitor, Medical Monitor and/or GSK study contact. 


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7.4. 
Treatment Compliance 
• 
Individual doses for a participant will be prepared from a bulk supply, the 
preparation of the dose will be confirmed by a second member of the study site staff.  
• 
Participants are dosed at the site. They will receive study treatment directly from the 
Investigator or designee, under medical supervision.  The date and time of each dose 
administered in the clinic will be recorded in the source documents.  The dose of 
study treatment and study participant identification will be confirmed at the time of 
dosing by a member of the study site staff other than the person administering the 
study treatment.  Study site personnel will examine each participant’s mouth to 
ensure that the study treatment was ingested. 
7.5. 
Concomitant Therapy 
Any medication or vaccine (including over-the-counter or prescription medicines, 
vitamins, and/or herbal supplements) that the participant is receiving at the time of 
enrolment or receives during the study must be recorded along with: 
• 
reason for use 
• 
dates of administration including start and end dates 
• 
dosage information including dose and frequency 
The Medical Monitor should be contacted if there are any questions regarding 
concomitant or prior therapy. 
Participants must abstain from taking prescription or non-prescription drugs (including 
vitamins and dietary or herbal supplements) within 7 days (or 14 days if the drug is a 
potential enzyme inducer) or 5 half-lives (whichever is longer) before the start of study 
treatment until completion of the follow-up visit, unless, in the opinion of the Investigator 
and Sponsor, the medication will not interfere with the study. A list of prohibited and 
permitted concomitant medication is provided in the SRM. 
8. 
DISCONTINUATION CRITERIA 
If study treatment/investigational product is interrupted or stopped this does not 
automatically result in the participant being withdrawn from the study. The investigator 
will make all effort to retain the patient in the study, provided the participant continues to 
provide their consent,  and to complete and record all scheduled safety assessments 
required by the protocol. For the avoidance of all doubt: this does not prejudice the rights 
of the investigator and study participants under ICH GCP and under applicable laws. The 
study participant retains the right to withdraw consent at any time for any reason. The 
investigator also retains the right to withdraw the patients from the study if in the 
investigator’s judgement, withdrawal is judged clinically necessary to protect a 
participant’s safety. 
If this results in the patient being placed on standard of care (i.e. Rifafour e-275 or 
equivalent generic alternative), then all assessments relevant to Rifafour e-275 (or 
equivalent generic alternative) will be performed as directed by the protocol (for 


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example, GSK3036656 pharmacokinetic assessments are not required, since the 
participant is not being dosed with GSK3036656). 
8.1. 
Discontinuation of Study Treatment 
8.1.1. 
Liver Chemistry Stopping Criteria 
Liver chemistry stopping and increased monitoring criteria have been designed to assure 
participant safety and evaluate liver event etiology. An algorithm for liver chemistry 
stopping and increased monitoring criteria is provided below. In addition, further 
information is contained in Section 13.7. 
Discontinuation of study treatment for abnormal liver tests is also required when: 
• in the presence of abnormal liver chemistries not meeting protocol-specified 
stopping rules, the Investigator believes study treatment discontinuation is in the 
best interest of the participant.  
 
Phase II Liver Chemistry Stopping and Increased Monitoring Algorithm 
 


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8.1.2. 
QTc Stopping Criteria 
A subject that meets either bulleted criterion below will be withdrawn from the study.   
• QTcF >500 msec, 
• Change from baseline: increase in QTcF >60 msec 
Withdrawal of participants is to be based on an average QTcF value of triplicate ECGs. If 
an ECG demonstrates a prolonged QT interval, obtain two more ECGs over a brief period 
of time (less than 10 minutes) and then use the averaged QTcF values of the three ECGs 
to determine whether the subject should be discontinued from the study. 
8.1.3. 
Haematology Stopping Criteria 
IP will be discontinued for a subject if the following haematology stopping criteria are 
met (confirmed on two samples or at the discretion of the investigator in consultation 
with the medical monitor) and participants should be followed up until values are not 
clinically significant. 
• 
A reduction in haemoglobin to below 8.0 g/dL; this criterion may be adjusted 
following DEC review (see Section 11). 
• 
A reduction in neutrophil count to below 500/mm3 (0.5 × 109/L) 
8.2. 
Individual/Cohort Stopping Criteria 
For an individual study participant, stopping criteria include, but are not limited to: 
• Severe signs or symptoms, or significant changes in any of the safety assessments 
that put the safety of the individual at risk (e.g. ECG, vital signs, laboratory tests 
etc.), as judged by the Investigator, in consultation with the Medical Monitor if 
necessary. 
• Any unacceptable adverse event that is thought to be related to the investigational 
product and any general safety finding that, in the opinion of the Investigator, 
gives cause for concern may result in the withdrawal of subject(s) and/or the 
study being paused or terminated and/or a dose adjustment. 
Dose escalation will be stopped if any of the following occurs in a cohort: 
1. There is substantially increased incidence and/or severity of clinically significant 
adverse events or withdrawals possibly related to GSK3036656 in the GSK3036656 
treatment subgroup at the last dose level administered as compared to the SoC 
subgroup. The Dose Escalation Committee in conjunction with the study 
Investigator will determine the significance of the adverse events or withdrawals 
and make a decision about whether stopping further dose escalation is necessary.  
2. At least one subject has a plasma AUC0–24 or Cmax higher than the exposure limits 
set in Section 5.6. 
If dose escalation is stopped due to reasons 1 or 2 above occurring at the last dose, dosing 
at a lower level could be allowed by the Dose Escalation Committee. The Dose 


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Escalation Committee will decide whether dosing at such level could be done and will 
select the dose to be administered. 
Further details regarding dose escalation and the Dose Escalation Committee composition 
and remit are in Section 11. 
8.3. 
Trial Stopping Criteria 
The trial will be stopped if either of the following occurs: 
• A serious adverse event that is considered to be at least possibly related to 
GSK3036656 and is not commonly seen in participants with TB in one or more 
participants on active treatment. 
• Severe, clinically significant non-serious adverse events that are considered by the 
investigator and the GSK Medical Monitor to be at least possibly related to 
GSK3036656 and are not commonly seen in participants with TB in 2 or more 
participants on active treatment in the same cohort. 
If, following an internal safety review, it is appropriate to restart the trial with the 
protocol unchanged, the South African Health Products Regulatory Authority (SAHPRA) 
and Independent Ethics Committee (IEC) will be informed. If an amendment to the 
protocol is required, the trial will not restart until the new amendment has been approved 
by the regulatory agency and Independent Ethics Committee (IEC).  
The Dose Escalation Committee (DEC) is empowered to stop the study within the remit 
specified in Section 11. 
8.4. 
Withdrawal from the Study 
• 
A participant may withdraw from the study at any time at his/her own request, 
or may be withdrawn at any time at the discretion of the Investigator for safety, 
behavioural, compliance or administrative reasons. 
• 
If the participant withdraws consent for disclosure of future information, the 
Sponsor may retain and continue to use any data collected before the withdrawal 
of consent. 
• 
If a participant withdraws from the study, he/she may request destruction of any 
samples taken and not tested, and the Investigator must document this in the site 
study records. 
• 
Refer to the SoA for data to be collected at the time of follow-up and for any 
further evaluations that need to be completed. 
8.5. 
Lost to Follow Up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.  
The following actions must be taken if a participant fails to return to the clinic for a 
required study visit: 


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• 
The site must attempt to contact the participant and reschedule the missed visit 
as soon as possible and counsel the participant on the importance of maintaining 
the assigned visit schedule and ascertain whether or not the participant wishes to 
and/or should continue in the study. 
• 
Before a participant is deemed lost to follow up, the Investigator or designee 
must make every effort to regain contact with the participant (where possible, 3 
telephone calls or local equivalent methods). These contact attempts should be 
documented in the participant’s medical record. 
• 
Should the participant continue to be unreachable, he/she will be considered to 
have withdrawn from the study with a primary reason of lost to follow-up.  
9. 
STUDY ASSESSMENTS AND PROCEDURES 
• 
Study procedures and their timing are summarized in the SoA.  
• 
The timing and number of planned study assessments, including safety, 
pharmacokinetic, pharmacodynamic/biomarker assessments may be altered during 
the course of the study based on newly available data (e.g., to obtain data closer to 
the time of peak plasma concentrations) to ensure appropriate monitoring. 
• 
Any changes in the timing or addition of time points for any planned study 
assessments must be documented and approved by the relevant study team member 
and then archived in the Sponsor and site study files, but will not constitute a 
protocol amendment. The IRB/IEC will be informed of any safety issues that require 
alteration of the safety monitoring scheme or amendment of the ICF. 
• 
Protocol waivers or exemptions are not allowed.  
• 
Immediate safety concerns must be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or 
discontinue study treatment. 
• 
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct. 
• 
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The Investigator will maintain a screening 
log to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable.  
• 
Procedures conducted as part of the participant’s routine clinical management (e.g., 
blood count) and obtained before signing of ICF may be utilized for screening or 
baseline purposes provided the procedure met the protocol-specified criteria and was 
performed within the time frame defined in the SoA. 
9.1. 
Microbiological Efficacy/Activity Assessments 
The EBA CFU0-14 as determined by the rate of change in log10CFU per mL sputum over 
the period baseline to Day 14 which will be summarised and described with a statistical 
model as an estimated average decrease per day for participants in each group.  


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The EBA TTP0-14 as determined by the percentage rate of change in TTP per mL sputum 
over the period baseline to Day 14, which will be summarised and described with a 
statistical model as an estimated average increase per day for participants in each group. 
Drug activity with CFU or TTP over different treatment periods such as baseline - Day2, 
and Day2-14, for cross-comparison with other published data. Data will be displayed 
graphically, together with modelled estimates. 
For the purposes of the microbiological endpoints assessments, the pre-treatment baseline 
will be defined as the mean of Day -2 and Day -1; if data is available at only one of these 
timepoints then that value will be used as baseline, and data prior to Day −2 will not be 
used to calculate the mean at baseline.  
Mycobacterial Characterisation: 
The identifying organism will be confirmed as Mtb at least once by polymerase chain 
reaction (PCR) at screening (GeneXpert or Line Probe) and a sample collected before 
treatment will be submitted for culture confirmation. 
Drug susceptibility testing of Mtb for sensitivity to rifampicin with a molecular method 
will be tested at the screening visit (GeneXpert) to determine eligibility. Susceptibility to 
RIF, INH, PZA and EMB will be confirmed on a culture grown from a sample collected 
before treatment either by phenotypical testing or line probe.  
Cultures from baseline and from day 14 sputum will be kept for determination of the 
minimum inhibitory concentration (MIC) of the investigational agents that the subject 
was treated with. If a day 14 culture is not available, the last available culture after day 8 
will be kept. In the event of significant changes in the MIC, bacterial isolates will be sent 
to the GSK Spain laboratory for further characterisation. Technical details are provided in 
the SRM. MIC data reporting will likely occur after the clinical database has been 
authorised for the primary and secondary efficacy and safety endpoints at the end of the 
study (i.e. after Database Freeze [DBF]). The report detailing the data will remain as a 
separate report and will not be included in the GSK clinical study report. 
9.2. 
Adverse Events 
The definitions of an AE or SAE can be found in Appendix 5. The Common 
Terminology Criteria for Adverse Events (CTCAE) v5 2017 will be used to define AE 
grade and severity. 
The Investigator and any designees are responsible for detecting, documenting, and 
reporting events that meet the definition of an AE or SAE and remain responsible for 
following up AEs that are serious, considered related to the study treatment or the study, 
or that caused the participant to discontinue GSK3036656 (see Section 8).  


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9.2.1. 
Time Period and Frequency for Collecting AE and SAE 
Information 
• 
All SAEs will be collected from the start of treatment until the follow-up visit at 
the time points specified in the SoA (Section 2).  However, any SAEs assessed 
as related to study participation (e.g., study treatment, protocol-mandated 
procedures, invasive tests, or change in existing therapy) or related to a GSK 
product will be recorded from the time a participant consents to participate in 
the study. 
• 
All AEs will be collected from the start of treatment until the follow-up visit at 
the time points specified in the SoA (Section 2). 
• 
Medical occurrences that begin before the start of study treatment but after 
obtaining informed consent will be recorded on the Medical History/Current 
Medical Conditions section of the case report form (CRF) not the AE section. 
• 
All SAEs will be recorded and reported to the Sponsor or designee immediately 
and under no circumstance must this exceed 24 hours, as indicated in Appendix 
5. The Investigator will submit any updated SAE data to the Sponsor within 
24 hours of it being available. 
• 
Investigators are not obligated to actively seek AEs or SAEs in former study 
participants. However, if the Investigator learns of any SAE, including a death, 
at any time after a participant has been discharged from the study, and he/she 
considers the event to be reasonably related to the study treatment or study 
participation, the Investigator must promptly notify the Sponsor. 
• 
The method of recording, evaluating, and assessing causality of AEs and SAEs 
and the procedures for completing and transmitting SAE reports are provided in 
Appendix 5. 
9.2.2. 
Method of Detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting an AE and/or a SAE. Open-ended 
and non-leading verbal questioning of the participant is the preferred method to inquire 
about AE occurrence.  
9.2.3. 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the Investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs, will be followed until the event is 
resolved, stabilized, otherwise explained, or the participant is lost to follow-up (as 
defined in Section 8.5). Further information on follow-up procedures is given in 
Appendix 5. 
9.2.4. 
Regulatory Reporting Requirements for SAEs 
• 
Prompt notification by the Investigator to the Sponsor of a SAE is essential so 
that legal obligations and ethical responsibilities towards the safety of 


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participants and the safety of a study treatment under clinical investigation are 
met.  
• 
The Sponsor has a legal responsibility to notify both the local regulatory 
authority and other regulatory agencies about the safety of a study treatment 
under clinical investigation. The Sponsor will comply with country-specific 
regulatory requirements relating to safety reporting to the regulatory authority, 
Institutional Review Boards (IRB)/ IEC, and investigators. 
• 
Investigator safety reports must be prepared for suspected unexpected serious 
adverse reactions (SUSAR) according to local regulatory requirements and 
Sponsor policy and forwarded to investigators as necessary. 
• 
An Investigator who receives an Investigator safety report describing a SAE or 
other specific safety information (e.g., summary or listing of SAE) from the 
Sponsor will review and then file it along with the IB and will notify the 
IRB/IEC, if appropriate according to local requirements. 
9.2.5. 
Cardiovascular and Death Events 
For any cardiovascular events detailed in Section 13.5 and all deaths, whether or not they 
are considered SAEs, specific Cardiovascular (CV) and Death sections of the CRF are 
required to be completed.  These sections include questions regarding cardiovascular 
(including sudden cardiac death) and non-cardiovascular death.  
The CV CRFs are presented as queries in response to reporting of certain CV MedDRA 
terms.  The CV information should be recorded in the specific cardiovascular section of 
the CRF within one week of receipt of a CV Event data query prompting its completion.   
The Death CRF is provided immediately after the occurrence or outcome of death is 
reported. Initial and follow-up reports regarding death must be completed within one 
week of when the death is reported. 
9.2.6. 
Pregnancy 
• 
Details of all pregnancies in female partners of male participants will be collected 
after the start of study treatment and up to 7 days after the final dose of study 
medication. 
• 
If a pregnancy is reported, the Investigator must inform GSK within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Appendix 6.  
9.3. 
Treatment of Overdose 
For this study, any total dose of GSK3036656 greater than the dose selected for that 
cohort (taken within a 23-hour period) will be considered an overdose. 
The sponsor does not recommend specific treatment for an overdose. 


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In the event of an overdose, the Investigator/treating physician should: 
1. Contact the Medical Monitor immediately. 
2. Closely monitor the participant for AE/SAE and laboratory abnormalities until study 
treatment can no longer be detected systemically (at least 14 days). 
3. Obtain a plasma sample for PK analysis if requested by the Medical Monitor 
(determined on a case-by-case basis). 
4. Document the quantity of the excess dose as well as the duration of the overdosing in 
the CRF. 
Decisions regarding dose interruptions or modifications will be made by the Investigator 
in consultation with the Medical Monitor based on the clinical evaluation of the 
participant. 
9.4. 
Safety Assessments 
Planned time points for all safety assessments are provided in the SoA. 
9.4.1. 
Physical Examinations 
• 
A complete physical examination will include, at a minimum, assessments of the 
Skin, Cardiovascular, Respiratory, Gastrointestinal and Neurological systems. 
Height and weight will also be measured and recorded. 
• 
Investigators must pay special attention to clinical signs related to previous 
serious illnesses. 
9.4.2. 
Vital Signs 
• 
Temperature, pulse rate, respiratory rate, and blood pressure will be assessed. 
• 
Blood pressure and pulse measurements will be assessed with a completely 
automated device. Position of the participant should be consistent across 
readings (e.g. semi-supine or supine). Manual techniques will be used only if an 
automated device is not available. 
• 
Blood pressure and pulse measurements must be preceded by at least 5 minutes 
of rest for the participant in a quiet setting without distractions (e.g., television, 
cell phones). 
• 
Vital signs (to be taken before blood collection for laboratory tests) will consist 
of at least 1 pulse and blood pressure measurement. Where a measurement is 
abnormal or significantly different from previous measurements, a further 2 
readings will be taken. When vital signs are measured in triplicate, values should 
be taken at least 1 minute but not more than 5 minutes apart and recorded in the 
CRF. 
9.4.3. 
Electrocardiograms 
• 
Single 12-lead ECG will be obtained as outlined in the SoA using an ECG 
machine that automatically calculates the heart rate and measures PR, QRS, 


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uncorrected QT intervals. QTcF will be calculated using heart rate and QT by 
Friderica's formula (see SRM). Also refer to ECG stopping criteria listed in 
Section 8.1.2. 
• 
In the event where triplicate ECG readings are required, 3 individual ECG 
tracings should be obtained as closely as possible in succession, but no more 
than 2 minutes apart. The full set of triplicates should be completed in less than 
10 minutes. Stopping criteria are in Section 8.1.2 
9.4.4. 
Echocardiograms 
• 
Echocardiography will be performed at screening on all participants who have 
undergone all other screening assessments, have been found eligible for the 
study, and are willing to enrol into the study. It will also be done at follow-up on 
the participants in the cohort that is anticipated to receive the highest dose of 
GSK3036656 as well as on any participant who has received a lower dose of 
GSK3036656 if, in the opinion of the Investigator, their clinical status warrants 
it. The dose escalation committee may decide to perform this assessment in 
additional cohorts in this study. 
• 
If feasible, the echocardiograms will be interpreted at a central core 
echocardiography lab and the screening and follow up echocardiograms for a 
particular participant will be obtained by the same technician.  
9.4.5. 
Clinical Safety Laboratory Assessments 
• 
Refer to Appendix 3 for the list of clinical laboratory tests to be performed and 
to the SoA for the timing and frequency.  
• 
The Investigator must review the laboratory report, document this review, and 
record any clinically significant changes occurring during the study in the AE 
section of the CRF. The laboratory reports must be filed with the source 
documents. Clinically significant abnormal laboratory findings are those which 
are not associated with the underlying disease, unless judged by the Investigator 
to be more severe than expected for the participant's condition. 
• 
All laboratory tests with values considered clinically significantly abnormal 
during participation in the study or within 24 hours after the last dose of study 
treatment should be repeated until the values return to normal or baseline or are 
no longer considered significantly abnormal by the Investigator or medical 
monitor.  
• 
If such values do not return to normal/baseline within a period of time judged 
reasonable by the Investigator, the aetiology should be identified and the 
Sponsor notified. 
• 
All protocol-required laboratory assessments, as defined in Appendix 3, must be 
conducted in accordance with the SRM and the SoA.  


T M F -1 3 3 3 1 4 2 0  
C O N FI D E N TI A L  
 
 
 
2 0 1 2 1 4  
 
5 2  
 
9. 5.  
P h ar m a c o ki n eti c s  
•  Bl o o d  sa m ples of a p pr o xi matel y 2  m L will be c oll ecte d f or meas ure me nt of 
plas ma  c o nce ntrati o ns of G S K 3 0 3 6 6 5 6  as s pecifie d i n t he S o A. I nstr u cti o ns f or 
t he c ollecti o n a n d ha n dli n g of bi ol o gical s a m ples will be pr o vi de d b y t h e S p o ns or. 
T he act ual d ate a n d ti me ( 2 4 -h o ur cl oc k ti me) of eac h sa m ple will be rec or de d.  
•  Sa m ples will be use d t o e val uate t he P K of G S K 3 0 3 6 6 5 6 . Sa m ples c ollecte d f or 
a nal ys es of G S K 3 0 3 6 6 5 6 plas ma  c o nce ntrati o n ma y als o be use d t o e val uate 
safet y or effic ac y as p ects relate d t o c o ncer ns arisi n g d uri n g or after t he st u d y.  
•  O nce t he plas ma  h as bee n a nal yze d f or G S K 3 0 3 6 6 5 6  a n y re mai ni n g plas m a  ma y 
b e a nal yz e d f or ot h er c o m p o u n d -relate d mat erial a n d t he res ults re p orte d u n der a 
se parat e pr ot oc ol. 
9. 6.  
P ot e nti al S urr o g at e Di s e a s e / Bi o mar k er s  
C CI


T M F -1 3 3 3 1 4 2 0  
C O N FI D E N TI A L  
 
 
 
2 0 1 2 1 4  
 
5 3  
 
C CI


T M F -1 3 3 3 1 4 2 0  
C O N FI D E N TI A L  
 
 
 
2 0 1 2 1 4  
 
5 4  
 
9. 7.  
I n ci d e nt al fi n di n g s 
I n ci de ntal fi n di n gs (I Fs) i n cli nical researc h are fi n di n gs wit h p ote ntial healt h or 
re pr o d ucti ve i m p orta n ce t hat are disc o v ere d i n t he c o urse of c o n d uctin g t he researc h, b ut 
are be y o n d t h e ai ms of t h e st u d y. I Fs i n t his st u d y ma y arise fr o m t he c ollecti n g a n d 
a nal ysi n g of res earc h i ma ges i.e. C X R or 
or i n t he tests or i nf or mati o n c ollecte d 
t o deter mi ne eli gi bilit y criteria i.e. a b n or mal vital si g ns, safet y bl o o ds, or E C G. 
T he pri nci pal i n vesti gat or ( PI) is res p o nsi ble f or ha n dli n g a n I F res p o nsi bl y a n d pr o m ptl y 
a n d me m bers of t he researc h tea m will pr o m ptl y re p ort a s us pecte d I F. If a n I F is 
disc o vere d t he PI will i nf or m t he partici pa nt a n d e x ercise his/ her j u d g me nt o n a case b y 
case basis t o deter mi ne t he wa y f or war d t hat is i n t he best i nterest of t he partici pa nt. T he 
PI will ma ke s ur e t hat all t he necess ar y d oc u me nt ati o n f or t he referral of t h e partici pa nt is 
p ut t o get her free of c ost t o t he partic i pa nt. 
1 0.  
S T A TI S TI C A L C O N SI D E R A TI O N S  
1 0. 1.  
S a m pl e Si z e D et er mi n ati o n  
1 0. 1. 1.  
Ori gi n al S a m pl e Si z e C al c ul ati o n  
T he pla n ne d sa m ple siz e f or t his st u d y is u p t o 1 0 0 partici pa nts ra n d o mise d de pe n di n g o n 
t he n u m ber of c o h orts ( 1 5 partici pa nts i n eac h G S K 3 0 3 6 6 5 6 treat me nt gr o u p); s ufficie nt 
partici pa nts will be scree ne d t o ac hie ve t his sa m ple size.  
N o f or mal h y p ot hesis testi n g is t o be teste d i n t his st u d y, he n ce n o f or mal sa m ple siz e 
calc ulati o n has bee n perf or me d, h o we v er, si m ulati o ns were c o n d ucte d t o deter mi ne t he 
i m pact of t he size of t he st u d y o n t he a bilit y t o d etect a treat me nt effect b ase d o n t he 
mea n dail y l o g 1 0 decli ne i n C F U/ m L i n partici p a nt s treate d wit h G S K 3 0 3 6 6 5 6. Of n ote, 
w hilst a p pr o xi matel y 2 5  s u bjects i n t he st u d y will be ra n d o mise d t o S o C , f or mal 
c o m paris o ns of G S K 3 0 3 6 6 5 6 t o S o C will n ot be ma de. T he si m ulati o ns perf or me d 
t heref ore si m pl y assess t he c ha n ge fr o m bas eli ne wit hi n eac h G S K 3 0 3 6 6 5 6 treat me nt 
gr o u p.  
C CI
C CI


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For the purposes of this analysis, untreated subjects were assumed to have a mean daily 
change from baseline in log10CFU of zero, any decrease from baseline in log10CFU was 
therefore considered to suggest a treatment effect. Previous EBA studies indicate that the 
standard deviation for the change from baseline in log10CFU is approximately 0.2 in 
treated subjects, therefore this estimate was used as the standard deviation for the 
simulations. Potential changes from baseline of −0.08 to 0.02, in increments of 0.01 were 
investigated.  
Data were simulated from a normal distribution, for each potential treatment effect.  
Simulations were repeated 1000 times for each potential treatment effect and the number 
of times the mean change from baseline met the following criteria was calculated: 
≥ 0.0 log10CFU (no response or negative response) 
< 0.0 log10CFU (positive response) 
≤ -0.06 log10CFU (good positive response, effect comparable with new individual 
drugs in recent EBA studies). 
Simulations were repeated for sample sizes of 15, 20 and 25 per arm, the results for the 
percentage of studies showing a mean change from baseline below zero is shown in the 
following figure.  
 
Percentage of Studies Showing a Mean Change < 0.0
0
10
20
30
40
50
60
70
80
90
100
True Underlying Change from Baseline
-0.08
-0.07
-0.06
-0.05
-0.04
-0.03
-0.02
-0.01
0.00
0.01
0.02
Percentage of Studies Showing a Mean Change < 0.0
Vs True Underlying Change from Baseline
SampleSize
N=15
N=20
N=25


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Assuming a true underlying change from baseline of −0.06, and a sample size of 15 
participants per treatment arm, there is approximately 90% chance of the observed mean 
change being a negative value (i.e., a positive response will be observed). Increasing the 
sample size does not greatly improve the probability of observing a positive result based 
on this true underlying treatment difference of -0.06.  
10.1.2. 
Sample Size Re-estimation 
Due to the slower than anticipated rate of study recruitment, during recruitment to cohort 
3 of the study, a review of the standard deviation of daily change from baseline in 
log10(CFU) was performed to assess if the initial estimate of the standard deviation (0.2) 
was comparable to the observed study data available at that time. The review included 
CFU data from participants in the first 2 cohorts and included only participants who 
completed assessments from baseline through to Day 14. The average daily change from 
baseline was calculated as change between baseline and Day 14 divided by 14, then the 
standard deviation summarised by treatment group. The results are displayed in the 
following table.  
Treatment Group 
N 
Daily Change from Baseline 
in Log10(CFU) Standard 
Deviation 
Standard-of-care 
9 
0.049 
GSK3036656 5mg 
15 
0.067 
GSK3036656 15mg 
13 
0.053 
 
The observed standard deviations were smaller than used in the original sample size 
simulation therefore the sample size simulations described in Section 10.1 were repeated 
using standard deviations of 0.1 and 0.15 and including additional sample sizes of 9 and 
12 participants per treatment arm. The results for the percentage of studies showing a 
mean change from baseline below zero, assuming a standard deviation of 0.15, is shown 
in the following figure.  


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Assuming a standard deviation of 0.15, a sample size of 9 participants per treatment arm 
would provide approximately the same level of confidence as originally planned 
assuming a standard deviation of 0.2 and a sample size of 15 participants per treatment 
arm i.e. Assuming a true underlying change from baseline of -0.06 and a sample size of 
9 participants per treatment arm, there is approximately 90% chance of the observed 
mean change being a negative value (i.e. a positive response). Therefore, this supports 
reducing the sample size in ongoing and future cohorts to 9 participants per GSK3036656 
treatment arm.  
 


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10.2. 
Populations for Analyses 
For purposes of analysis, the following populations are defined: 
Population 
Description 
Screened 
All participants who were screened for eligibility. 
Enrolled  
All participants who passed screening and entered the study.  
Randomised 
All participants who were randomly assigned to treatment in the 
study.  
Pharmacokinetic (PK)  
Participants in the safety population who received at least one 
dose of GSK3036656 and have at least one evaluable PK sample. 
Participants will be analysed according to the treatment actually 
received. 
Efficacy 
Participants in the safety population who provided at least two 
evaluable overnight sputum sample.  
Safety 
All randomized participants who received at least 1 dose of study 
treatment. Participants will be analysed according to the treatment 
they actually received. 
 
Data from the standard of care arm will be pooled for the final analysis.  
 
10.3. 
Statistical Analyses 
10.3.1. 
Activity/Pharmacokinetic Analyses 
Endpoint 
Statistical Analysis Methods 
Primary 
Rate of change in log10CFU per mL direct respiratory sputum samples over 
the period baseline to Day 14 (EBA CFU0−14). This will be analysed using a 
mixed effects model including treatment, day, BMI and treatment-by-day as 
covariates.  
This endpoint will be analysed using the efficacy population.  
Secondary 
PK Endpoints 
Pharmacokinetic analysis will be the responsibility of the Clinical 
Pharmacology Modeling and Simulation Department, (CPMS), 
GlaxoSmithKline. Plasma GSK3036656 concentration-time data will be 
analyzed by non-compartmental methods with WinNonlin 5.2 or higher. 


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Endpoint 
Statistical Analysis Methods 
Calculations will be based on the actual sampling times recorded during the 
study. 
From the plasma concentration-time data, the following pharmacokinetic 
parameters will be determined, as data permit: 
• maximum observed blood concentration (Cmax) 
• time to Cmax (tmax) 
• area under the plasma concentration-time curve [AUC0−t and 
AUC0−24] 
• trough concentration (Cτ). 
AUC0−t or AUC0−24 and Cmax may be used for assessment of dose 
proportionality. Trough concentration (Cτ) samples collected on the specified 
days will be used to assess attainment of steady state. 
Pharmacokinetic data will be presented in graphical and/or tabular form and 
will be summarized descriptively. 
Statistical analyses of the pharmacokinetic parameter data will be the 
responsibility of Statistics, Programming and Data Strategy (SPDS), 
GlaxoSmithKline. Distributional assumptions underlying the statistical 
analyses will be assessed by visual inspection of residual plots. Normality 
will be examined by normal probability plots, while homogeneity of variance 
will be assessed by plotting the residuals against the predicted values for the 
model. Alternative analyses of the data will be performed if any of the model 
assumptions appear to be violated. Full details on the statistical aspects will 
be detailed in the Reporting and Analysis Plan (RAP). 
Dose Proportionality 
Dose proportionality will be assessed via analyses of AUC0-t or AUC0-24 and 
Cmax. A statistical analysis will be performed using the power model. The 
analysis will be performed on loge-transformed data. For each of these 
parameters a mixed effects model will be fitted with loge (dose) as a fixed 
effect and individual subject fitted as random effects. Estimates of the mean 
slopes of loge (dose) will be reported along with corresponding 90% 
confidence intervals (slope≈1 implies dose proportionality). 
Achievement of Steady State 
Trough concentration levels, Cτ, collected pre-morning dose will be plotted 
by collection day and dose. To evaluate whether steady state was achieved, 
statistical analysis of Cτ will be performed after a log-transformation of the 
dose data. A mixed effect model will be fitted with dose, day and dose-by-
day interaction as fixed effects (with dose as a factor and day as a 
continuous covariate) and subject as a random effect. The coefficients of the 


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Endpoint 
Statistical Analysis Methods 
slopes for the day effect for each dose, along with corresponding 90% 
confidence intervals, will be used to determine whether steady state was 
achieved. 
Efficacy/Activity Endpoints 
EBA CFU0−2, EBA CFU2−14, EBA TTP0−14, EBA TTP0−2 and EBA TTP2−14 will 
be analysed similarly to the primary endpoint. These endpoints will be 
analysed using the efficacy population.  
Exploratory 
Will be analysed and reported separately.  
 
10.3.2. 
Safety Analyses 
All safety analyses will be performed on the Safety Population.  
Endpoint 
Statistical Analysis Methods 
Secondary 
Safety data will be presented in tabular and/or graphical format and 
summarised descriptively according to GSK’s Integrated Data Standards 
Library (IDSL) standards. 
Adverse Events 
Adverse event reporting will be performed using the MedDRA (Medical 
Dictionaries for Regulatory Activities) coding system. Counting of adverse 
events will be based on the number of participants, not the number of AEs.  
In addition to all adverse events, there will be separate summaries for: 
i. Serious adverse events 
ii. Drug-related adverse events 
iii. Adverse events leading to treatment / study withdrawal 
In addition, AEs will be displayed by CTCAE grade and severity. 
Clinical Laboratory Values / Vital Signs 
Change from baseline in clinical laboratory data (haematology, clinical 
chemistry and urinalysis) and vital signs data (SBP, DBP, heart rate and body 
temperature) will be summarised descriptively by dose group and timepoint.  
Laboratory and vital signs data will also be evaluated by summarising the 
worst-case results as number and percentage of participants in each dose 
group.   
ECG 


T M F -1 3 3 3 1 4 2 0  
C O N FI D E N TI A L  
 
 
 
2 0 1 2 1 4  
 
6 1  
 
E n d p oi nt  
St ati sti c al A n al ysi s M et h o d s  
C h a n ge fr o m b as eli ne i n E C G will b e s u m m aris e d d escriptiv ely by d os e gro u p 
a n d ti m e p oi nt f or all p articipa nts. A s u m m ary of E C G findi n gs a n d Q Tc v al ues 
will als o b e pro d uce d.  
 
1 0. 3. 3.  
Ot h er A n al y s e s  
1 0. 3. 4.  
Effi c a c y A n al y s e s  
N o f or mal i nteri m a nal ys es are pl a n ne d  f or t his st u d y. H o we ver, s afet y, t ol era bilit y a n d 
p har mac o ki netic d ata will be re vie we d bef ore eac h d ose escal ati o n . I n a d diti o n, t he 
pri mar y efficac y e n d p oi nt ma y als o be a nal yse d as s pecifie d i n S ecti o n 1 1 . 
1 1.  
D O S E E S C A L A TI O N  
After t he i nitial d ose of G S K 3 0 3 6 6 5 6, t he decisi o n t o pr ocee d t o eac h s u bse q ue nt d ose 
le vel will be ma de b y t he D ose Escalati o n C o m mittee ( D E C) bas e d o n safet y, t olera bilit y 
a n d preli mi nar y G S K 3 0 3 6 6 5 6 p har mac o ki netic data fr o m t he pri or  c o h ort. T he D E C ma y 
als o i ncl u de i n t heir deli berati o ns , efficac y data, if t hat is a vaila ble. Mi ni m u m 
re q uire me nts f or data are as f oll ows: P K data i n at least 7  s u bjects recei vi n g 
G S K 3 0 3 6 6 5 6 a n d select e d safet y data fr o m  all s u bjects i n a c o h ort.  A d ose escalati o n 
c o m mittee c harter will be pr o d uce d t h at will c o ntai n t he f oll o wi n g d etails:  
•  C o m mittee me m bers  
•  Data re vi e w re q uire me nts  
•  Pr ocess f or i nf or mi n g t he et hics c o m mittee  of a n y safet y c o n cer ns  if a p pr o priate 
•  Facilit y f or re q uesti n g a d diti o nal perti ne nt i nf or mati o n f or m t he i n vesti gat or  
D ose escalati o n will be base d o n p o p ulati o n P K m o delli n g (if feasi ble) . D ose escal ati o ns 
will n ot be hi g her t ha n 3 -f ol d. 
T he p o p ulati o n P K m o del will be a fit f or p ur p ose m o del. Ca n di date m o del selecti o n will 
be pri maril y base d o n a si g nifica nt re d ucti o n i n t he o bjecti ve f u ncti o n val ue ( ≥ 3. 3 2, χ 2 
< 0. 0 5) a n d i m pr o ve m e nt i n t he fits of dia g n ostic s catter pl ots.  I nter -i n di vi d ual varia bilit y 
will be m o delle d usi n g a n e x p o ne ntial err or m o del a n d resi d ual err or will b e descri b e d b y 
a pr o p orti o nal, pr o p orti o nal pl us a d diti ve, or a d diti ve err or m o d el, de pe n di n g o n t he data. 
M o del perf or m a nce will be e val uat e d usi n g a vis ual pre dicti ve c h ec k.  Si m ulati o ns f or 
d ose rec o m me n d ati o ns will be c o n d ucte d t o deter mi ne t he pr o ba bi lit y of a n i n di vi d ual 
s u bject e x cee di n g t he defi ne d e x p os ure mar gi ns f or A U C a n d C ma x. 
Alter nati vel y, if a p o p ulati o n P K m o del is n ot feasi ble, d ose escal ati o n will be base d o n a 
d ose -e x p os ure m o del of t he f or m:  
C CI


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log(AUC) = a + b*log(DOSE) + c*log(BWT/70) 
log(CMAX) = d + e*log(DOSE) + f*log(BWT/70) 
where a and d are AUC and Cmax values, respectively; c = -0.75 and f = -1.00 are set 
values for allometric scaling; and b and e are scaling factors for dose proportionality. 
A proposed dose will be acceptable if the predicted probability of an individual 
exceeding pre-defined exposure limits (Section 5.6) on any day of the dosing period, as 
estimated by PK modeling, is no more than 10%. 
The primary endpoint may be analysed once data is available for 12 evaluable subjects, 
as per the sample size re-estimation calculations, on the second consecutive cohort that 
reaches or exceeds the target PK plasma exposure for efficacy (based on the murine 
infection model), and subsequent cohorts. The purpose of this efficacy analysis is to 
optimise dosing for subsequent cohorts (e.g. to help estimate the dose response curve) as 
well as to aid internal decision making.  
The DEC is empowered to take the following decisions for subsequent cohorts: 
• To select a higher dose (including a loading dose that may be given over 1 or 
more days) within the limits defined in Section 5.6. 
• To select a dose lower than, or the same as, a preceding dose. 
• To stop dosing. 
• To include additional pharmacokinetic assessments. 
• To include additional timepoints for an existing safety assessment. 
• To adjust the haemoglobin exclusion and stopping criteria if no haematological 
abnormalities are observed in the review of safety data from the highest dose 
cohort (Cohort 3).  For the subsequent cohort(s) receiving a lower dose of 
GSK3036656, the haemoglobin exclusion criterion will be lowered to <8.0 g/dL, 
and the haemoglobin stopping criterion will be lowered to <6.0 g/dL. Patients 
with a confirmed haemoglobin <8.0g/dL after randomisation will require 
enhanced observations, with a repeat haemoglobin level and discussion of patient 
status with the GSK medical monitor. 
 
 


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12. 
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Basteiro AL, et al. β-lactams against tuberculosis—new trick for an old dog? N Eng J 
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Donald PR, Sirgel FA, Venter A, Parkin DP, Seifart HI, van de Wal BW, et al. Early 
bactericidal activity of antituberculosis agents. Expert Rev Anti Infect Ther. 2003; 1:141-
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Donald PR, Sirgel FA, Venter A, Parkin DP, Van De Wal BW, Barendse A, et al. Early 
bactericidal activity of amoxicillin in combination with clavulanic acid in patients with 
sputum smear-positive pulmonary tuberculosis. Scandinavian journal of infectious 
diseases. 2001;33(6):466-9. 
Furin JJ, Du Bois J, van Brakel E, Chheng P, Venter A, Peloquin CA, et al. Early 
Bactericidal Activity of AZD5847 in Patients with Pulmonary Tuberculosis. Antimicrob 
Agents Chemother. 2016;60(11):6591-9. 
Jindani A, Aber VR, Edwards EA, Mitchison. The early bactericidal activity of drugs in 
patients with pulmonary tuberculosis. Am Rev Resp Dis 1980; 121(6): 939-949. 
Matteelli A, Carvalho AC, Dooley KE, Kritski A. TMC207: the first compound of a new 
class of potent anti-tuberculosis drugs. Future Microbiol 2010 Jun; 5(6):849-58. 
Mdluli, K and Nuermberger, E. Pre-Clinical Drug Combination Studies to Identify Novel 
Regimens for TB. In: Recent Advances in TB Drug Development symposium, 40th 
Union World Conference, International Union Against TB and Lung Disease, Cancun, 
2009. 
Rustomjee R, Diacon AH, Allen J, Venter A, Reddy C, Patientia RF, et al. Early 
bactericidal activity and pharmacokinetics of the diarylquinoline TMC207 in treatment of 
pulmonary tuberculosis. Antimicrob Agents Chemother. 2008; 52:2831-5 
Wallis RS, Dawson R, Friedrich SO, Venter A, Paige D, Zhu T, et al. Mycobactericidal 
activity of sutezolid (PNU-100480) in sputum (EBA) and blood (WBA) of patients with 
pulmonary tuberculosis. PLoS One. 2014;9(4):e94462. 
World Health Organization [WHO]. Global tuberculosis report 2016a. 
http://www.who.int/tb 
World Health Organization [WHO]. The Short MDR-TB regimen 2016b. 
http://www.who.int/tb/Short_MDR_regimen_factsheet.pdf 


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13. 
APPENDICES 
13.1. 
Appendix 1: Abbreviations and Trademarks 
AE 
Adverse Event 
AIDS 
Acquired Immune Deficiency Syndrome 
ALT 
Alanine Aminotransferase 
AMX 
Amoxicillin 
AST  
Aspartate Aminotransferase 
AUC  
Area Under the Plasma Concentration Time Curve 
AUC0-24 
Area Under the Plasma Concentration Time Curve from Zero to End of Dosing 
Interval  
BD 
Twice Daily 
CFU 
Colony Forming Units 
Cmax  
Maximum Observed Plasma Concentration 
Cmin 
Minimum Observed Plasma Concentration at the End of the Dosing Interval 
CRF 
Case Report Form 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Events 
DBP 
Diastolic Blood Pressure 
DS 
Drug Sensitive 
EBA 
Early Bactericidal Activity 
EC 
Ethics Committee 
ECG  
Electrocardiogram 
EMB 
Ethambutol 
EWV 
Early Withdrawal Visit 
GCP  
Good Clinical Practice 
GGT 
Gamma-Glutamyltransferase 
HIV  
Human Immunodeficiency Virus 
HRZE 
Isoniazid/Rifampicin/Pyrazinamide/Ethambutol 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
IV 
Intravenous 
IP 
Investigational Product 
IUATLD 
International Union Against Tuberculosis and Lung Disease 
INH 
Isoniazid 
LDH 
Lactate Dehydrogenase 
MDR 
Multi Drug Resistant 
MGIT 
Mycobacterial Growth Indicator Tube 
MIC  
Minimum Inhibitory Concentration 
MOXI 
Moxifloxacin 
Mtb 
Mycobacterium tuberculosis 
PCR  
Polymerase Chain Reaction 


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PD 
Pharmacodynamic  
PK  
Pharmacokinetic 
PR 
Electrocardiographic PR Interval 
PZA 
Pyrazinamide 
QT 
Electrocardiographic QT Interval 
QTc 
Corrected QT Interval 
RAP 
Reporting and Analysis Plan 
RIF/RF 
Rifampicin 
SAE 
Serious Adverse Event 
SBP 
Systolic Blood Pressure 
SoC 
Standard of care 
SRM 
Study Reference Manual 
t 
Time 
t½ 
Apparent Terminal Elimination Phase Half-Life 
TAR 
Target Attainment Rate 
TB 
Tuberculosis 
TEAEs 
Treatment-Emergent Adverse Events 
Tmax 
Time at Which Cmax is Observed 
TMIC 
Time over Minimum Inhibitory Concentrations 
TTP  
Time to Sputum Culture Positivity 
ULN 
Upper Limit of Normal 
WHO  
World Health Organization 
XDR 
Extremely Drug Resistant 
 
Trademark Information 
Trademarks of the GlaxoSmithKline 
group of companies 
 
Trademarks not owned by the 
GlaxoSmithKline group of companies 
NONE 
 
Rifafour e-275 
 
 
WinNonlin 


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13.2. 
Appendix 2: EBA definitions 
EBA 
 
An agent’s ability to kill mycobacteria originating within pulmonary cavities 
during the first weeks of treatment. 
EBA CFU 
 
Determination of EBA by quantification of solid medium of viable Colony 
Forming Units (CFU) of M. tuberculosis from an overnight sputum collection.  
EBA TTP 
 
Determination of EBA by measurement in an automated liquid culture system 
of time to positivity (TTP) of M. tuberculosis from an overnight sputum 
collection. 
 


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13.3. 
Appendix 3: Clinical Laboratory Tests 
• 
The tests detailed in Table 2 will be performed by the local laboratory.  
• 
Protocol-specific requirements for inclusion or exclusion of participants are 
detailed in Section 6 of the protocol. 
• 
Additional tests may be performed at any time during the study as determined 
necessary by the Investigator or required by local regulations. 
Table 2 
Protocol-Required Safety Laboratory Assessments 
Laboratory 
Assessments 
Parameters 
Haematology 
Platelet Count  
RBC Indices: 
MCV 
MCH 
%Reticulocytes 
WBC count with 
Differential: 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
RBC Count 
Haemoglobin 
Hematocrit 
Coagulation test (INR, 
PT, APTT) 
Clinical 
Chemistry1 
BUN 
Potassium 
Aspartate 
Aminotransferase 
(AST) 
Total, indirect, 
and direct 
bilirubin 
 
Creatinine 
Sodium 
Alanine 
Aminotransferase 
(ALT) 
gamma-glutamyl 
transferase (GGT), 
lactic 
dehydrogenase 
(LDH), sodium, 
potassium, 
calcium (corrected 
for albumin), 
chloride 
Total Protein 
 
Glucose 
(random/fasting) 
Calcium 
(corrected for 
albumin) 
Alkaline 
phosphatase 
 
 
Routine 
Urinalysis 
• Specific gravity 
• pH, glucose, protein, blood, micro-albumin ketones, bilirubin, 
urobilinogen, nitrite, sodium, leukocytes by dipstick 
• Microscopic examination (if blood or protein is abnormal) 


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Laboratory 
Assessments 
Parameters 
Other 
Screening 
Tests 
• Urine drug screen (to include at minimum: amphetamines, cocaine, 
opiates. 
• Serology (HIV antibody, hepatitis B surface antigen [HBsAg], and hepatitis 
C virus antibody) 
• Cardiac safety screening: Troponin. 
NOTES: 
1. 
Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver stopping 
or monitoring event are given in Section 8.1 and Appendix 7 All events of ALT 3 × upper limit of normal (ULN) 
and bilirubin 2 × ULN (>35% direct bilirubin) or ALT 3 × ULN and international normalized ratio (INR) >1.5, if 
INR measured, which may indicate severe liver injury (possible Hy’s Law), must be reported as an SAE 
(excluding studies of hepatic impairment or cirrhosis). 
 


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13.4. 
Appendix 4: Study Governance Considerations 
Regulatory and Ethical Considerations 
• 
This study will be conducted in accordance with the protocol and with: 
• Consensus ethical principles derived from international guidelines 
including the Declaration of Helsinki and Council for International 
Organizations of Medical Sciences (CIOMS) International Ethical 
Guidelines 
• Applicable ICH Good Clinical Practice (GCP) Guidelines 
• Applicable laws and regulations 
• 
The protocol, protocol amendments, ICF, Investigator Brochure, and other 
relevant documents (eg, advertisements) must be submitted to an IRB/IEC by 
the Investigator and reviewed and approved by the IRB/IEC before the study is 
initiated.  
• 
Any amendments to the protocol will require IEC/IRB approval before 
implementation of changes made to the study design, except for changes 
necessary to eliminate an immediate hazard to study participants.  
• 
The Investigator will be responsible for the following: 
• Providing written summaries of the status of the study to the IRB/IEC 
annually or more frequently in accordance with the requirements, policies, 
and procedures established by the IRB/EC 
• Notifying the IRB/IEC of SAE or other significant safety findings as 
required by IRB/IEC procedures 
• Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European 
regulation 536/2014 for clinical studies (if applicable), and all other 
applicable local regulations 
Financial Disclosure 
Investigators and sub-investigators will provide the sponsor with sufficient, accurate 
financial information as requested to allow the sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study. 
Informed Consent Process 
• 
The Investigator or his/her representative will explain the nature of the study to 
the participant or his/her legally authorized representative and answer all 
questions regarding the study.  
• 
Participants must be informed that their participation is voluntary. Participants 
or their legally authorized representative will be required to sign a statement of 


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informed consent that meets the requirements of 21 CFR 50, local regulations, 
ICH guidelines, Health Insurance Portability and Accountability Act (HIPAA) 
requirements, where applicable, and the IRB/IEC or study center.  
• 
The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent 
must also sign the ICF. 
• 
Participants must be re-consented to the most current version of the ICF(s) 
during their participation in the study.  
• 
A copy of the ICF(s) must be provided to the participant or the participant’s 
legally authorized representative.  
The ICF may contain a separate section that addresses the use of remaining mandatory 
samples for optional exploratory research in accordance with SOP-GSKF-410. The 
investigator or authorized designee will explain to each participant the objectives of the 
exploratory research. Participants will be told that they are free to refuse to participate 
and may withdraw their consent at any time and for any reason during the storage period. 
A separate signature will be required to document a participant's agreement to allow any 
remaining specimens to be used for exploratory research. Participants who decline to 
participate will not provide this separate signature. 
Data Protection 
• 
Participants will be assigned a unique identifier by the Sponsor. Any participant 
records or datasets that are transferred to the Sponsor will contain the identifier 
only; participant names or any information which would make the participant 
identifiable will not be transferred.  
• 
The participant must be informed that his/her personal study-related data will be 
used by the Sponsor in accordance with local data protection law. The level of 
disclosure must also be explained to the participant.  
• 
The participant must be informed that his/her medical records may be examined 
by Clinical Quality Assurance auditors or other authorized personnel appointed 
by the Sponsor and anTBiotic consortium members, by appropriate IRB/IEC 
members, and by inspectors from regulatory authorities. 
Publication Policy 
• 
The results of this study may be published or presented at scientific meetings. If 
this is foreseen, the Investigator agrees to submit all manuscripts or abstracts to 
the Sponsor before submission. This allows the sponsor to protect proprietary 
information and to provide comments.  
• 
The Sponsor will comply with the requirements for publication of study results. 
In accordance with standard editorial and ethical practice, the Sponsor will 
generally support publication of multicenter studies only in their entirety and not 
as individual site data. In this case, a coordinating Investigator will be 
designated by mutual agreement. 


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• 
Authorship will be determined by mutual agreement and in line with 
International Committee of Medical Journal Editors authorship requirements. 
Dissemination of Clinical Study Data 
• 
Where required by applicable regulatory requirements, an Investigator signatory 
will be identified for the approval of the clinical study report.  The Investigator 
will be provided reasonable access to statistical tables, figures, and relevant 
reports and will have the opportunity to review the complete study results at a 
GSK site or other mutually-agreeable location. 
• 
GSK will also provide the Investigator with the full summary of the study 
results.  The Investigator is encouraged to share the summary results with the 
study participants, as appropriate. 
• 
The procedures and timing for public disclosure of the results summary and for 
development of a manuscript for publication will be in accordance with GSK 
Policy. 
• 
A manuscript will be progressed for publication in the scientific literature if the 
results provide important scientific or medical knowledge. 
• 
Anonymised analysable datasets from this study may be provided, through a 
secure system, following an independent assessment of the scientific merit of a 
rigorously defined research question from a third party. 
Data Quality Assurance 
• 
All participant data relating to the study will be recorded on printed or electronic 
CRF unless transmitted to the Sponsor or designee electronically (eg, laboratory 
data). The Investigator is responsible for verifying that data entries are accurate 
and correct by physically or electronically signing the CRF.  
• 
The Investigator must maintain accurate documentation (source data) that 
supports the information entered in the CRF.  
• 
The Investigator must permit study-related monitoring, audits, IRB/IEC review, 
and regulatory agency inspections and provide direct access to source data 
documents.  
• 
The Sponsor or designee is responsible for the data management of this study 
including quality checking of the data.  
• 
Study monitors will perform ongoing source data verification to confirm that 
data entered into the CRF by authorized site personnel are accurate, complete, 
and verifiable from source documents; that the safety and rights of participants 
are being protected; and that the study is being conducted in accordance with the 
currently approved protocol and any other study agreements, ICH GCP, and all 
applicable regulatory requirements.  
• 
Records and documents, including signed ICF, pertaining to the conduct of this 
study must be retained by the Investigator for 25 years from the issue of the final 
Clinical Study Report (CSR)/ equivalent summary unless local regulations or 
institutional policies require a longer retention period. No records may be 


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destroyed during the retention period without the written approval of the 
Sponsor. No records may be transferred to another location or party without 
written notification to the Sponsor.  
Source Documents 
• 
Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
Investigator’s site. 
• 
Data reported on the CRF or entered in the eCRF that are transcribed from 
source documents must be consistent with the source documents or the 
discrepancies must be explained. The Investigator may need to request previous 
medical records or transfer records, depending on the study. Also, current 
medical records must be available. 
• 
Definition of what constitutes source data can be found in the Source Document 
Agreement. 
Study and Site Closure 
GSK or its designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of GSK. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed. 
The Investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the Sponsor or Investigator may include 
but are not limited to: 
• 
Failure of the Investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the Sponsor's procedures, or GCP guidelines 
• 
Inadequate recruitment of participants by the Investigator 
• 
Discontinuation of further study treatment development 


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13.5. 
Appendix 5: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting 
Definition of AE 
AE Definition 
• 
An AE is any untoward medical occurrence in a clinical study participant, 
temporally associated with the use of a study treatment, whether or not considered 
related to the study treatment. 
• 
NOTE: An AE can therefore be any unfavorable and unintended sign (including 
an abnormal laboratory finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of a study treatment. 
 
Events Meeting the AE Definition  
• 
Any abnormal laboratory test results (hematology, clinical chemistry, or 
urinalysis) or other safety assessments (e.g., ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the Investigator (ie, not 
related to progression of underlying disease). 
• 
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
• 
New conditions detected or diagnosed after study treatment administration even 
though it may have been present before the start of the study. 
• 
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-
harming intent. Such overdoses should be reported regardless of sequelae. 
• 
"Lack of efficacy" or "failure of expected pharmacological action" per se will not 
be reported as an AE or SAE. Such instances will be captured in the 
efficacy/activity assessments. However, the signs, symptoms, and/or clinical 
sequelae resulting from lack of efficacy/activity will be reported as AE or SAE if 
they fulfil the definition of an AE or SAE.  
• 
The signs, symptoms, and/or clinical sequelae resulting from lack of 
efficacy/activity will be reported as AE or SAE if they fulfil the definition of an 
AE or SAE. Also, "lack of efficacy" or "failure of expected pharmacological 
action" constitutes an AE or SAE. 
 


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Events NOT Meeting the AE Definition  
• 
Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by 
the Investigator to be more severe than expected for the participant’s condition. 
• 
The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition. 
• 
Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is the AE. 
• 
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
• 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) 
present or detected at the start of the study that do not worsen. 
 
Definition of SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (eg, hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease). 
A SAE is defined as any untoward medical occurrence that, at any dose: 
a. Results in death 
b. Is life-threatening 
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe. 
c. 
Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AE. If a 
complication prolongs hospitalization or fulfils any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the 
AE should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE. 


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d. Results in persistent disability/incapacity 
• 
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
• 
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhoea, 
influenza, and accidental trauma (eg, sprained ankle) which may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption. 
e. 
Is a congenital anomaly/birth defect 
f. 
Other situations: 
• 
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that 
may not be immediately life-threatening or result in death or hospitalization but 
may jeopardize the participant or may require medical or surgical intervention to 
prevent one of the other outcomes listed in the above definition. These events 
should usually be considered serious. 
Examples of such events include invasive or malignant cancers, intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization, or development of 
drug dependency or drug abuse. 
 
Definition of Cardiovascular Events 
Cardiovascular Events (CV) Definition: 
Investigators will be required to fill out the specific CV event page of the CRF for the 
following AEs and SAEs: 
• 
Myocardial infarction/unstable angina 
• 
Congestive heart failure 
• 
Arrhythmias 
• 
Valvulopathy 
• 
Pulmonary hypertension 
• 
Cerebrovascular events/stroke and transient ischemic attack 
• 
Peripheral arterial thromboembolism 
• 
Deep venous thrombosis/pulmonary embolism 
• Revascularization 
 


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Recording AE and SAE 
AE and SAE Recording 
• 
When an AE/SAE occurs, it is the responsibility of the Investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) 
related to the event. 
• 
The Investigator will then record all relevant AE/SAE information in the CRF. 
• 
It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to GSK in lieu of completion of the GSK /AE/SAE CRF page. 
• 
There may be instances when copies of medical records for certain cases are 
requested by GSK. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to GSK. 
• 
The Investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis 
(not the individual signs/symptoms) will be documented as the AE/SAE. 
Assessment of Intensity 
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to categories according to the definitions in CTCAE 
v5.0.  
An event is defined as ‘serious’ when it meets at least 1 of the predefined 
outcomes as described in the definition of an SAE. 
 
Assessment of Causality 
• 
The Investigator is obligated to assess the relationship between study treatment 
and each occurrence of each AE/SAE. 
• 
A "reasonable possibility" of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out. 
• 
The Investigator will use clinical judgment to determine the relationship. 
• 
Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study treatment 
administration will be considered and investigated. 
• 
The Investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment. 
• 
For each AE/SAE, the Investigator must document in the medical notes that 
he/she has reviewed the AE/SAE and has provided an assessment of causality. 
• 
There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to GSK. However, it is very 


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important that the investigator always make an assessment of causality for 
every event before the initial transmission of the SAE data to GSK. 
• 
The Investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment. 
• 
The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. 
 
Follow-up of AE and SAE 
• 
The Investigator is obligated to perform or arrange for the conduct of 
supplemental measurements and/or evaluations as medically indicated or as 
requested by GSK to elucidate the nature and/or causality of the AE or SAE as 
fully as possible. This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other health care 
professionals. 
• 
If a participant dies during participation in the study or during a recognized 
follow-up period, the investigator will provide GSK with a copy of any post-
mortem findings including histopathology. 
• 
New or updated information will be recorded in the originally completed CRF. 
• 
The Investigator will submit any updated SAE data to GSK within 24 hours of 
receipt of the information. 
Reporting of SAE to GSK 
SAE Reporting to GSK via Electronic Data Collection Tool 
• 
The primary mechanism for reporting SAE to GSK will be the electronic data 
collection tool. 
• 
If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) in order to report the event within 24 hours. 
• 
The site will enter the SAE data into the electronic system as soon as it becomes 
available. 
• 
The Investigator or medically-qualified sub-investigator must show evidence 
within the eCRF (e.g., check review box, signature, etc.) of review and verification 
of the relationship of each SAE to IP/study participation (causality) within 72 
hours of SAE entry into the eCRF. 
• 
After the study is completed at a given site, the electronic data collection tool will 
be taken off-line to prevent the entry of new data or changes to existing data. 
• 
If a site receives a report of a new SAE from a study participant or receives 
updated data on a previously reported SAE after the electronic data collection tool 
has been taken off-line, then the site can report this information on a paper SAE 
form (see next section) or to the medical monitor by telephone. 


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• 
Contacts for SAE reporting can be found in the SRM. 
 
SAE Reporting to GSK via Paper CRF 
• 
Email facsimile transmission of the SAE paper CRF is the preferred method to 
transmit this information to the medical monitor. 
• 
In rare circumstances and in the absence of facsimile/email capability, notification 
by telephone is acceptable with a copy of the SAE data collection tool sent by 
overnight mail or courier service. 
• 
Initial notification via telephone does not replace the need for the Investigator to 
complete and sign the SAE CRF pages within the designated reporting time 
frames. 
• 
Contacts for SAE reporting can be found in the SRM. 
 
 


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13.6. 
Appendix 6: Contraceptive Guidance and Collection of 
Pregnancy Information 
Contraception Guidance 
Male participants 
• 
Male participants with female partners of child-bearing potential are eligible to 
participate if they agree to ONE of the following:  
• Are abstinent from penile-vaginal intercourse as their usual and preferred 
lifestyle (abstinent on a long term and persistent basis) and agree to remain 
abstinent for a period of 90 days after the last dose of study medication 
(one spermatogenesis cycle). 
• Agree to use a male condom plus an additional method of contraception 
with a failure rate of <1% per year as described in Table 3 when having 
penile-vaginal intercourse with a woman of childbearing potential, for a 
period of 90 days after the last dose of study medication.  
• 
Men with a pregnant or breastfeeding partner must agree to remain abstinent 
from penile-vaginal intercourse or use a male condom during each episode of 
penile penetration during the treatment period and for 6 days after (five terminal 
half-lives). 
• 
In addition, male participants must refrain from donating sperm during the 
treatment period and for 90 days after (one spermatogenesis cycle). 


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Table 3 
Highly Effective Contraceptive Methods 
Highly Effective Contraceptive Methods That Are User Dependent a 
Failure rate of <1% per year when used consistently and correctly.  
Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulation  
• oral 
• intravaginal  
• transdermal  
Progestogen-only hormonal contraception associated with inhibition of ovulation  
• injectable  
Highly Effective Methods That Are User Independent  
• Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulation 
• Intrauterine device (IUD) 
• Intrauterine hormone-releasing system (IUS) 
• bilateral tubal occlusion 
Vasectomized partner  
(A vasectomized partner is a highly effective contraception method provided that the partner is 
the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. If 
not, an additional highly effective method of contraception should be used.)  
Sexual abstinence  
(Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study drug. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study 
and the preferred and usual lifestyle of the participant.)  
NOTES:  
a.Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent with 
local regulations regarding the use of contraceptive methods for participants in clinical studies.  
 
Collection of Pregnancy Information 
Male participants with partners who become pregnant 
• 
Investigator will attempt to collect pregnancy information on any male participant’s 
female partner of a male study participant who becomes pregnant while participating 
in this study. This applies only to participants who receive study treatment. 
• 
After obtaining the necessary signed informed consent from the pregnant female 
partner directly, the Investigator will record pregnancy information on the 


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appropriate form and submit it to GSK within 24 hours of learning of the partner’s 
pregnancy.  
• 
Partner will also be followed to determine the outcome of the pregnancy. 
Information on the status of the mother and child will be forwarded to GSK 
• 
Generally, follow-up will be no longer than 6 to 8 weeks following the estimated 
delivery date. Any termination of the pregnancy will be reported regardless of fetal 
status (presence or absence of anomalies) or indication for procedure.  


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13.7. 
Appendix 7: Liver Safety: Required Actions and Follow-up 
Assessments 
Liver chemistry stopping criteria and required follow up assessments  
Elevated liver enzymes, transient liver dysfunction, hepatotoxicity and hepatitis are listed 
as side-effects in the package inserts for Rifafour e-275 (Rifafour, 2002) or equivalent 
generic alternative, associated with multiple drug components. Therefore, participants 
allocated to Rifafour e-275 (or equivalent generic alternative) treatment who experience 
Liver Chemistry Stopping criteria are not mandated in the first instance to undergo those 
follow-up assessments (which are intended to investigate aetiology). The investigations 
may still be performed, if required in the judgement of the investigator. 
 
Liver Chemistry Stopping Criteria  
ALT-absolute 
ALT  5xULN 
ALT Increase 
ALT  3xULN persists for 4 weeks 
Bilirubin1, 2 
ALT  3xULN and bilirubin  2xULN (>35% direct bilirubin) 
INR2 
ALT  3xULN and INR>1.5, if INR measured 
Cannot 
Monitor 
ALT  3xULN and cannot be monitored weekly for 4 weeks 
Symptomatic3 
ALT   3xULN associated with symptoms (new or worsening) believed to be 
related to liver injury or hypersensitivity 
Required Actions and Follow up Assessments  
Actions 
Follow Up Assessments 
• Immediately discontinue study treatment  
• Report the event to GSK within 24 hours 
• Complete the liver event CRF and complete an 
SAE data collection tool if the event also meets 
the criteria for an SAE2 
• Perform liver chemistry event follow up 
assessments  
• Monitor the participant until liver chemistries  
resolve, stabilize, or return to within baseline 
(see MONITORING below) 
• Do not restart/rechallenge participant with 
study treatment unless allowed per protocol 
For all study participants: 
• Obtain INR and recheck with each 
liver chemistry assessment until the 
transaminases values show downward 
trend 
• Record the appearance or worsening 
of clinical symptoms of liver injury, or 
hypersensitivity, on the AE report form 
• Record use of concomitant 
medications on the concomitant 
medications report form including 
acetaminophen, herbal remedies, 
other over the counter medications. 


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and GSK Medical Governance approval is 
granted (see below)   
• If restart/rechallenge not allowed per 
protocol or not granted, permanently 
discontinue study treatment and continue 
participant in the study for any protocol 
specified follow up assessments  
 
 
MONITORING: 
For bilirubin or INR criteria:  
• Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within 24 
hrs 
• Monitor participants twice weekly until liver 
chemistries resolve, stabilize or return to within 
baseline  
• A specialist or hepatology consultation is 
recommended 
For All other criteria:  
• Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within 24-72 
hrs  
• Monitor participants weekly until liver 
chemistries resolve, stabilize or return to within 
baseline 
• Record alcohol use on the liver event 
alcohol intake case report form (CRF) 
page  
 
For participants on GSK303656 arm 
• Viral hepatitis serology4 
•  Obtain blood sample for 
pharmacokinetic (PK) analysis as 
soon as possible, and certainly within 
14 days after last dose 5 
• Serum creatine phosphokinase (CPK) 
and lactate dehydrogenase (LDH). 
• Fractionate bilirubin, if total 
bilirubin2xULN 
• Obtain complete blood count with 
differential to assess eosinophilia 
 
 
For bilirubin or INR criteria: 
For participants on GSK303656 arm only 
• Auto-immune screen: Anti-nuclear 
antibody, anti-smooth muscle 
antibody, Type 1 anti-liver kidney 
microsomal antibodies, and 
quantitative total immunoglobulin 
G (IgG) or gamma globulins. 
• Serum 
paracetamol/acetaminophen 
adduct high performance liquid 
chromatography (HPLC) assay 
(quantifies potential 
acetaminophen contribution to 
liver injury in participants with 
definite or likely acetaminophen 
use in the preceding week 
[James, 2009]).  
• Liver imaging (ultrasound, 
magnetic resonance, or 
computerised tomography) and /or 
liver biopsy to evaluate liver 


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disease; complete Liver Imaging 
and/or Liver Biopsy CRF pages. 
1. Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that subject if ALT  3xULN and bilirubin  2xULN.. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary 
bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver injury.  
2. All events of ALT  3xULN and bilirubin  2xULN (>35% direct bilirubin) or ALT  3xULN and INR>1.5, if INR 
measured which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis); INR measurement is not required and the threshold value stated 
will not apply to participants receiving anticoagulants 
3. New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, rash or 
eosinophilia) 
4. Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen (HbsAg) and Hepatitis B Core Antibody (IgM); 
Hepatitis C RNA; Cytomegalovirus IgM antibody; Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, 
obtain heterophile antibody or monospot testing);  Hepatitis E IgM antibody  
For PK sampling; record the date/time of the PK blood sample draw and the date/time of 
the last dose of study treatment prior to PK blood sample draw on the CRF. If the date or 
time of the last dose is unclear, provide the participant’s best approximation. If the 
date/time of the last dose cannot be approximated OR a PK sample cannot be collected in 
the time period indicated above, do not obtain a PK sample. Instructions for sample 
handling and shipping are in the SRM. 
 
Liver chemistry criteria for a Liver Monitoring Event and follow-up actions: 
These Increased Monitoring Criteria apply to all participants who experience a Liver 
Event, regardless of which treatment the participant has been randomized to. 
Liver Chemistry Increased Monitoring Criteria – Liver Monitoring Event 
Criteria 
Actions 
ALT 3×ULN and <5×ULN and 
bilirubin <2×ULN, without 
symptoms believed to be related to 
liver injury or hypersensitivity, and 
who can be monitored weekly for 4 
weeks. 
• Notify the GSK medical monitor within 24 
hours of learning of the abnormality by email 
or phone to discuss participant safety. 
• Participant can continue study intervention.   
• Participant must return weekly for repeat liver 
chemistries (ALT, AST, ALP, bilirubin) until 
they resolve, stabilise or return to within 
baseline.  
• If at any time participant meets the liver 
chemistry stopping criteria, proceed as 
described above 
• If, after 4 weeks of monitoring, ALT <3×ULN 
and bilirubin <2×ULN, monitor participant 


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twice monthly until liver chemistries 
normalize or return to within baseline 
The site will complete the liver event eCRF (Monitoring Event) in InForm and should 
also consider whether the AE reporting guidelines apply. 
 
References 
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee 
WM. Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen 
Overdose and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784. 
Rifafour e-275 tablet electronic package inserts. 2002. Accessed 20 Feb 2019.: 
http://home.intekom.com/pharm/hmr/rifaf275.html 


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13.9. 
Appendix 9: Protocol Amendment History 
The Protocol Amendment Summary of Changes Table for the current amendment is 
located directly before the Table of Contents (TOC). 
Amendment 4 (17-FEB-2021) 
Overall Rationale for the Amendment: 
• To allow for Standard of Care medication administered in the study to be either 
Rifafour e-275 or an equivalent generic alternative. 
• Addition of ‘e-275’ to all references to Rifafour, for consistency. 
• To allow for analysis of the primary endpoint data to be performed on additional 
cohorts. 
CHANGES 
Synopsis / Overall Design: 
A single-centre, open-labelled, clinical trial in up to five sequential cohorts of participants 
with rifampicin-susceptible tuberculosis (DS-TB). Each cohort will involve participants 
being randomised to one of two possible treatments: either GSK3036656 or Standard-of-
care (SoC) regimen for DS-TB (i.e. Rifafour e-275 or equivalent generic alternative). 
The ratio of participants assigned to GSK3036656 vs Rifafour e-275 (or equivalent 
generic alternative) will be 3:1. 
 
Schedule of Activities / PK sampling time and events table: 
C. PK sampling is only to be performed on participants receiving GSK3036656. PK samples will not be taken from 
participants receiving Rifafour e-275 (or equivalent generic alternative). 
 
5. Study Design / Overall Design 
The study will comprise up to 5 cohorts of participants. It is intended that 15 participants 
in each cohort will receive GSK3036656 and 5 will receive standard-of-care regimen for 
DS-TB (i.e. Rifafour e-275 or equivalent generic alternative). There will be no placebo 
in this study. The study will be randomized, but not blinded (i.e., it will be ‘open-label’) 
with neither participant nor Investigator blinded to treatment. Study participants will 
revert to the standard treatment for TB (i.e. Rifafour e-275 or equivalent generic 
alternative) once the study treatment (Day 1 to Day 14) has been completed. All 
laboratory staff involved in analysing and reporting the primary and secondary change in 
log10CFU counts and TTP endpoints results will be blinded to treatment allocation. 
Cohorts will proceed sequentially starting A through D, with preliminary safety, 
tolerability and pharmacokinetic data from the previous cohort reviewed prior to 
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5.2 Study Schematic 
 
 
 
 
 
 
 
5.4 Participant and Study Completion 
Following completion of the study treatment phase and after discharge from hospital the 
participants will be provided with their first dose/s of standard TB therapy (i.e. Rifafour 
e-275 or equivalent generic alternative) with appropriate counselling. All participants 
will be referred to the local community TB clinics to receive the remainder of a full 
course of standard antituberculosis chemotherapy according to national guidelines. The 
participants will be provided with a referral letter to take with them to the TB clinic. 
Within a week of the participant’s discharge from the study clinic, a follow-up call will 
be made by the study site staff to the TB clinic to determine if the participant attended the 
clinic. 
 
5.5 Scientific Rationale for Study Design 
The Rifafour e-275 (or equivalent generic alternative) treatment group is included as a 
benchmark for the EBA quantitative mycobacteriology and to evaluate whether HRZE in 
this population gives similar EBA results to that demonstrated in prior studies with this 
combination. A negative control arm, where subjects are left untreated, would be 
unethical due to the availability of effective treatment and the consequences of not 
treating TB. 
 
SCREENING 
from -9 days 
prior to first 
dose 
14-Day treatment period – 
GSK3036656 
Day 15 
start/continue 
Rifafour*
1 
1
14-Day treatment period – 
Rifafour
1 
1
 
Follow-up at 
Day 28 
*This is not part of the study but is the post-study definitive treatment of TB. 
1Rifafour e-275 or equivalent generic alternative. 


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7.1 Treatments Administered 
Study Treatment 
Name: 
 
GSK3036656 
Rifafour e-275 (or equivalent 
generic equivalent) 
Dosage 
formulation: 
 
Capsule 
Tablet 
Unit dose 
strength(s)/Dosage 
level(s): 
1 mg or 5 mg or 25 mg GSK3036656 
capsules 
(as free base equivalent) 
Standard dose: 
150/75/400/275 mg of 
Rifampicin, Isoniazid, 
Pyrazinamide and Ethambutol 
respectively per tablet 
Route of 
Administration  
Oral 
Oral 
Dosing 
instructions: 
 
Refer to study reference manual 
Refer to South African National 
TB Treatment Guidelines 
(including pyridoxine as 
required) 
Packaging and 
Labelling 
 
Study Treatment will be provided in 
HDPE bottles. Each HDPE bottle will 
be labelled as required per country 
requirement.  
Will be provided by the 
manufacturer. 
Manufacturer 
WuXi AppTec (1 and 5 mg capsules) 
Aptuit (25 mg capsule) 
Rifafour e-275: Sanofi-Aventis 
or appropriate alternative  
Equivalent Generic 
alternative to Rifafour e-275: 
Appropriate suppliers  
 


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Rifafour e-275 (or equivalent generic alternative). 
Some participants will be treated with standard, intensive phase pulmonary TB treatment 
as recommended in the SA National TB Treatment Guidelines to verify that the 
laboratory assays used measure the expected magnitude of activity. This is HRZE  
(Rifafour e-275 or equivalent generic alternative) (HRZE: H=isoniazid: R=rifampicin: 
Z=pyrazinamide: E=ethambutol). The Rifafour e-275 (or equivalent generic 
alternative) treatment group is included as a benchmark for the EBA quantitative 
mycobacteriology and to evaluate whether HRZE in this population gives similar EBA 
results to that demonstrated in prior studies using this combination. 
Rifafour e-275 (or equivalent generic alternative) Package Insert contains its known 
and potential risks and benefits. 
 
8. Discontinuation Criteria 
If this results in the patient being placed on standard of care (i.e. Rifafour e-275 or 
equivalent generic alternative), then all assessments relevant to Rifafour e-275 (or 
equivalent generic alternative) will be performed as directed by the protocol (for 
example, GSK3036656 pharmacokinetic assessments are not required, since the 
participant is not being dosed with GSK3036656). 
 
11. Dose Escalation 
The primary endpoint may be analysed for all available cohorts after the final visit of the 
last subject on the second consecutive cohort that reaches or exceeds the target PK 
plasma exposure for efficacy (based on the murine infection model), and subsequent 
cohorts. The purpose of this efficacy analysis is to optimise dosing for subsequent 
cohorts (e.g. to help estimate the dose response curve) as well as to aid internal decision 
making.  
 
13.7 Appendix 7: Liver Safety: Required Actions and Follow-up Assessments 
Elevated liver enzymes, transient liver dysfunction, hepatotoxicity and hepatitis are listed 
as side-effects in the package inserts for Rifafour e-275 (see References) or equivalent 
generic alternative, associated with multiple drug components. Therefore, participants 
allocated to Rifafour e-275 (or equivalent generic alternative) treatment who 
experience Liver Chemistry Stopping criteria are not mandated in the first instance to 
undergo those follow-up assessments (which are intended to investigate aetiology). The 
investigations may still be performed, if required in the judgement of the investigator. 
 
 


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Amendment 3 24-JUL-2019 
Overall Rationale for the Amendment: 
To document the increase in exposure limits and change in eligibility criteria following 
the availability of new non-clinical data. 
Further changes made to the protocol are detailed in the table below. 


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S e cti o n #  
D e s cri pti o n of C h a n g e  
Bri ef R ati o n al e  
Sc h e dul e of 
Ass ess m e nts 
t a bl e 
D u plic ati o n of tests u n nec ess ary.  
Sc h e dul e of 
Ass ess m e nts 
t a bl e; 
f o otn ote E 
R e m ov al of “or al” fr o m f o ot n ot e  
Sit e pri m arily us e ty m pa nic or axill ary 
t e m p er atur e assess m e nt. 
Sc h e dul e of 
Ass ess m e nts 
t a bl e; 
f o otn ote F 
Mi n or r e -w or di n g.  
Cl arity of u nd erst an di ng. 
Sc h e dul e of 
Ass ess m e nts 
t a bl e; 
f o otn ote H 
R e m ov e f oot n ot e r ef er enc e t o 
D ay 1 5  
N ot r e q uired, discre p ancy i n t h e pr ot ocol 
f o u nd by I nv esti g ator. 
Sc h e dul e of 
Ass ess m e nts 
t a bl e; 
f o otn ote K 
Mi ni mis ati o n of risk t o p artici p a nts.  
Sc h e dul e of 
Ass ess m e nts 
t a bl e; 
f o otn ote O 
A d d ed text th at MI C sa m pl es s e nt 
t o G S K, Sp ai n will n ot be r ep ort e d 
i n C S R. 
T o cl arify t h at t h e MI C testi ng of t h e 
b act erial is olat es se nt f or furt h er 
c h ar act eriz atio n to G S K Spai n will b e 
r e p ort ed a n d a n alys ed s e p ar at ely.  
S o A  
A d diti on of a n E C G at t h e Early 
Wit h dr a w al Visit ( E W V)  
Mist ak e nly o mitt e d i n pr evi ous v ersio ns  
S o A P K ta bl e A d diti on of 1 0 -mi n ut e wi nd o w f or 
t h e pr e-d ose (‘ 0’) ti m e p oi nt o n 
D ay 1 4.  
 
Cl arific ati o n t hat ti mi n g of P K 
s a m pl es fr o m D ay 1 4 is r elativ e t o 
d osi n g o n D ay 1 4  
 
A d diti on of P K sa m pl e wi ndo w 
all o w a nc es t a ble  
Wi n d o w n ecess ary to e ns ure all 
ass ess m e nts a n d pr oce dur es c a n b e 
c o m pl et ed i n a ti mely m a nner. 
 
E ns ur e clarity of u n derst a ndi n g.  
C CI
C CI


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S e cti o n #  
D e s cri pti o n of C h a n g e  
Bri ef R ati o n al e  
9. 6.1  
A p p en dix 3  
R e m ov al of t ext “ T h e r es ults of 
e ac h t est m ust be e nt er ed int o 
t h e C R F” 
 
R e m ov al of ‘uri n e alco h ol’ 
 
 
 
R e m ov al of uri n e h C G, F S H a n d 
o estr a diol i n fe m al es  
D at a will b e tr a nsferre d electr o nic ally  
 
 
Uri n e alc o h ol t est erro ne o usly list e d i n 
A p p en dix 3 b ut not i n t abl e of eve nts. 
T his t est will n ot be d o n e. This is 
st a n dar d G S K te m pl at e t ext t h at s h oul d 
n ot h av e b ee n p art of this prot oc ol.  
 
F e m al es will b e exclu d ed  
3. 3  
N e w A U C & C m ax exp os ure 
li mits a n d s u p p orti ng n o n-cli nic al 
i nf or mati o n 
N e w n o n -cli nic al d ata s u p ports 
i ncr e asi n g t h e A U C & C m ax li mits 
dict ati ng d ose l evel c h oices i n t h e st udy  
5. 1  
I ncr e as e i n m axi m u m n u m ber of 
c o h orts 
T o pr ovi de fl exi bility for 3 p ot e nti al 
sc e n arios: a l o w er d os e is i ncl u d ed to 
h el p d escribi n g t he ex pos ure -r es p o nse 
r el ati o ns hip, a d ose n e e ds to b e 
r e p e ate d or a hi g h er d ose th a n curre ntly 
pr oj ect e d is f easi bl e d u e t o o bs erv ed P K 
b ei n g ov er pr edict ed.  
5. 6  
U p d ate d pr o b ability r at es t a bl e 
b as ed o n i ncr e ase d A U C & C max 
ex p osur e li mits  
N e w n o n -cli nic al d ata s u p ports 
i ncr e asi n g t h e A U C & C m ax li mits 
dict ati ng d ose l evel c h oices i n t h e st udy  
6. 1  
R e m ov al of eligi bilit y of f e m al es 
Ot h er crit eri a r e -w or di ng  
N e w no n -clinical d at a i n dic at es f e m al es 
m ust n ot b e e nr olle d.  
6. 2  
A d diti on of ‘ F e m al e’ to exclusi o n 
crit eri a 
Ot h er crit eri a r e -w or di ng  
N e w no n -clinical d at a i n dic at es f e m al es 
m ust n ot b e e nr olle d.  
6. 3.1  
R e m ov al of U V ex pos ur e 
r estricti o n 
N e w i nf or m atio n fr o m n o n -clinical st u di es 
n o w s u pp orts r e mov al of t he r estricti o n.  
C CI


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D e s cri pti o n of C h a n g e  
Bri ef R ati o n al e  
6. 3.2  
R e m ov al of a r e quir e m e nt to 
a bst ain fr o m w ater f or a p erio d of 
ti m e aft er d osi ng 
St u dy tr e at m ent ca n b e a d mi nist er e d 
wit h o ut r eg ar d t o f o od/ w ater. 
8  
A d diti on of t ext cl arifyi n g 
disc o nti nu ati on of st u dy tr eat m e nt  
A s u bj ect c an b e disc onti n ue d fr o m 
r ec eivi n g stu dy tr eat m e nt but r e m ai n i n 
t h e stu dy. 
9. 1  
Cl arific ati o n of t ech nic al d etails 
f or MI C pr ovi d ed i n ot h er 
d oc u m ent atio n  
P er st an d ar d  pr actic e, t echnic al d et ails 
ar e i ncl u de d in a diff er ent stu dy 
d oc u m ent.  
9. 2.6  
U p d ate d text to r efl ect excl usi o n 
of f e m ales  
N e w no n -clinical d at a i n dic at es f e m al es 
m ust n ot b e e nr olle d.  
9. 4.1  
R e m ov al of t h e d escriptio n of a 
bri ef p hysical ex a m  
N ot r e q uir ed i n t his pr ot oc ol a n d w as 
t e m pl at e t ext t hat s ho ul d h av e b ee n 
r e m ov e d origi n ally. 
9. 6.1  
T ext r e q uir e d for i nt er n al G S K p ur pos es  
9. 6.2  
R e pl acin g t ext to clarify g e n etic 
t esti n g. 
A d diti o n of t ext clarifyin g pr oc ess 
f or a n alysis 
H u m an D N A testin g will n ot be c o n d uct ed.  
 
T ext r e q uir e d for i nt er n al G S K p ur pos es  
1 0. 1  
U p d ate d nu m ber of s ubj ects  
C o nsist e ncy wit h u p dat e d d esig n i nt e nt.  
1 0. 3. 1  
U p d ate d clarific atio n of r e p orti n g of 
ex pl or at ory e n dp o ints 
Cl arity of u n d erst a ndi n g of i nte nt.  
1 0. 3. 4  
U p d ate d t ext c onc er ni n g data 
r evie w trig g ers 
Cl arity of u n d erst a ndi n g of i nte nt.  
1 1  
U p d ate d t ext c onc er ni n g data 
r evie w trig g ers 
Cl arity of u n d erst a ndi n g of i nte nt.  
A p p en dix 3  
U p d ate d scr e e nin g t ests  
C o nsist e ncy wit h d esig n i nt ent.  
A p p en dix 4  
A d diti o n of t ext clarifyin g e ntities 
t h at m ay r ec eive d at a 
C o nsist e ncy wit h d esig n i nt ent.  
A p p en dix 6  
R e m ov al of t ext r el at ed t o 
pr e g n ancy t esti n g.  
F e m al es will n ot b e inclu d ed, u p d ates 
m a d e r efl ecti n g t his d esi g n i nt e nt.  
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Section # 
Description of Change 
Brief Rationale 
Appendix 7 
Incorporation of PK monitoring 
algorithm table previously 
contained within a separate study 
document. 
 
Clarification of requirements for 
procedures relative to which 
treatment a participant is 
receiving. 
Ensure clarity of understanding and 
remove duplication 
 
 
Remove requirement for unnecessary 
procedures in participants receiving  
Rifafour. 
 
CHANGES 
Synopsis 
Overall Design: 
A single-centre, open-labelled, clinical trial in up to five four sequential cohorts of 
participants with rifampicin-susceptible tuberculosis (DS-TB). Each cohort will involve 
participants being randomised to one of two possible treatments: either GSK3036656 or 
Standard-of-care (SoC) regimen for DS-TB (Rifafour e-275). The ratio of participants 
assigned to GSK3036656 vs Rifafour will be 3:1. 
Number of Participants: up to approximately 100 80 participants will be enrolled. 
Treatment Groups and Duration: Up to 5 4 cohorts; 20 participants in each cohort (15 
participants will receive GSK3036656, and 5 participants will receive SoC in each 
cohort). 
 


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Section 2 Schedule of Activities 
Period 
Screening 
Dosing 
Follow-up 
Visit 
1 
2 
3 
4 
5 to 10 
11 
12 to 16 
17 
18 
Early 
Withdrawal 
19 
Day 
(-9 to -
3) A 
-2B 
-1 
1 
2 to 7C 
8 
9 to 13C 
14 
15 
28 
( 
7) 
Documentation of Positive GeneXpert and/or 
TB smear (TB clinic/site of initial diagnosis) 
X 
 
 
 
 
 
 
 
 
 
 
Written Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Demography (including smoking history) 
X 
 
 
 
 
 
 
 
 
 
 
Medical & Treatment History 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion/Eligibility Assessment 
X 
 
 
 
 
 
 
 
 
Chest X-ray 
X 
 
 
 
 
 
 
 
 
 
Physical ExaminationD 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs E 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-Lead ECG  
X 
 
 
 
 
 
 
X 
X 
X 
RandomisationM 
 
X 
 
 
 
 
 
 
 
 
Echocardiogram (may be conducted at any of 
the screening visits) 
X 
 
 
 
 
 
 
XS 
XS 
Blood PKF 
 
 
 
 
 
 
XF 
X 
X 
X 
 
Spot Sputum (confirm TB & adequate bacterial 
load) G 
X 
 
 
 
 
 
 
 
 
 
 
Rifampicin Resistance Test (rapid)G 
(microscopy and GeneXpert tests may be 
repeated on an overnight sputum sample if 
needed) 
X 
 
 
 
 
 
 
 
 
 
 
Haematology, Clinical Chemistry, Urinalysis H 
X 
 
 
X 
X 
X 
 
X 
 
X 
X 
Cardiac safety biomarkersT 
X 
X 
X 
 
 
X 
 
 
 
Urine Drug ScreenI 
X 
XI 
 
 
 
 
 
 
 
 
 


T M F -1 3 3 3 1 4 2 0  
C O N FI D E N TI A L  
 
 
 
2 0 1 2 1 4  
 
 
 
9 8  
 
P eri o d  
Scr e e ni n g  
D o si n g  
F oll o w -u p  
Vi sit  
1  
2  
3  
4  
5 t o 1 0  
1 1  
1 2 t o 1 6  
1 7  
1 8  
E arl y 
Wit h dra w al  
1 9  
D a y  
(-9 t o -
3) A  
-2 B  
-1  
1  
2 t o 7 C  
8  
9 t o 1 3 C  
1 4  
1 5  
2 8 
( 
7)  
Uri n e Pr e g n a ncy T est R  
 
X  
 
 
 
 
X  
X  
 
 
HI V T est ( a n d C D 4 C o u nt if HI V c o nfir m e d)  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
X  
X  
 
 
X  
 
X  
 
 
 
 
X  
X  
 
 
X  
 
X  
 
 
X  
 
 
 
 
X  
 
 
H os pit al A d missi o n  
X B  
X B  
 
 
 
 
 
 
 
 
 
Ov er ni g ht S p ut u m L 
X  
X  
X  
X  
X  
X  
X  
X  
 
 
 
I P A d mi nistr ati o n a n d C o m pli a nc e C h eck N  
 
 
 
X  
X  
X  
X  
X  
 
 
 
Myc o b act eri ol o gy Ass ess m e nts O  
 
X  
X  
 
 
 
 
X  
 
 
 
H os pit al Disc h ar g e  
 
 
 
 
 
 
 
 
X  
X  
 
C o nc o mit a nt M e dic ati o n  
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
A dv ers e Ev e nts P  
 
 
 
X  
X  
X  
X  
X  
X  
X  
X  
P oi nt of C ar e Bl o o d Gl uc os e or H b A 1c Q  
 
X  
 
 
 
 
X  
 
 
A.  T h e Visit 1  ( d ay -9 t o -3) ti m e p eri o d will b e u p t o a m axi m u m of 7 d ays b ut will b e k e pt as s h ort as p ossi bl e.  
B.   P artici p a nts c a n pr oc e e d wit h t h e Visit 2 ( d ay -2) ass ess m e nts as s o o n as t h eir Visit 1 ( d ay -9 t o -3) ass ess m e nts h av e b e e n c o m pl et e d i. e. Visits 1 a n d 2  m ay occ ur o n t h e s a m e 
d ay as l o n g as t h e scr e e ni n g r es ults ar e av ail a bl e i n ti m e f or r a n d o mis ati o n. P artici p a nts m ay b e h os pit alis e d d uri n g t h e e nt ir e pr e-tr e at m e nt p eri o d if t h e I nv esti g at or c o nsi d ers it 
a dvis a bl e f or r e as o ns of s af ety or c o m pli a nc e.  
C.  All  ev e nts list e d as occ urri n g o n Visit 5 ( d ay 2) t o Visit 1 0 ( d ay 7) a n d Visit 1 2 ( d ay 9) t o Visit 1 6 ( d ay 1 3) will b e c o n d uct e d  e ac h d ay d uri n g t h es e visits.  
D.  H ei g ht ( m) will o nly b e c oll ect e d o nc e at Visit 1 ( d ay -9 t o -3). A f ull p hysic al ex a mi n ati o n will  b e p erf or m e d at Visit 1 ( d ay -9 t o -3), wit h sy m pt o m -dir ect e d p hysic al ex a mi n ati o ns at 
Visit 1 7 ( d ay 1 4), Visit 1 9 ( d ay 2 8) a n d E arly Wit h dr a w al Visit ( E W V).  Sy m pt o m dir ect e d p hysic al ex a mi n ati o ns m ay b e c o n d uct e d as r e q uir e d d uri n g t h e st u dy (visits 4 t o 1 6).  
R e q uir e m e nts f or t h e p hysic al ex a mi n ati o n ar e s p ecifi e d i n t h e S R M.  
E.  Syst olic bl o o d pr ess ur e ( S B P) a n d di ast olic bl o o d pr ess ur e ( D B P) ( m m H g), h e art r at e ( b e ats p er mi nut e [ b p m]), b o dy t e m p er at ur e (° C) a n d w ei g ht (k g). T o b e p erf or m ed wit hi n 4 
h o urs pri or t o t h e first d aily d osi n g o n Visit 4 ( d ay 1) t hr o u g h t o Visit 1 7 ( d ay 1 4) a n d wit hi n 2 h o urs b ef or e t h e ti m e d osi n g w o u l d h av e occ urr e d o n Visit 1 8 ( d ay 1 5). O n d ays 
w h er e t h e f oll o wi n g ass ess m e nts ar e d o n e t h e or d er s h o ul d b e: vit al si g ns b ef or e bl o o d dr a ws f or P K or s af ety ass ess m e nts.  
F.  P Ks will b e p erf or m e d as n ot e d i n t h e P K t a bl e.  A si n gl e pr e -d os e P K s a m pl e will b e c oll ect e d o n e ac h of D ays 1 2 & 1 3, a n d s eri al P K bl o o d s a m pli n g will occ ur o n D ay 1 4 (s e e 
P K t a bl e b el o w).  At E W V a P K s a m pl e will b e  b ef ore  t ak e n pr e-d os e of  t h e ti m e of t h e pl a n n e d first d aily d osi n g.  If t his is n ot p ossi bl e, a s p o nt a n e o us P K s a m pl e will b e t ak e n.  
C CI


T M F -1 3 3 3 1 4 2 0  
C O N FI D E N TI A L  
 
 
 
2 0 1 2 1 4  
 
 
 
9 9  
 
G.  S p ut u m s m e ar micr osc o py a n d m ol ec ul ar r a pi d t est f or c o nfir m ati o n of Myc o b act eri u m t u b erc ul osis a n d rif a m pici n s usc e pti bility  ( G e n e X p ert). If t h e first s p ot s p ut u m s a m pl e 
s h o w s a n u nf a v o ura bl e  r es ult, t h e t ests m ay b e r e p e at e d o n a  fr es hly c oll ect e d s p ot sp ut u m or ov er ni g ht s p ut u m s a m pl e a n d t h at r es ult us e d i nst e a d.  
H.  L a b or at ory ass ess m e nts: h a e m at ol o gy ( h a e m o gl o bi n, h a e m at ocrit, r e d bl o o d c ell c o u nt, w hit e bl o o d c ell c o u nt wit h diff er e nti al , pl at el et c o u nt). Cli nic al C h e mistry ( al b u mi n, ur e a, 
cr e ati ni n e, dir ect, i n dir ect a n d t ot al bilir u bi n, t ot al pr ot ei n, alk ali n e p h os p h at as e, as p art at e a mi n otr a nsf er as e ( A S T), al a ni n e a mi n otr a nsf er as e ( AL T), g a m m a-gl ut a myl tr a nsf er as e 
( G G T), l actic d e hy dr o g e n as e ( L D H), s o di u m, p ot assi u m, c alci u m (c orr ect e d f or al b u mi n), c hlori d e, r a n d o m/f asti n g gl uc os e). Uri n alysis ( p H, s p ecific gr avity, pr ot ei n, gl uc os e, 
micr o -al b u mi n, k et o n es, bilir u bi n, cr e ati ni n e, nitrit e, s o di u m, ur o bili n o g e n, bl o o d, l e uk ocyt es, micr osc o py). C o a g ul ati o n t est (I N R , P T, A P T T). T o b e p erf or m e d o n Visit 4 (d ay 1), 
Visit 6 or 7 ( d ay 3 or 4), Visit 1 1 ( d ay 8)..  R ef er t o A p p e n di x 3 f or d et ail s.  
I. 
Uri n e dr u g scr e e n: c oc ai n e, a m p h et a mi n es a n d o pi at es. Uri n e dr u g scr e e n c a n b e r e p e at e d at Visit 2 ( d ay -2) f or p artici p a nts w h o w er e n ot h os pit aliz e d at Visit 1 ( d ay -9  t o -3). 
J. 
K.  
L.  
Ov er ni g ht s p ut u m s a m pli n g m ay st art at Scr e e ni n g visit ( d ay -9 t o -3) or o n Visit 2 ( d ay – 2) a n d will c o nti n u e d aily u ntil Visit 7 ( d ay 4). A d diti o n al s a m pli n g will b e c o n d uct e d at visit 
9 ( d ay 6), Visit 1 1 ( d ay 8), Visit 1 3 ( d ay 1 0), Visit 1 5 ( d ay 1 2) a n d Visit 1 7 ( d ay 1 4). S p ut u m s a m pli n g will st o p o n t h e m or ni n g of Visit 1 8 ( d ay 1 5). S p ut u m c oll ecti o n will st art i n t h e 
aft er n o o ns at 1 5: 0 0 h o urs ( 1 h o ur) a n d c o nti n u e f or 1 6 h o urs ov er ni g ht. T h e 1 6 -h o ur s p ut u m s a m pli n g f or e ac h of t h e s a m pli n g d ays m ust b e fi nis h e d pri or t o t h e a d mi ni str ati o n 
of t h e n ext d ay’s I P.  
Ov er ni g ht s p ut u m c oll ecti o n m ay b e c oll ect e d as m a ny ti m es as r e q uir e d ov er t h e scr e e ni n g p eri o d u ntil a n eli gi bl e s a m pl e is o bt ai n e d. Of t h e pr e -tr e at m e nt p eri o d s a m pl es 
c oll ect e d, o nly t h e Visit 2 ( d ay-2) a n d Visit 3( d ay -1) ov er ni g ht s p ut u m s a m pl es will b e us e d f or t h e effic acy e n d p oi nt t ests.  
T h e d ay s p ut u m c oll ecti o n st arts r efl ects t h e d ay t o w hic h t h at s a m pl e a p pli es. e. g. a s a m pl e w h os e c oll ecti o n st arts o n d ay 1 a n d e n ds o n d ay 2, is d esi g n at e d as t h e d ay 1 
ov er ni g ht  s p ut u m s a m pl e ( a n d r es ults).  
M.  R a n d o miz ati o n m ay occ ur o nc e all t h e scr e e ni n g r es ults ar e av ail a bl e a n d t h e I nv esti g at or h as d et er mi n e d t h at t h e p artici p a nt  is eli gi bl e f or t h e tri al.  
N.  Aft er t h e first d os e of I P, s u bs e q u e nt d os es of I P will b e a d mi nist er e d  2 3 t o 2 5 h o urs aft er t h e pr evi o us d os e.  
O.  Mi ni m u m i n hi bit ory c o nc e ntr ati o n ( MI C) a n d s p eci ati o n of t h e i nf ecti n g or g a nis m by p oly m er as e c h ai n r e acti o n ( P C R) will b e es ti m at e d fr o m a c ult ur e c oll ect e d o n a pr e-tr e at m e nt 
d ay ( d ay -1 or d ay -2) a n d fr o m t h e l ast  av ail a bl e c ult ur e o n a tr e at m e nt d ay ( d ay 1 4 or e arli er, b ut n ot e arli er t h a n d ay 8). Dr u g s usc e pti bility t esti n g of M. t u b erc ul osis  f or s e nsitivity 
t o rif a m pici n wit h a m ol ec ul ar m et h o d will b e t est e d at Visit 1.  Susc e pti bility t o I N H, Rif, E M B a n d P Z A will b e t est e d o n a c ult ur e gr o w n fr o m a b as eli n e s a m pl e ( d ay -2 or d ay -1). 
T h e a n alysis of a ny b act eri al is ol at es s e nt t o G S K, S p ai n f or f urt h er c h ar act eris ati o n i n t h e ev e nt of MI C c h a n g e will n ot b e  r e p ort e d i n t h e cli nic al st u dy r e p ort a n d will b e r e port e d 
s e p ar at ely.  
P.  A dv ers e ev e nts ( A E) will b e c oll ect e d by t h e I nv esti g at or fr o m t h e ti m e a p artici p a nt r ec eiv es his/ h er first d os e of I P t hr o u g h t o t h e Visit 1 9 ( d ay 2 8) F oll o w u p Visit.  
Q.  
R.  
 
S.  O nly t o b e p erf or m e d o n p artici p a nts r ec eivi n g t h e a ntici p at e d hi g h est d os e or o n p artici p a nts wit h c h a n g es i n cli nic al st at u s w arr a nti n g a f oll o w-u p ec h o i n t h e o pi ni o n of t h e 
i nv esti g at or. T h e d os e esc al ati o n c o mmitt e e m ay d eci d e t o p erf or m t his ass ess m e nt i n a d diti o n al c o h orts wit hi n t his st u dy.  
T.  S a m pl es will b e ass ay e d f or: Tr o p o ni n I. T h e first t w o s a m pl es at l e ast 2 4 h o urs a p art, o n e d uri n g t h e scr e e ni n g p h as e a n d o n e pri or t o t h e first d os e of st u dy tr e at m e nt.  D ay 1 4 
s a m pl e wi n d o w is ± 2 4 h o urs. T hir d s a m pl e t o b e t ak e n o n D ay 3.  
C CI
C CI
C CI


TMF-13331420  
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STUDY VISIT  
Visit 12 
to 15 
Visit 16 
Visit 17 
Visit 18 
STUDY DAY 
Day 12 
Day 13 
Day 14 
Day 15 
STUDY HOURB  
 
 
0 
0.5 
1 
1.5 
2 
3 
4 
6 
8 
12 
24 
Pharmacokinetic 
samplingC 
XA 
XA 
XD 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
A. Sample to be taken within 30 minutes pre-dose. 
B. All values are relative to the time of day that the study treatment is administered on Day 14. 
C. PK sampling is only to be performed on participants receiving GSK3036656. PK samples will not be taken from participants receiving Rifafour. 
D. Sample to be taken within 10 minutes pre-dose 
 
PK Sample timing window allowances 
Sample timepoint 
Sample collection window allowed 
Pre dose  
Not applicable (see footnotes above) 
0h - 4h post  
  5 min 
> 4h – 12h post 
 15 min 
> 12h – 24h post 
 1 h 
 
 


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Section 3.3.1 Risk Assessment 
Potential Risk of Clinical Significance  
Summary of Data/Rationale for Risk 
Mitigation Strategy  
Investigational Product (IP) GSK3036656 
Reduction in red blood cell count 
Non-Clinical 
In a 4-week rat study (doses 3, 10 & 30 mg/kg/d) -  
dose-dependent decline in reticulocytes (by up to 
52% in males and 62% in females) at day 7 followed 
by normal levels by day 14 and increased levels by 
day 29/30 compared to controls. Hgb levels 
decreased by 10-13% compared to controls on day 
14 and day 29/30. 
In a 4 week dog study (doses 5, 10 & 20 mg/kg/d) -  
mild dose-dependent decrease in Hgb on day 14 (by 
about 10% compared to controls) with recovery by 
week 4. Reticulocyte counts unaffected. Dogs not 
bled on day 7. 
No histopathological changes in bone marrow or 
other relevant histopathology in the 4-week studies. 
Clinical 
In the 201040 study, a possible trend of decreased 
haemoglobin from baseline to follow-up was noted in 
aggregate haematology data.  The mean change 
from baseline to follow-up was -4.9 g/L in the 15 mg 
Standard safety haematology and clinical 
chemistry assessments will be performed and 
both trends and changes outside normal range 
will be monitored as part of laboratory safety 
assessments. 
 
Participants whose haemoglobin drops below 
pre-specified limits (<8.0 g/dL) will be withdrawn 
from the study (Section 8.1.3). 
 
While women of non-childbearing potential are 
permitted in this study, women who are 
susceptible to heavy periods or heavy vaginal 
bleeding or spotting will be excluded in order to 
minimize blood loss and avoid confounding 
effects on the interpretation of haematology 
parameters. 


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Potential Risk of Clinical Significance  
Summary of Data/Rationale for Risk 
Mitigation Strategy  
repeat dose cohort, compared to -1.5 g/L in the 
placebo group. None of the values hit potential 
clinical importance (PCI) criteria, and declines were 
not clinically relevant. 
No clinically significant trends in reticulocyte values 
were observed, and there were no values of potential 
clinical importance reported for reticulocytes. 
GSK3036656 is cleared through the 
kidneys 
The main route of clearance for GSK3036656 is 
renal and there is therefore a risk that participants 
with low creatinine clearance will accumulate 
GSK3036656 and exceed predefined exposure 
limits.  
Participants with a creatinine clearance less 
than 75 mL/min have been excluded.  
Reduction in white blood cell count 
Non-Clinical 
In the 4-week rat study, decrease of up to 37% in 
total leucocyte count on day 29/30 compared to 
controls. 
In the 4-week dog study, no reported effects on white 
blood cells. 
Clinical 
No clinically significant trends in leukocyte or 
neutrophil count values were observed. Two subjects 
showed PCI values. One subject had low neutrophil 
White blood cell count will be monitored as part 
of laboratory safety assessments. Any clinically 
significant changes will be followed up until 
levels are not clinically significant. 
 
Participants developing neutrophil counts 
<500/mm3 (1.0x109/L) will be withdrawn from 
the study (Section 8.1.3). 


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Potential Risk of Clinical Significance  
Summary of Data/Rationale for Risk 
Mitigation Strategy  
count (normal range 1.57-6.81 × 10^9/L) from 
screening (1.38) until follow-up (1.41), and also 
showed low leukocyte count (normal range 3.3-9.8 × 
10^9/L) on Day 4 (2.5), Day 10 (2.6) and Day 14 
(2.9) and was within normal range at follow-up. Given 
the low screening values, this observation was 
considered likely related to the subject’s Black or 
African American race. A second subject had a 
single low neutrophil count at follow-up (1.48). 
 
Heart valvular and vascular pathology 
Non-Clinical 
In a 7-day dog dose range finding (DRF) study – 
minimal focal subendocardial hemorrhage on the 
atrial surface of the left atrioventricular valve 
observed in both animals at the top dose of 60 
mg/kg/d. 
In a 10-day dog investigative study at 65 mg/kg/d – 
vascular lesions (including minimal focal necrosis 
and inflammatory infiltrate) in 3 out of 8 dogs. 
In the 4-week dog GLP study - no heart or valve 
changes were observed up to the top dose of 20 
mg/kg/day and there was no increase in 
inflammatory markers.  
 
This pathology is not monitorable in humans. 
To avoid risk to humans, dosing will be limited 
to doses at which individual exposures [AUC (0-
24)] do not exceed 4.9 µg.h/ml – 1/30 of the 
dog NOAEL exposure (from the 4-week GLP 
study) at which no heart pathology was seen. 
To avoid risk to study participants, dosing 
will be limited to doses at which individual 
exposures do not exceed AUC0-24 and 
Cmax to 15µg.hr/ml and 1.5µg/ml 
respectively. 


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Potential Risk of Clinical Significance  
Summary of Data/Rationale for Risk 
Mitigation Strategy  
In the 17 week GLP dog study there were no 
heart or valve changes up to the top dose of 
45mg/kg/day. 
 
In the 17 week rat study there were no changes in 
cardiac pathology up to the top dose of 
30mg/kg/day.  
Valvular or vascular pathology were not observed in 
rats. This pathological change is not commonly seen 
in animals, and its mechanism and significance to 
humans are not clear. A correlation between the 
presence of hemodynamic changes and the 
presence of this pathology is suspected, but currently 
unproven. 
Clinical 
Echocardiograms were performed at screening and 
follow up in the 201040 FTIH study in order to 
exclude participants with pre-existing valve or other 
cardiac abnormalities from the study, and to detect 
the presence of abnormalities after completion of the 
study.  No abnormalities were detected. 
No SAEs, or AEs of cardiovascular nature were 
reported.  There was no change from baseline in 
heart rate observed at any dose.  No trends in 
blood pressure change were observed.  Cardiac 
telemetry and echocardiogram-related 
These exposures are 10-fold below the 
lowest NOAEL achieved in the 17 week 
studies (rat)  
In addition, although the pathology is not 
monitorable in humans, echocardiograms will be 
performed for all participants at screening and, 
for subjects receiving the highest dose of 
GSK3036656 or whose clinical status warrants 
it, also at follow-up (or early withdrawal). 
Cardiac troponin will be measured. 
  


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Potential Risk of Clinical Significance  
Summary of Data/Rationale for Risk 
Mitigation Strategy  
interpretations were within normal range.  There 
were no clinically significant ECG observations.  
There were no troponin I abnormalities in 
participants after receiving study drug 


T M F -1 3 3 3 1 4 2 0  
C O N FI D E N TI A L  
 
 
 
2 0 1 2 1 4  
 
 
 
 
1 0 6  
 
Secti o n 5. 1  
T he st u d y will c o m prise u p t o 5  c o h orts of partici pa nts. It is i nte n de d t hat 1 5 partici pa nts 
i n eac h c o h ort will recei ve G S K 3 0 3 6 6 5 6 a n d 5 will recei ve st a n dar d-of -care re gi me n f or 
D S -T B ( Rifaf o ur e -2 7 5).   
…  
Secti o n 5. 6  
E x p os ure li mits of A U C 0 – 2 4 of 1 5  μ g. h/ m L a n d C ma x of  1. 5  u g/ m L were s et, base d o n 
i nf or mati o n i n Secti o n 3. 3 . 
A l oa di n g d os e of G S K 3 0 3 6 6 5 6 ma y b e a d mi nistere d o n t he first da y  ( or o ver m ulti ple 
d a ys w here re q uire d i n or der t o n ot e x cee d A U C a n d C m a x e x p os ure li mits) of st u d y 
treat me nt a d mi nistrati o n i n eac h c o h ort. 
T a ble 1  
L oa di n g D ose 
( m g)a 
Pr o ba bilit y 
Da y 1 c 
Mai nte na nce 
D ose ( m g) b 
pr o ba bilit y 
Da y 1 4 d 
Tar get 
Attai n me nt Rate e 
1 5  
< 1 %  
5  
< 1 %  
< 1 %  
2 5  
< 1 %  
1 0  
< 1 %  
1 0 0 %  
5 0  
< 1 %  
2 0  
< 1 %  
1 0 0 %  
7 5  
6. 9 0 %  
3 0  
5. 8 0 %  
1 0 0 %  
a D a y 1  
  
  
  
  
b  D a y 2 -1 4  
 
 
 
  
cper tri al pr o b a bilit y of a n i n di vi d u al p artici p a nt e xcee di n g t he e x p os ure li mits 
[ A U C0 – 2 4 = 1 5 u g. h/ m L or C m a x = 1. 5 u g/ m L] o n D a y 1 (si m ul ati o ns b ase d o n a 
l o w er li mit of 7 5 m L/ mi n f or cre ati ni ne cle ar a n ce) 
d  per tri al pr o b a bilit y of a n i n di vi d u al p artici p a nt e xcee di n g t he e x p os ure li mits 
[ A U C0 – 2 4 = 1 5 u g. h/ m L or C m a x = 1. 5 u g/ m L] o n D a y 1 4 (si m ul ati o ns b ase d o n 
a l o w er li mit of 7 5 m L/ mi n f or cre ati ni ne cle ar a nce)  
e per tri al pr o b a bilit y of > 9 0 % of p artici p a n ts e xcee di n g t he t ar g et e x p os ure f or 
effic ac y  
 
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Section 6.1 
Sex 
10. Male or female of non-childbearing potential 
a. Male participants: 
A male participant with female partners of child-bearing potential must agree to use 
contraception as detailed in Appendix 5. 
Female participants:  
A female participant is eligible to participate if she is not pregnant (see Appendix 5), 
not breastfeeding, and at least one of the following conditions applies: 
Pre-menopausal females with one of the following: 
Tubal ligation 
Hysteroscopic tubal occlusion procedure with follow-up confirmation of bilateral 
tubal occlusion or documented bilateral salpingectomy  
Hysterectomy 
Bilateral Oophorectomy 
Postmenopausal females: postmenopausal will be defined as 12 months of 
spontaneous amenorrhea without an alternative medical cause. Post-menopausal 
status will be confirmed by a simultaneous FSH and estradiol levels test. 
11. 
Capable of giving signed informed consent as described in Appendix 3 which 
includes compliance with the requirements and restrictions listed in the informed consent 
form (ICF) and in this protocol. 
Section 6.2 
6.  
History of photosensitivity 
8. 
Known or suspected, current or history of within the past 2 years, Current 
alcohol or drug abuse, that is, in the opinion of the Investigator, sufficient to compromise 
the safety or cooperation of the participant. 
12. 
Treatment received with any drug active against Mtb (including but not limited to 
isoniazid, ethambutol, fluoroquinolones, rifampicin), or with immunosuppressive 
medications such as TNF-alpha inhibitors or systemic or inhaled corticosteroids (used 
for > 5 consecutive days), within 2 weeks prior to screening. Refer to the SRM for 
details. 
14. 
Participants with the following abnormal laboratory values at screening as defined 
by graded by the enhanced Common Terminology Criteria for Adverse Events (CTCAE 
v 5 2017): 


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16 Women who are susceptible to heavy periods or heavy vaginal bleeding, in the 
investigator’s judgement or spotting will be excluded in order to minimize blood loss and 
avoid confounding effects on the interpretation of haematology parameters. 
Section 6.3.1 
Participants should minimise any exposure to sources of ultra-violet radiation, e.g. refrain 
from sunbathing; use of tanning salons/sunbeds, starting on the day of first dosing until 
five half-lives (6 days) after the last dose on day 14 (as per Section 3.3). 
Section 6.3.2 
• Water is allowed at dosing in order to administer study medication. No water is 
allowed from dosing until 2 hours afterwards; Water is allowed ad libitum at all 
other times. 
Section 8 
If study treatment/investigational product is interrupted or stopped this does not 
automatically result in the participant being withdrawn from the study. The 
investigator will make all effort to retain the patient in the study, provided the 
participant continues to provide their consent,  and to complete and record all 
scheduled safety assessments required by the protocol. For the avoidance of all 
doubt: this does not prejudice the rights of the investigator and study participants 
under ICH GCP and under applicable laws. The study participant retains the right 
to withdraw consent at any time for any reason. The investigator also retains the 
right to withdraw the patients from the study if in the investigator’s judgement, 
withdrawal is judged clinically necessary to protect a participant’s safety. 
If this results in the patient being placed on standard of care (RifaFour), then all 
assessments relevant to RifaFour will be performed as directed by the protocol (for 
example, GSK3036656 pharmacokinetic assessments are not required, since the 
participant is not being dosed with GSK3036656). 
Section 7.2 
On or prior to day 1, eligible participants will be assigned a unique number 
(randomization number) in ascending numerical order at the study site. 
Section 8.1.1 
Discontinuation of study treatment for abnormal liver tests is also required when: 
Section 9.1 
Mycobacterial Characterisation: 
Cultures from baseline and from day 14 5 sputum will be kept for determination of the 
minimum inhibitory concentration (MIC) of the investigational agents that the subject 
was treated with. If a day 14 5 culture is not available, the last available culture after day 


T M F -1 3 3 3 1 4 2 0  
C O N FI D E N TI A L  
 
 
 
2 0 1 2 1 4  
 
 
 
 
1 0 9  
 
8 will be ke pt. I n t he e ve nt of si g nific a nt c h a n ges i n t he MI C, b acteri al is ol ates will 
be se nt t o t he G S K S p ai n l a b or at or y f or f urt her c h ar acteris ati o n. Tec h nic al det ails 
are pr o vi de d i n t he S R M.  
Secti o n 9. 2. 6  
Details of all pre g n a ncies i n  pre g n a ncies i n fe male partici pa nts a n d, if i n dicate d, fe mal e 
part ners of m ale partici p a nts will be c ollecte d after t he start of st u d y treat me nt a n d u p t o 
7 da ys after t h e fi nal d os e of st u d y m e dicati o n . 
•  A b n or mal pre g n a nc y o ut c o mes (e. g., s p o nta n e o us a b orti o n, fe tal deat h, still birt h, 
c o n ge nital a n o malies, ect o pic pre g na n c y) are c o nsi dere d S A E.  
Secti o n 9. 4. 1  
•  A brief p h ysic al e x a mi nati o n will i ncl u de, at a mi ni m u m, assess me nts of t he s ki n, 
l u n gs, car di o vasc ular s yste m, a n d a b d o me n (li ver a n d s plee n). 
Secti o n 9. 4. 2  
•  
Vital si g ns (t o be ta k e n b ef ore bl o o d c ollecti o n f or la b orat or y tests) will c o nsist 
of at least 1 p ulse a n d bl o o d press ure meas ure m e nt. W here a meas ure me nt is 
a b n or mal or si g nifica ntl y differe nt fr o m pre vi o us meas ure me nts, t his will be 
re peat e d. W here B P an d p ulse is re peate d a b o ve, a f urt her 2 rea di n gs rec or de d at 
least 1 mi n a part will be o btai ne d f or c o nfir mati o n a n d t he a vera ge of t he 2 
rec or de d i n t he C R F. 
Secti o n 9. 4. 3  
At eac h ti me p oi nt at w hi c h  I n t he e ve nt w here tri plicate E C G re a di n gs are  re q uire d, 3 
i n di vi d ual E C G traci n gs s h o ul d be o btai ne d as cl osel y as p ossi ble i n s uccessi o n, b ut n o 
m ore t ha n 2 mi n utes a part.  
Secti o n 9. 6. 1  
C CI


T M F -1 3 3 3 1 4 2 0  
C O N FI D E N TI A L  
 
 
 
2 0 1 2 1 4  
 
 
1 1 0  
 
Secti o n 1 0. 1  
T he pla n ne d sa m ple siz e f or t his st u d y is a p pr o xi matel y 6 0 -8 0  u p t o 1 0 0  partici pa nts 
ra n d o mise d de pe n di n g o n t he n u m ber of c o h orts ( 1 5 partici pa nts i n eac h G S K 3 0 3 6 6 5 6 
treat me nt gr o u p); s ufficie nt partici pa nts will be scree ne d t o ac hie ve t his sa m ple size. 
Of n ote, w hilst a p pr o xi matel y 2 0  2 5  s u bjects i n t he st u dy will be ra n d o mise d t o S O C, 
f or mal c o m paris o ns of G S K 3 0 3 6 6 5 6 t o S O C will n ot be ma de. 
Secti o n 1 0. 3. 1  
Ex pl or atory  
Will b e d escri b ed i n th e R A P a n aly se d a n d re p ort e d se p ar at ely.   
 
Secti o n 1 0. 3. 4  
N o f or mal i nteri m a nal ys es are pl a n ne d f or t his st u d y. H o we ver, safet y, t ol era bilit y a n d 
p har mac o ki netic d ata will be re vie we d bef ore eac h d ose escal ati o n. I n a d diti o n, t he 
pri mar y efficac y e n d p oi nt ma y als o be a nal yse d after t he fi nal visit of t he last s u bject f or 
t he c o h ort w hic h recei ves t he a ntici pate d hi g hest d ose  as s pecifie d i n secti o n 1 1 . f or 
f urt her det ails. 
Secti o n 1 1  
T he pri mar y e n d p oi nt ma y be a nal yse d f or all a v aila ble c o h orts aft er t he fi n al visit of t he 
last s u bject o n f or t he sec o n d c o nsec uti ve c o h ort t h at re ac hes o r e x cee ds t he t ar get 
P K pl as m a e x p os ure f or effic ac y ( b ase d o n t he m uri ne i nfecti o n m o del).   w hic h 
recei v es t he a ntici pate d hi g hest d ose (as deter mi ne d b y t he D E C). T he p ur p ose of t his 
effic ac y a n al ysis is t o o pti mise d osi n g f or s u bse q u e nt c o h orts (e. g. t o hel p esti mate t he 
d ose res p o nse c ur ve) as well as t o ai d i nter nal decisi o n ma ki n g.  
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The DEC is empowered to take the following decisions for subsequent cohorts: 
To select a higher dose (including a loading dose that may be given over 1 or more 
days) within the limits defined in Section 5.6. 
Section 13.3 
 
Other 
Screening 
Tests 
• Folicle-stimulating hormone and estradiol (as to confirm post-menopausal 
status) 
• Alcohol and Urine drug screen (to include at minimum: amphetamines, 
cocaine, opiates. 
• Urine human chorionic gonadotropin (hCG) pregnancy test (as needed 
for women of childbearing potential)2 
• Serology (HIV antibody, hepatitis B surface antigen [HBsAg], and hepatitis 
C virus antibody) 
• Cardiac safety screening: Troponin. 
• The results of each test must be entered into the CRF. 
1. 
Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver stopping or 
monitoring event are given in Section 8.1 and Appendix 7 All events of ALT 3 × upper limit of normal (ULN) and 
bilirubin 2 × ULN (>35% direct bilirubin) or ALT 3 × ULN and international normalized ratio (INR) >1.5, if INR 
measured, if INR measured, which may indicate severe liver injury (possible Hy’s Law), must be reported as an 
SAE (excluding studies of hepatic impairment or cirrhosis). 
D. Local urine testing will be standard for the protocol unless serum testing is required by local regulation or IRB/IEC. 
 
Section 13.4  
The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
Sponsor and anTBiotic consortium members, by appropriate IRB/IEC members, and 
by inspectors from regulatory authorities. 
Section 13.6 
Pregnancy Testing 
Pregnancy testing will be performed whenever a menstrual cycle is missed or when 
pregnancy is otherwise suspected until the follow-up visit. 
Female Participants who become pregnant 
• 
Investigator will collect pregnancy information on any female participant, who 
becomes pregnant while participating in this study.  


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• 
Information will be recorded on the appropriate form and submitted to GSK within 
24 hours of learning of a participant's pregnancy.  
• 
Participant will be followed to determine the outcome of the pregnancy. The 
Investigator will collect follow up information on participant and neonate, which will 
be forwarded to GSK Generally, follow-up will not be required for longer than 6 to 8 
weeks beyond the estimated delivery date.   
• 
Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure.  
• 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or 
SAE.  
• 
A spontaneous abortion is always considered to be an SAE and will be reported as 
such.   
• 
Any SAE occurring as a result of a post-study pregnancy which is considered 
reasonably related to the study treatment by the Investigator, will be reported to GSK 
as described in Section 13.5. While the Investigator is not obligated to actively seek 
this information in former study participants, he or she may learn of an SAE through 
spontaneous reporting.  
Any female participant who becomes pregnant while participating will be withdrawn 
from the study. 
• Agree to use a male condom plus an additional method of contraception 
with a failure rate of <1% per year as described in Table 3 when having 
penile-vaginal intercourse with a woman of childbearing potential, for a 
period of 90 days after the last dose of study medication.  
 
Section 13.7 
Elevated liver enzymes, transient liver dysfunction, hepatotoxicity and hepatitis are 
listed as side-effects in the package inserts for Rifafour e-275 (see References), 
associated with multiple drug components. Therefore, participants allocated to 
Rifafour e-275 treatment who experience Liver Chemistry Stopping criteria are not 
mandated in the first instance to undergo those follow-up assessments (which are 
intended to investigate aetiology). The investigations may still be performed, if 
required in the judgement of the investigator. 


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Required Actions and Follow up Assessments  
Actions 
Follow Up Assessments 
• Immediately discontinue study treatment  
• Report the event to GSK within 24 hours 
• Complete the liver event CRF and complete an 
SAE data collection tool if the event also meets 
the criteria for an SAE2 
• Perform liver chemistry event follow up 
assessments  
• Monitor the participant until liver chemistries  
resolve, stabilize, or return to within baseline 
(see MONITORING below) 
• Do not restart/rechallenge participant with 
study treatment unless allowed per protocol 
and GSK Medical Governance approval is 
granted (see below)   
• If restart/rechallenge not allowed per 
protocol or not granted, permanently 
discontinue study treatment and continue 
participant in the study for any protocol 
specified follow up assessments  
 
 
MONITORING: 
For bilirubin or INR criteria:  
• Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within 24 
hrs 
• Monitor participants twice weekly until liver 
chemistries resolve, stabilize or return to within 
baseline  
• A specialist or hepatology consultation is 
recommended 
For All other criteria:  
• Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
For all study participants: 
• Obtain INR and recheck with each 
liver chemistry assessment until the 
transaminases values show downward 
trend 
• Record the appearance or 
worsening of clinical symptoms of 
liver injury, or hypersensitivity, on 
the AE report form 
• Record use of concomitant 
medications on the concomitant 
medications report form including 
acetaminophen, herbal remedies, 
other over the counter medications. 
• Record alcohol use on the liver 
event alcohol intake case report 
form (CRF) page  
 
For participants on GSK303656 arm 
• Viral hepatitis serology4 
•  Obtain blood sample for 
pharmacokinetic (PK) analysis as 
soon as possible, and certainly within 
14 days after last dose 5 
• Serum creatine phosphokinase (CPK) 
and lactate dehydrogenase (LDH). 
• Fractionate bilirubin, if total 
bilirubin2xULN 
• Obtain complete blood count with 
differential to assess eosinophilia 
 
 
For bilirubin or INR criteria: 
For participants on GSK303656 arm 
only 


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liver event follow up assessments within 24-72 
hrs  
• Monitor participants weekly until liver 
chemistries resolve, stabilize or return to within 
baseline 
• Auto-immune screen: Anti-
nuclear antibody, anti-smooth 
muscle antibody, Type 1 anti-liver 
kidney microsomal antibodies, 
and quantitative total 
immunoglobulin G (IgG) or 
gamma globulins. 
• Serum 
paracetamol/acetaminophen 
adduct high performance liquid 
chromatography (HPLC) assay 
(quantifies potential 
acetaminophen contribution to 
liver injury in participants with 
definite or likely acetaminophen 
use in the preceding week [James 
2009]). NOTE: not required in 
China  
• Liver imaging (ultrasound, 
magnetic resonance, or 
computerised tomography) and /or 
liver biopsy to evaluate liver 
disease; complete Liver Imaging 
and/or Liver Biopsy CRF pages. 
 
Liver chemistry criteria for a Liver Monitoring Event and follow-up actions: 
These Increased Monitoring Criteria apply to all participants who experience a 
Liver Event, regardless of which treatment the participant has been randomized to. 
Liver Chemistry Increased Monitoring Criteria – Liver Monitoring Event 
Criteria 
Actions 
ALT 3×ULN and <5×ULN and 
bilirubin <2×ULN, without 
symptoms believed to be related 
to liver injury or hypersensitivity, 
and who can be monitored 
weekly for 4 weeks. 
• Notify the GSK medical monitor within 24 
hours of learning of the abnormality by 
email or phone to discuss participant 
safety. 
• Participant can continue study 
intervention.   
• Participant must return weekly for repeat 
liver chemistries (ALT, AST, ALP, 
bilirubin) until they resolve, stabilise or 
return to within baseline.  


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• If at any time participant meets the liver 
chemistry stopping criteria, proceed as 
described above 
• If, after 4 weeks of monitoring, ALT 
<3×ULN and bilirubin <2×ULN, monitor 
participant twice monthly until liver 
chemistries normalize or return to within 
baseline 
The site will complete the liver event eCRF (Monitoring Event) in InForm and 
should also consider whether the AE reporting guidelines apply. 
References 
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee 
WM. Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen 
Overdose and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784. 
Rifafour e-275 tablet electronic package inserts. Accessed 20 Feb 2019.: 
http://home.intekom.com/pharm/hmr/rifaf275.html 
END OF CHANGES 
 
Amendment 2 24-SEP-2018 
The primary motivation for this amendment was to update the eligibility criteria to 
impose a minimum renal function (as defined by creatinine clearance) in light of the first-
in-human data that showed the main route of clearance for GSK3036656 is through the 
kidneys. As a result of the long half-life of GSK3036656, updated dosing strategy has 
also been implemented incorporating the use of loading doses.  
Further changes made to the protocol are detailed in the table below. 


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Section # 
Description of Change 
Brief Rationale 
Whole 
document 
Minor updates including 
typographical corrections 
Inconsistencies between different parts 
of the document have been resolved and 
clarifications inserted where required. 
2 
Removal of QTc endpoint 
The intent of including Holter monitoring 
assessments in the EBA study was to 
collect data similar to that obtained in a 
thorough QT (TQT) study.  These data 
would be used for an exposure-response 
analysis.  However, since a positive 
control (moxifloxacin) will not be used in 
the EBA study (as required in a TQT 
study) and the EBA study is unlikely to 
achieve maximum concentrations of 
GSK3036656 that are in the range of 4- 
to 10-times the therapeutic dose (as 
required for 1 arm in a TQT study), the 
decision was made to remove Holter 
monitoring assessments from the EBA 
study. 
3.3.1 
Depigmentation 
Depigmentation was seen in some 
animals in a 4-month GLP toxicology 
study. The risk-benefit assessment has 
been updated.  Patients with vitiligo will 
be excluded from the study to avoid 
confounding in baseline and follow-up 
skin assessments. 
3.3.1 
Benefit-risk table - Clinical 
subsections updated with data 
from finalised 201040 CSR 
Finalised data from the First in Human 
clinical trial are now available and have 
been incorporated. 
2 & 3.3.1 
Cardiac BNP assessment 
removed 
Cardiac BNP is an acute phase reactant 
and has been reported to be elevated in 
a wide range of inflammatory conditions. 
Cardiac BNP monitoring is therefore 
considered to be of limited value in the 
context of patients with tuberculosis. 


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Section # 
Description of Change 
Brief Rationale 
5.6 
Loading doses 
The long half-life of GSK3036656 means 
that 6 days are needed to achieve steady 
state concentrations in blood. The 
possibility of using loading doses has 
been included so that steady state may 
be reached more quickly. A rationale for 
how doses will be chosen has been 
included. 
6.2 
Removal of exclusion for patients 
with previous TB. 
This criterion is obsolete. Until recently it 
was useful to exclude these patients 
based on the probability of rifampicin 
resistance TB in these subjects. Sputum 
smears have recently been replaced with 
GeneXpert MTB/RIF in the public health 
system and now provides reliable 
information about rifampicin resistance. 
6.1.8 
Renal clearance threshold 
The main route of clearance for 
GSK3036656 is renal. There is therefore 
a risk that participants with low creatinine 
clearance will accumulate GSK3036656 
and these patients have therefore been 
excluded. 
8.1.3 
Haematology stopping criteria 
Black Africans have a wider normal 
range for neutrophil counts. The 
threshold for stopping IP is therefore 
revised from 1000/mm3 to 500/mm3. 
9.3 
Overdose window 
The IP dosing has been permitted within 
a 2-hour window (24 hours±1 hour). The 
definition of an overdose has been 
updated to reflect this change. 
10.3.4 & 11 
Efficacy data analysis 
There is uncertainty in how the efficacy 
of GSK3036656 will translate from 
animal models to the clinic. An efficacy 
data analysis following the cohort which 
receives the anticipated highest dose, 
will permit the sponsor to optimise dosing 
for subsequent cohorts as well as to aid 
internal decision making. 
The dose escalation committee (DEC) 
has been empowered to assess and act 
on this data. 


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Section # 
Description of Change 
Brief Rationale 
Appendix 6 
Contraception guidance 
The previous guidance was unclear and 
included durations in both weeks and 
days. This has now been clarified 
 
CHANGES 
 


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Period 
Screening 
Dosing 
Follow-up 
Visit 
1 
2 
3 
4 
5 to 10 
11 
12 to 16 
17 
18 
Early 
Withdrawal 
19 
Day 
(-9 to -
3) A 
-2B 
-1 
1 
2 to 7C 
8 
9 to 13C 
14 
15 
28 
( 
7) 
Documentation of Positive GeneXpert and/or 
TB smear (TB clinic/site of initial diagnosis) 
X 
 
 
 
 
 
 
 
 
 
 
Written Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Demography (including smoking history) 
X 
 
 
 
 
 
 
 
 
 
 
Medical & Treatment History 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion/Eligibility Assessment 
X 
 
 
 
 
 
 
 
 
Chest X-ray 
X 
 
 
 
 
 
 
 
 
 
Physical ExaminationD 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs E 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-Lead ECG  
X 
 
 
 
 
 
 
X 
 
X 
RandomisationM 
 
X 
 
 
 
 
 
 
 
 
Echocardiogram (may be conducted at any of 
the screening visits) 
X 
 
 
 
 
 
 
XS 
XS 
Blood PKF 
 
 
 
 
 
 
 
X 
X 
X 
 
Spot Sputum (confirm TB & adequate bacterial 
load) G 
X 
 
 
 
 
 
 
 
 
 
 
Rifampicin Resistance Test (rapid)G 
(microscopy and GeneXpert tests may be 
repeated on an overnight sputum sample if 
needed) 
X 
 
 
 
 
 
 
 
 
 
 
Haematology, Clinical Chemistry, Urinalysis H 
X 
 
 
X 
X 
X 
 
X 
 
X 
X 
Cardiac safety biomarkersT 
X 
X 
X 
 
 
X 
 
 
 
Urine Drug ScreenI 
X 
XI 
 
 
 
 
 
 
 
 
 
Urine Pregnancy TestR 
 
X 
 
 
 
 
X 
X 
 
 
HIV Test (and CD4 Count if HIV confirmed) 
X 
 
 
 
 
 
 
 
 
 
 


T M F -1 3 3 3 1 4 2 0  
C O N FI D E N TI A L  
 
 
 
2 0 1 2 1 4  
 
 
 
1 2 0  
 
P eri o d  
Scr e e ni n g  
D o si n g  
F oll o w -u p  
Vi sit  
1  
2  
3  
4  
5 t o 1 0  
1 1  
1 2 t o 1 6  
1 7  
1 8  
E arl y 
Wit h dra w al  
1 9  
D a y  
(-9 t o -
3) A  
-2 B  
-1  
1  
2 t o 7 C  
8  
9 t o 1 3 C  
1 4  
1 5  
2 8 
( 
7)  
 
 
 
X  
X  
 
 
X  
 
X  
 
 
 
 
X  
X  
 
 
X  
 
X  
 
 
X  
 
 
 
 
X  
 
 
H os pit al A d missi o n  
X B  
X B  
 
 
 
 
 
 
 
 
 
Ov er ni g ht S p ut u m L 
X  
X  
X  
X  
X  
X  
X  
X  
 
 
 
I P A d mi nistr ati o n a n d C o m pli a nc e C h eckN  
 
 
 
X  
X  
X  
X  
X  
 
 
 
Myc o b act eri ol o gy Ass ess m e nts O  
 
X  
X  
 
 
 
 
X  
 
 
 
H os pit al Disc h ar g e  
 
 
 
 
 
 
 
 
X  
X  
 
C o nc o mit a nt M e dic ati o n  
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
A dv ers e Ev e nts P  
 
 
 
X  
X  
X  
X  
X  
X  
X  
X  
P oi nt of C ar e Bl o o d Gl uc os e or H b A 1c Q  
 
X  
 
 
 
 
X  
X  
 
 
 
A.  T h e Visit 1 ( d ay -9 t o -3) ti m e p eri o d will  b e u p t o a m axi m u m of 7 d ays b ut will b e k e pt as s h ort as p ossi bl e.  
B.   P artici p a nts c a n pr oc e e d wit h t h e Visit 2 ( d ay -2) ass ess m e nts as s o o n as t h eir Visit 1 ( d ay -9 t o -3) ass ess m e nts h av e b e e n c o m pl et e d i. e. Visits 1 a n d 2 m ay occ ur o n t h e s a m e 
d ay as l o n g as t h e scr e e ni n g r es ults ar e av ail a bl e i n ti m e f or r a n d o mis ati o n. Partici p a nts m ay b e h os pit alis e d d uri n g t h e e ntir e pr e -tr e at m e nt p eri o d if t h e I nv esti g at or c o nsi d ers it 
a dvis a bl e f or r e as o ns of s af ety or c o m pli a nc e.  
C.  All ev e nts list e d as occ urri n g o n Visit 5 ( d ay 2) t o Visit 1 0 ( d ay 7) a n d Visit 1 2 ( d ay 9) t o Visit 1 6 ( d ay 1 3) will b e c o n d uct e d e ac h d ay d uri n g t h es e visits.  
D.  H ei g ht ( m) will o nly b e c oll ect e d o nc e at Visit 1 ( d ay -9 t o -3). A f ull p hysic al ex a mi n ati o n will b e p erf or m e d at Visit 1 ( d ay -9 t o -3), wit h sy m pt o m -dir ect e d p hysic al ex a mi n ati o ns at 
Visit 1 7 ( d ay  1 4), Visit 1 9 ( d ay 2 8) a n d E arly Wit h dr a w al Visit ( E W V).  Sy m pt o m dir ect e d p hysic al ex a mi n ati o ns m ay b e c o n d uct e d as r e q uir e d  d uri n g t h e st u dy (visits 4 t o 1 6).  
R e q uir e m e nt s f or t h e p h y si c al e x a mi n ati o n ar e s p e cifi e d i n t he S R M.  
E.  Syst olic bl o o d pr ess ur e ( S B P) a n d di ast olic bl o o d pr ess ur e ( D B P) ( m m H g), h e art r at e ( b e ats p er mi nut e [ b p m]), b o dy t e m p er at ur e (° C; or al) a n d w ei g ht (k g). T o b e p erfor m e d 
wit hi n 4 h o urs pri or t o t h e first d aily d osi n g o n Visit 4 ( d ay 1) t hr o u g h t o Visit 1 7 ( d ay 1 4) a n d wit hi n 2 h o u rs b ef or e t h e ti m e d osi n g w o ul d h av e occ urr e d o n Visit 1 8 ( d ay 1 5). O n 
d ays w h er e t h e f oll o wi n g ass ess m e nts ar e d o n e t h e or d er s h o ul d b e: vit al si g ns b ef or e bl o o d dr a ws f or P K or s af ety ass ess m e nt s. 
F.  P Ks will b e p erf or m e d as n ot e d i n t h e P K t a bl e. At E W V a P K s a m pl e will b e t ak e n pr e -d os e of t h e ti m e of t h e pl a n n e d first d aily d osi n g.  If t his is n ot p ossi bl e, a s p o nt a n e o us P K 
s a m pl e will b e t ak e n. 
C CI


T M F -1 3 3 3 1 4 2 0  
C O N FI D E N TI A L  
 
 
 
2 0 1 2 1 4  
 
 
 
1 2 1  
 
G.  S p ut u m s m e ar micr osc o py a n d m ol ec ul ar r a pi d t est f or c o nfir m ati o n of Myc o b act eri u m t u b erc ul osis a n d rif a m pici n s usc e pti bility ( G e n e X p ert). If r e q uir e d b y t h e i n v e sti g at or, t h e 
first s p ot s p ut u m or o v er ni g ht s p ut u m  d o es n ot s h o w u n e q uiv oc al r es ults, t h e t ests m ay b e r e p e at e d o n fr es hly c oll ect e d s p ot s p ut u m or ov er ni g ht s p ut u m a n d t h at r e s ult us e d 
i n st e a d. 
H.  L a b or at or y ass ess m e nts: h a e m at ol o gy ( h a e m o gl o bi n, h a e m at ocrit, r e d bl o o d c ell c o u nt, w hit e bl o o d c ell c o u nt wit h diff er e nti al, pl at el e t c o u nt). Cli nic al C h e mistry ( al b u mi n, ur e a, 
cr e ati ni n e, dir ect, i n dir ect a n d t ot al bilir u bi n, t ot al pr ot ei n, alk ali n e p h os p h at as e,  as p art at e a mi n otr a nsf er as e ( A S T), al a ni n e a mi n otr a nsf er as e ( A L T), g a m m a -gl ut a myl tr a nsf er as e 
( G G T), l actic d e hy dr o g e n as e ( L D H), s o di u m, p ot assi u m, c alci u m (c orr ect e d f or al b u mi n), c hl ori d e, r a n d o m/f asti n g gl uc os e). Urin alysis ( p H, s p ecific gr avity, pr ot ei n, gl uc os e, 
micr o -al b u mi n, k et o n es, bilir u bi n, cr e ati ni n e, nitrit e, s o di u m, ur o bili n o g e n, bl o o d, l e uk ocyt es, micr osc o py). C o a g ul ati o n t est (I N R , P T, A P T T). T o b e p erf or m e d o n Visit 4 ( d ay 1), 
Visit 6 or 7 ( d ay 3 or 4), Visit 1 1 ( d ay 8) a n d wit hi n 2 h o urs b ef or e t h e ti m e d osi n g w o ul d h av e occ urr e d o n Visit 1 8 ( d ay 1 5).  
I. 
Uri n e dr u g scr e e n: c oc ai n e, a m p h et a mi n es a n d o pi at es. Uri n e dr u g scr e e n c a n b e r e p e at e d at Visit 2 ( d ay -2) f or p artici p a nts w h o w er e n ot h os pit aliz e d at Visit 1 ( d ay -9 t o -3). 
J. 
K.  
L.  
Ov er ni g ht s p ut u m s a m pli n g m ay st art at Scr e e ni n g visit ( d ay -9 t o -3) or o n Visit 2 ( d ay – 2) a n d will c o nti n u e d aily u ntil Visit 7 ( d ay 4). A d diti o n al s a m pli n g will b e c o n d uct e d at visit 
9 ( d ay 6), Visit 1 1 ( d ay 8), Visit 1 3 ( d ay 1 0), Visit 1 5 ( d ay 1 2) a n d Visit 1 7 ( d ay 1 4). S p ut u m s a m pli n g will st o p o n t h e m or ni n g of Visit 1 8 ( d ay 1 5). S p ut u m c oll ecti o n will st art i n t h e 
aft er n o o ns at 1 5: 0 0 h o urs ( 1 h o ur) a n d c o nti n u e f or 1 6 h o urs ov er ni g ht. T h e 1 6-h o ur s p ut u m s a m pli n g f or e ac h of t h e s a m pli n g d ays m ust b e fi nis h e d pri or t o t h e a d mi nistr ati o n 
of t h e n ext d ay’s I P.  
Ov er ni g ht s p ut u m c oll ecti o n m ay b e c oll ect e d a s m a n y ti m e s a s re q uir e d o v er t h e s cr e e ni n g p eri o d u ntil a n eli gi bl e s a m pl e i s o bt ai n e d . Of t h e pr e-tr e at m e nt p eri o d s a m pl es 
c oll ect e d, o nly t h e Visit 2 ( d ay-2) a n d Visit 3( d ay -1) ov er ni g ht s p ut u m s a m pl es will b e us e d f or t h e effic acy e n d p oi nt t ests.  
T h e d ay s p ut u m c oll ecti o n st arts r efl ects t h e d ay t o w hic h t h at s a m pl e a p pli es. e. g. a s a m pl e w h os e c oll ecti o n st arts o n d ay 1 a n d e n ds o n d ay 2, is d esi g n at e d as t h e d ay 1 
ov er ni g ht s p ut u m s a m pl e ( a n d r es ults).  
M.  R a n d o miz ati o n m ay occ ur o nc e all t h e scr e e ni n g r es ults ar e av ail a bl e a n d t h e I nv esti g at or h as d et er mi n e d t h at t h e p artici p a nt is eli gi bl e f or t h e tri al.  
N.  Aft er t h e first d os e of I P, s u bs e q u e nt d os es of I P will b e a d mi nist er e d 2 3 t o 2 5 h o urs aft er t h e pr evi o us d os e.  
O.  Mi ni m u m i n hi bit ory c o nc e ntr ati o n ( MI C) a n d s p eci ati o n of t h e i nf ecti n g or g a nis m by p oly m er as e c h a i n r e acti o n ( P C R) will b e esti m at e d fr o m a c ult ur e c oll ect e d o n a pr e-tr e at m e nt 
d ay ( d ay -1 or d ay -2) a n d fr o m t h e l ast av ail a bl e c ult ur e o n a tr e at m e nt d ay ( d ay 1 4 or e arli er, b ut n ot e arli er t h a n d ay 8). Dr u g s usc e pti bilit y t esti n g of M. t u b erc ul osis  f or s e nsitivity 
t o rif a m pici n wit h a m ol ec ul ar m et h o d will b e t est e d at Visit 1.  Susc e pti bility t o I N H, Rif, E M B a n d P Z A will b e t est e d o n a c ult ur e gr o w n fr o m a b as eli n e s a m pl e ( d ay -2 or d ay -1). 
P.  A dv ers e ev e nts ( A E) will b e c oll ect e d by t h e I nv esti g at or fr o m t h e ti m e a p artici p a nt r ec eiv es his/ h er first d os e of I P t hr o u g h t o t h e Visit 1 9 ( d ay 2 8) F oll o w u p Visit.  
Q.  
R.  T h e uri n e pr e g n a ncy t est at D a y -2 or D a y -1 a n d D a y  1 4 m ust pr ec e d e t h e 
 a n d d o es n ot h av e t o b e r e p e at e d o n t h e ot h er d ays. 
S.  O nly t o b e p erf or m e d o n p artici p a nts r ec eivi n g t h e a ntici p at e d hi g h est d os e or o n p artici p a nts wit h c h a n g es i n cli nic al st at us w arr a nti n g a f oll o w -u p ec h o i n t h e o pi ni o n of t h e 
i nv esti g at or. T h e d os e esc al ati o n c o m mitt e e m ay d eci d e t o p erf or m t his ass ess m e nt i n a d diti o n al c o h orts wit hi n t his st u dy. 
T.  S a m pl es will b e ass ay e d f or: Tr o p o ni n I. T h e first t w o s a m pl es at l e ast 2 4 h o urs a p art, o n e d uri n g t h e scr e e ni n g p h as e a n d o n e pri or t o t h e first d os e of st u dy tr e at m e nt. D ay 1 4 
s a m pl e wi n d o w is ± 2 4 h o urs. T hir d s a m pl e t o b e t ak e n o n D ay 3.  
 
C CI
C CI
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Section 3.3.1 Risk Assessment 
Potential Risk of Clinical Significance  
Summary of Data/Rationale for Risk 
Mitigation Strategy  
Investigational Product (IP) GSK3036656 
Reduction in red blood cell count 
Non-Clinical 
In a 4-week rat study (doses 3, 10 & 30 mg/kg/d) -  
dose-dependent decline in reticulocytes (by up to 
52% in males and 62% in females) at day 7 followed 
by normal levels by day 14 and increased levels by 
day 29/30 compared to controls. Hgb levels 
decreased by 10-13% compared to controls on day 
14 and day 29/30. 
In a 4 week dog study (doses 5, 10 & 20 mg/kg/d) -  
mild dose-dependent decrease in Hgb on day 14 (by 
about 10% compared to controls) with recovery by 
week 4. Reticulocyte counts unaffected. Dogs not 
bled on day 7. 
No histopathological changes in bone marrow or 
other relevant histopathology in the 4-week studies. 
Clinical 
In the 201040 study, a possible trend of 
decreased haemoglobin from baseline to follow-
up was noted in aggregate haematology data.  
Standard safety haematology and clinical 
chemistry assessments will be performed and 
both trends and changes outside normal range 
will be monitored as part of laboratory safety 
assessments. 
 
Participants whose haemoglobin drops below 
pre-specified limits (<8.0 g/dL) will be withdrawn 
from the study (Section 8.1.3). 
 
While women of non-childbearing potential are 
permitted in this study, women who are 
susceptible to heavy periods or heavy vaginal 
bleeding or spotting will be excluded in order to 
minimize blood loss and avoid confounding 
effects on the interpretation of haematology 
parameters. 


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Potential Risk of Clinical Significance  
Summary of Data/Rationale for Risk 
Mitigation Strategy  
The mean change from baseline to follow-up was 
-4.9 g/L in the 15 mg repeat dose group, 
compared to -1.5 g/L in the placebo group. None 
of the values hit potential clinical importance 
(PCI) criteria, and declines were not clinically 
relevant. 
No clinically significant trends in reticulocyte 
values were observed, and there were no values 
of potential clinical importance reported for 
reticulocytes. 
 
GSK3036656 is cleared through the 
kidneys 
The main route of clearance for GSK3036656 is 
renal and there is therefore a risk that 
participants with low creatinine clearance will 
accumulate GSK3036656 and exceed predefined 
exposure limits.  
Participants with a creatinine clearance less 
than 75 mL/min have been excluded.  
Reduction in white blood cell count 
Non-Clinical 
In the 4-week rat study, decrease of up to 37% in 
total leucocyte count on day 29/30 compared to 
controls. 
In the 4-week dog study, no reported effects on white 
blood cells. 
White blood cell count will be monitored as part 
of laboratory safety assessments. Any clinically 
significant changes will be followed up until 
levels are not clinically significant. 
 


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Potential Risk of Clinical Significance  
Summary of Data/Rationale for Risk 
Mitigation Strategy  
Clinical 
No clinically significant trends in leukocyte or 
neutrophil count values were observed. Two 
subjects showed PCI values. One subject had 
low neutrophil count (normal range 1.57-6.81 × 
10^9/L) from screening (1.38) until follow-up 
(1.41), and also showed low leukocyte count 
(normal range 3.3-9.8 × 10^9/L) on Day 4 (2.5), 
Day 10 (2.6) and Day 14 (2.9) and was within 
normal range at follow-up. Given the low 
screening values, this observation was 
considered likely related to the subject’s Black or 
African American race. A second subject had a 
single low neutrophil count at follow-up (1.48). 
 
Participants developing neutrophil counts 
<500/mm3 (1.0x109/L) will be withdrawn from 
the study (Section 8.1.3). 
Heart valvular and vascular pathology 
Non-Clinical 
In a 7-day dog dose range finding (DRF) study – 
minimal focal subendocardial hemorrhage on the 
atrial surface of the left atrioventricular valve 
observed in both animals at the top dose of 60 
mg/kg/d. 
 
This pathology is not monitorable in humans. 
To avoid risk to humans, dosing will be limited 
to doses at which individual exposures [AUC (0-
24)] do not exceed 4.9 µg.h/ml – 1/30 of the 
dog NOAEL exposure (from the 4-week GLP 
study) at which no heart pathology was seen. 


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Potential Risk of Clinical Significance  
Summary of Data/Rationale for Risk 
Mitigation Strategy  
In a 10-day dog investigative study at 65 mg/kg/d – 
vascular lesions (including minimal focal necrosis 
and inflammatory infiltrate) in 3 out of 8 dogs. 
In the 4-week dog GLP study - no heart or valve 
changes were observed up to the top dose of 20 
mg/kg/day and there was no increase in 
inflammatory markers.  
Valvular or vascular pathology were not observed in 
rats. This pathological change is not commonly seen 
in animals, and its mechanism and significance to 
humans are not clear. A correlation between the 
presence of hemodynamic changes and the 
presence of this pathology is suspected, but currently 
unproven. 
Clinical 
Echocardiograms were performed at screening and 
follow up in the 201040 FTIH study in order to 
exclude participants with pre-existing valve or other 
cardiac abnormalities from the study, and to detect 
the presence of abnormalities after completion of the 
study.  No abnormalities were detected. 
In addition, although the pathology is not 
monitorable in humans, echocardiograms will be 
performed for all participants at screening and, 
for subjects receiving the highest dose of 
GSK3036656 or whose clinical status warrants 
it, also at follow-up (or early withdrawal). 
Cardiac troponin will be measured. 
  
Hemodynamic changes 
Non-Clinical 
 


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Potential Risk of Clinical Significance  
Summary of Data/Rationale for Risk 
Mitigation Strategy  
Hemodynamic changes in several studies at ≥100 
mg/kg in rats and ≥20 mg/kg in dogs - increased 
heart rate (rats and dogs), increased (rats) or 
decreased (dogs) blood pressure. 
Clinical 
Data from the 201040 FTIH study showed no 
significant changes in vital signs assessments during 
the study, and no clinically significant changes in 
ECG or telemetry assessments including QTc and 
PR intervals. 
Vital signs monitoring will be implemented in 
this study. 
Phototoxicity 
Non-Clinical 
As GSK3036656 absorbs light in the UVB 
wavelength range (>290 nm), there is a potential for 
phototoxicity in clinical populations.  
 
Clinical 
There were no adverse events reported in the 
201040 FTIH study which would be considered 
consistent with phototoxicity. 
Participants with a history of photosensitivity will 
be excluded from participating in the study 
(Exclusion Criteria, Section 6.1). 
All study participants will be instructed to 
minimise exposure to sunlight and other 
sources of ultraviolet radiation (Section 6.3.1) 


T M F -1 3 3 3 1 4 2 0  
C O N FI D E N TI A L  
 
 
 
2 0 1 2 1 4  
1 2 7  
 
C CI


T M F -1 3 3 3 1 4 2 0  
C O N FI D E N TI A L  
 
 
 
2 0 1 2 1 4  
 
 
 
1 2 8  
 
P ot e nti al Ri sk of Cli ni cal Si g nifi c a n ce  
S u m m ar y of D ata/ R ati o n ale f or Ri s k  
Miti g ati o n Str at e g y  
 
D ev el o p m ent of bact eri al r esist a nc e to 
G S K 30 3 66 56.  
A d mi nistr ati o n of G S K3 0 366 5 6 as a m o n ot h er apy 
c o ul d p ote nti ally l ea d to th e d ev el op m e nt of 
r esist a nc e t o th e co m p ou n d i n M . t u b erc ul osis d urin g 
t h e co urs e of th e stu dy. 
T h e risk of d ev elo p m e nt of r esist a nc e i n th e 
E B A m on oth er a py st udy is c o nsi d er ed to b e l o w 
b as ed o n i n -vitr o dat a with G S K 30 3 66 56 a n d 
hist oric al ex perie nc e wit h E B A st udi es i n 
g e ner al. Susc e ptibility t esti ng o n s a m pl es of M . 
t u b erc ulosis fr o m p articip a nts will b e c o nd ucte d 
a n d ass ess ed as p art of th e st u dy t o m onit or f or 
t h e d ev elo p m e nt of r esist a nc e t o G S K3 0 36 6 56. 
I n-vitr o d at a i ndic at es t hat resist a nc e t o 
G S K 30 3 66 56 d o es n ot co nfer a ny cli nic ally 
si g nific a nt cross r esist anc e t o S o C 
a nti t u b erc ul ar tre at m ent 
Ski n d epi g m e nt ati on  
N o n -Cli ni c al  
I n a 4-m o nth d og toxic ol o gy st u dy ( dos es 0, 6, 20 & 
4 5 m g/kd/ d ay): l oss of pi g me nt ati o n o n th e ey eli ds, 
T h e d ur ati on of d osi ng i n t his st u dy ( 14 d ays) is  
s h ort er th a n t h at use d i n t he d o g t oxic ol ogy 
st u dy a n d t h e m axi mu m exp os ur e ( A U C 0 -24) h as 
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Potential Risk of Clinical Significance  
Summary of Data/Rationale for Risk 
Mitigation Strategy  
nose or muzzle of all animals at 45 mg/kg/day group 
(week 17 AUC0–t mean 405 µg.h/mL) and most 
animals in the 20 mg/kg/day group (week 17 AUC0–t 
176 µg.h/mL). PNL-2 (a melanocyte marker) 
immunohistochemistry staining demonstrated 
moderate cytoplasmic positivity in a population of 
cells in the basal region of the epidermis (interpreted 
to be melanocytes). The decreased pigmentation 
was therefore not associated with a loss of 
melanocytes in affected animals on 
immunohistochemistry. Depigmentation was not 
observed in the 0 or 6 mg/kg/day group (59.4 
ug/h/mL). Depigmentation was not observed in the 
two previous 4 week dog toxicology studies up to 
45 mg/kg/day (week 4 AUC0-t. 388 ug.h/mL) 
Clinical 
No adverse events were reported in the 201040 FTIH 
study that would be considered consistent with 
depigmentation. 
been capped at 4.9 ug.h/mL (greater than 10-
fold margin to the 6 mg/kg/day dose).  
The physical examination of study participants 
will include visual examination of the skin. 
Participants with vitiligo will be excluded from 
the study to avoid confounding skin assessment 
at baseline and follow-up physical examinations. 
 
 
 
 


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Section 5.6  
Dose Justification 
A loading dose of GSK3036656 may be administered on the first day of study 
treatment administration in each cohort. The long half-life of GSK3036656 (45 
hours) means that subjects will take up to 10 days to reach steady-state 
concentrations, which is not optimal for a 14-day treatment study. A loading dose 
will allow participants to reach steady-state concentrations in 2 to 3 days for a given 
maintenance dose regimen.  
The probability rates for individual participants to exceed GSK3036656 exposure 
limits and achieve the efficacy target for proposed loading and maintenance dose 
regimens are shown in Table 1. 
Table 1 
Probability rates of individual participants for proposed loading and 
maintenance doses 
 
Loading Dose 
(mg)a 
Probability 
Day 1c 
Maintenance 
Dose (mg)b 
Probability  
Day 14d 
Target 
Attainment 
Ratee 
10 
< 1% 
2.5 
< 1% 
< 1% 
15 
< 1% 
5 
< 1% 
< 1% 
20 
2.4% 
10 
7.9% 
100% 
a Day 1 
b Day 2-14 
c per trial probability of an individual participant exceeding the exposure limits 
[AUC0–24 = 4.9  ug.h/mL or Cmax = 0.443 ug/mL] on Day 1 (simulations based on 
a lower limit of 75 mL/min for creatinine clearance) 
d per trial probability of an individual participant exceeding the exposure limits 
[AUC0–24 = 4.9 ug.h/mL or Cmax = 0.443 ug/mL] on Day 14 (simulations based on 
a lower limit of 75 mL/min for creatinine clearance) 
e per trial probability of >90% of participants exceeding the target exposure for 
efficacy 
 
The starting dose regimen for this study will be 15 mg loading dose on Day 1 and 5 
mg maintenance dose on Day 2-14, based on the above information, with the option 
to investigate a lower dose in subsequent cohorts should the preliminary data 
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The loading dose (if applicable) and maintenance dose for each cohort will be 
chosen on the basis that it is not predicted to exceed the pre-specified safety cap, and 
the dose used will be decided by the Dose Escalation Committee (Section 11). 
Section 6.1. Inclusion Criteria 
8. 
A creatinine clearance ≥75 mL/min (Cockroft-Gault formula). 
Section 6.2 
Exclusion Criteria 
3. 
A previous episode of treated TB less than 3 years ago. 
Section 8.1.3 8.1.3. Haematology Stopping Criteria 
• A reduction in neutrophil count to below 500/mm3 (0.5 × 109/L). 
Section 9.3 
Treatment of Overdose 
For this study, any total dose of GSK3036656 greater than the dose selected for that 
cohort (taken within a 23-hour period) will be considered an overdose. 
Section 10.3.4  
Efficacy Analyses 
No formal interim analyses are planned for this study. However, safety, tolerability and 
pharmacokinetic data will be reviewed before each dose escalation. In addition, the 
primary efficacy endpoint may also be analysed after the final visit of the last 
subject for the cohort which receives the anticipated highest dose. See Section 11 for 
further details. 
Section 11 
Dose Escalation 
After the initial dose of GSK3036656, the decision to proceed to each subsequent dose 
level will be made by the Dose Escalation Committee (DEC) based on safety, tolerability 
and preliminary GSK3036656 pharmacokinetic data from the prior cohort. The DEC 
may also include in their deliberations, efficacy data, if that is available. Minimum 
requirements for data are as follows: PK data in at least 10 subjects receiving 
GSK3036656 and selected safety data from all subjects in a cohort. A dose escalation 
committee charter will be produced that will contain the following details: 
• 
Committee members 
• 
Data review requirements 
• 
Process for informing the ethics committee of any safety concerns if appropriate 
• 
Facility for requesting additional pertinent information form the investigator 
Dose escalation will be based on population PK modelling (if feasible). or on the 
assumption of dose–exposure proportionality (i.e., doubling the dose gives an 
approximate doubling of exposure). If prior PK results show less than proportional 


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increase in exposure with increasing dose, the prediction will be based on the assumption 
that the fold exposure increase to fold dose increase ratio will be the same with the 
current dose escalation as it was with the previous one. If prior PK results show more 
than proportional increase in exposure with dose, subsequent. Dose escalations will not 
be higher than 3-fold. 
The population PK model will be a fit for purpose model. Candidate model selection will 
be primarily based on a significant reduction in the objective function value (≥ 3.32, χ2 
<0.05) and improvement in the fits of diagnostic scatter plots.  Inter-individual variability 
will be modelled using an exponential error model and residual error will be described by 
a proportional, proportional plus additive, or additive error model, depending on the data. 
Model performance will be evaluated using a visual predictive check.  Simulations for 
dose recommendations will be conducted to determine the probability of an individual 
subject exceeding the defined exposure margins for AUC and Cmax. 
Alternatively, if a population PK model is not feasible, dose escalation will be based 
on a dose-exposure model of the form: 
log(AUC) = a + b*log(DOSE) + c*log(BWT/70) 
log(CMAX) = d + e*log(DOSE) + f*log(BWT/70) 
where a and d are AUC and Cmax values, respectively; c = -0.75 and f = -1.00 are 
set values for allometric scaling; and b and e are scaling factors for dose 
proportionality. 
A proposed dose will be acceptable if the predicted probability of an individual 
exceeding pre-defined exposure limits (Section 5.6) on any day of the dosing period, as 
estimated by PK modeling, is no more than 10%. 
The primary endpoint may be analysed for all available cohorts after the final visit 
of the last subject for the cohort which receives the anticipated highest dose (as 
determined by the DEC). The purpose of this efficacy analysis is to optimise dosing 
for subsequent cohorts (e.g. to help estimate the dose response curve) as well as to 
aid internal decision making.  
The DEC is empowered to take the following decisions for subsequent cohorts: 
• 
To select a higher dose within the limits defined in section 5.6. 
• 
To select a dose lower than, or the same as, a preceding dose. 
• 
To stop dosing. 
• 
To include additional pharmacokinetic assessments. 
• 
To include additional timepoints for existing safety assessment. 
 


TMF-13331420  
CONFIDENTIAL 
 
 
 
201214 
 
 
 
 
133 
 
Section 13.6 Appendix 6  
Contraception Guidance 
Male participants 
• Male participants with female partners of child-bearing potential are eligible to 
participate if they agree to ONE of the following:  
• Are abstinent from penile-vaginal intercourse as their usual and preferred lifestyle 
(abstinent on a long term and persistent basis) and agree to remain abstinent for a 
period of 90 days after the last dose of study medication (one spermatogenesis 
cycle). 
• Agree to use a male condom plus an additional method of contraception with a 
failure rate of <1% per year as described in Table 3 when having penile-vaginal 
intercourse with a woman of childbearing potential. 
• Men with a pregnant or breastfeeding partner must agree to remain abstinent from 
penile-vaginal intercourse or use a male condom during each episode of penile 
penetration during the treatment period and for 6 days after (five terminal half-
lives). 
• In addition, male participants must refrain from donating sperm during the treatment 
period and for 90 days after (one spermatogenesis cycle). 
 
 
 


T M F -1 3 3 3 1 4 2 0  
C O N FI D E N TI A L  
 
 
 
2 0 1 2 1 4  
 
 
 
 
1 3 4  
 
A me n d me nt 1  (2 0 -Fe b -2 0 1 8 ) 
O ver all R ati o n ale f or t he A me n d me nt:   
 Mi n or 
t y p o gra p hical c orrecti o ns t hr o u g h o ut t he d oc u m e nt ha ve als o bee n a p plie d. 
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T M F -1 3 3 3 1 4 2 0  
C O N FI D E N TI A L  
 
 
 
2 0 1 2 1 4  
 
 
 
 
1 3 5  
 
S e cti o n #  
D e s cri pti o n of C h a n g e  
Bri ef R ati o n al e  
3. 3.1  
3. C orr ecti on of ty p ogr a phic al 
error r e g ar di ng m e nstru ati on  
Cl arity a n d co nsist ency of th e d oc u m ent 
a n d i m pl e m ent ati o n of a d diti o n al s af ety 
m e as ur es for p articipa nts  
5. 1  
D esi g n cl arity  
6. 1 & 6.2  
1. 
 
 m ust be 
2 5 y e ars of a ge or old er.  
2. W or di n g cl arific ati o n f or 
i ncl usi o n crit eri a # 5 
3. W or di n g cl arific ati o n f or 
i ncl usi o n crit eri a # 6 
4. W or di n g cl arific ati o n f or 
excl usi o n crit eri a # 11  
6. C h a n ge d text to m atch 3.3. 1 
r e g ar di ng m e nstr uati on 
D esi g n cl arity & clarity a nd c o nsist e ncy of 
t h e d oc u m ent. 
9. 1  
Cl arific ati o n w or di ng i n sectio n 
h e ad er an d d efi nitio n of ti me p oi nt 
n o m e ncl at ur e  
Cl arity a n d co nsist ency of th e d oc u m ent  
9. 6 & 1 3.8  
All d oc u m ent  
Mi n or ty p o gra p hical c orrectio ns  
Cl arity of d ocu m e nt  
 
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T M F -1 3 3 3 1 4 2 0  
C O N FI D E N TI A L  
 
 
 
2 0 1 2 1 4  
 
 
 
 
1 3 6  
 
S e cti o n 3. 3. 1 Ri s k A s s e s s m e nt  
C H A N G E S  
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T M F -1 3 3 3 1 4 2 0  
C O N FI D E N TI A L  
 
 
 
2 0 1 2 1 4  
 
 
 
 
1 3 7  
 
. T he le vel of ris k ma y 
t heref ore be ass u me d t o 
br oa dl y fall wit hi n t he 
I C R P 6 2 i nter me diate 
Cate g or y II b, w here t he 
be nefit s h o ul d be m ore 
directl y ai me d at t he c ure or 
pre ve nti o n of diseas e.  
 
 Cli nicall y 
j ustifie d (t hera pe utic or 
dia g n ostic) e x p os ures are 
n ot i ncl u de d i n t he 
e x p os ure calc ulati o n. 
Partici pa nts are as ke d 
a b o ut a n y occ u p ati o nal 
e x p os ure or pre vi o us 
partici pati o n i n researc h 
st u dies at scree ni n g s o 
t hat d ose esti mates ca n 
be o btai ne d w here 
necessar y.  
T he st u d y will e x cl u de 
w o me n of c hil d beari n g 
p ote ntial.  
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T M F -1 3 3 3 1 4 2 0  
C O N FI D E N TI A L  
 
 
 
2 0 1 2 1 4  
 
 
 
 
1 3 8  
 
 
S e cti o n 5. 1 O v er all D e si g n  
C H A N G E S  
I n a d diti o n, t he mi ni m u m a g e f or i ncl usi o n f or p artici p a nts recr uite d t o t hese 2 
c o h orts will be r aise d f r o m ≥1 8 t o ≥2 5 ye ars ol d.  
S e cti o n 6. 1 I n cl u si o n crit eri a  
C H A N G E S  
A ge  
1.  Partici pa nt m ust be 1 8  t o 6 5 years of a ge i ncl usi ve, at t he ti me of si g ni n g t h e 
i nf or me d c o nse nt.  
2.  
S e cti o n 9. 1  Mi cr o bi ol o gi c al Effi c a c y/ A cti vit y A s s e s s m e nt s  
C H A N G E S  
Dr u g acti vit y wit h C F U or T T P o ver differe nt treat me nt peri o ds s uc h as b aseli ne - D a y 2 , 
a n d D a y 2 -1 4, f or cr oss -c o m paris o n wit h ot her p u blis he d data. Data will be dis pla ye d 
gra p hicall y, t o get her wit h m o delle d esti mates.  
F or t he p ur p oses of t he mic r o bi ol o gic al e n d p oi nts assess me nts, t he pre -tre at me nt 
b aseli ne will be defi ne d as eit her D a y -2 a n d/ or D a y -1.  
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T M F -1 3 3 3 1 4 2 0  
C O N FI D E N TI A L  
 
 
 
2 0 1 2 1 4  
 
 
 
 
1 3 9  
 
M yc o b acteri al C h ar acteris ati o n:  
T he i de ntif yi n g or ga nis m will be c o nfir me d as M yc o bacteri u m t u ber c ul osis at least o nce 
b y p ol y merase c h ai n reacti o n ( P C R) at scree ni n g ( Ge ne X pert or Li ne Pr o b e) a n d a 
sa m ple c ollecte d b ef ore treat me nt will be s u b mitte d f or c ult ure c o nfir m ati o n . 
 
S e cti o n 9. 6.  P ot e nti al S urr o g at e Di s e a s e/ Bi o m ar k er s  
C H A N G E S  
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T M F -1 3 3 3 1 4 2 0  
C O N FI D E N TI A L  
 
 
 
2 0 1 2 1 4  
 
1 4 0  
 
C CI

SAP_001.pdf: 
 
 
 
 
Reporting and Analysis Plan 
 
Study ID:  201214 
 
Official Title of Study: Reporting and Analysis Plan for a Phase IIa open-label trial to 
investigate the early bactericidal activity, safety and tolerability of GSK3036656 in 
participants with drug sensitive pulmonary tuberculosis. 
 
 
Approval Date of Document: 01-Feb-2022 
 
 


 
C O N FI D E N TI A L  
 
T h e Gl a x o S mit h Kli n e gr o u p of c o m p a ni e s  
 
2 0 1 2 1 4  
 
1  
 
Di visi o n  
: W orl d wi de  De vel o p me nt  
I nf or m ati o n T y pe 
: Re p orti n g a n d A nal ysis Pla n  ( R A P) 
Title  
: Re p orti n g a n d A nal ysis Pla n f or a P hase IIa o p e n -la bel trial 
t o i n vesti gate t he earl y b acterici d al acti v it y, s afet y a n d 
t olera bilit y of G S K 3 0 3 6 6 5 6 i n partici pa nts wit h dr u g -
se nsiti ve p ul m o nar y t u berc ul osis.  
C o m p o u n d N u m ber  : G S K 3 0 3 6 6 5 6  
Effecti ve D ate  
: Refer t o D oc u m e nt Date  
 
Descri pti o n:  
•  
T he p ur p ose of t his R A P is t o descri be t he pla n ne d a nal ys es a n d o ut p ut t o b e 
i ncl u de d i n t he Clinical St u d y Re p ort  ( C S R) f or Pr ot oc ol T M F -1 3 3 3 1 4 2 0 . 
•  
T his R A P is i nte n de d t o descri be  a nal ysis re q uir e me nts d uri n g t he st u d y t o s u p p ort  
t he d ose escalati o n a nal yses  a n d t he fi nal a n al yses re q uire d f or t he  st u d y i n ter ms of 
c o n ve yi n g t he c o nte nt of t he Stat istical A nal ysis C o m plete ( S A C) d eli vera ble.   
 
R A P A ut h or(s):  
A ut h or  
D ate  
 ( Ori gi nal) 
Statistics Lea der ( Cli nical Statistics, Bi ostatistics) 
 
 ( A me n d me nt 1) 
Ma na ger Statistics ( Cli nical Statistics, Bi ostatistics)  
Refer t o D oc u m e nt 
Date  
 ( A me n d m e nt 1) 
Se ni or Statisticia n ( De vel o p me nt Bi ostatistics)  
Refer t o D oc u m e nt 
Date  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C o p yri g ht 2 0 2 1 t he Gla x o S mit h Kli ne gr o u p of c o m pa nies. All ri g hts r eser ve d.  
U na ut h orise d c o p yi n g or use of t his i nf or mati o n is pr o hi bite d.
P P D
P P D
P P D


 
C O N FI D E N TI A L  
 
 
2 0 1 2 1 4  
 
2  
 
R A P Te a m R e vie w C o nfir m ati o n : 
( Met h o d: V ee v a V a ult  e T M F) 
Re vie wer  
 
Cli nical P har mac ol o g y, Cli nical P har mac ol o g y M o delli n g & Si m ulati o n 
( C P M S) ( C o-A ut h or)  
 
, Gl o b al Healt h ( Cli nical Re prese ntati ve a n d Me dical 
Writi n g Dele gate)  
 
Pr o gra m mi n g Ma n a ger ( Cli nical Pr o gra m mi n g, Bi ostatistics)  
 
, Safet y E val uati o n & Ris k Ma na ge m e nt ( S E R M) 
R A P Cli nic al St atistics a n d Cli nic al Pr o gr a m mi n g Li ne A p pr o v als : 
( Met h o d: V ee v a V a ult  e T M F)  
A p pr o ver  
D ate  
 
Refer t o D oc u m e nt Date  
 (De v el o p me nt  Bi ostatistics)  
 
Refer t o D oc u m e nt Date  
Pr o gra m mi n g Lea der ( Cli nical Pr o gra m mi n g, Bi ostatistics)  
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D


 
CONFIDENTIAL 
 
 
 
201214 
3 
 
TABLE OF CONTENTS 
PAGE 
1. 
INTRODUCTION ...................................................................................................... 6 
1.1. 
RAP Amendments ........................................................................................ 7 
2. 
SUMMARY OF KEY PROTOCOL INFORMATION .................................................. 9 
2.1. 
Changes to the Protocol Defined Statistical Analysis Plan ............................ 9 
2.2. 
Study Objective(s) and Endpoint(s)............................................................... 9 
2.3. 
Study Design .............................................................................................. 11 
2.4. 
Statistical Analyses ..................................................................................... 12 
3. 
PLANNED ANALYSES .......................................................................................... 13 
3.1. 
Interim Analyses ......................................................................................... 13 
3.2. 
Final Analyses ............................................................................................ 14 
4. 
ANALYSIS POPULATIONS ................................................................................... 14 
4.1. 
Protocol Deviations ..................................................................................... 15 
5. 
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS ..................................................................................................... 16 
5.1. 
Study Treatment & Sub-group Display Descriptors ..................................... 16 
5.2. 
Baseline Definitions .................................................................................... 16 
5.3. 
Examination of Covariates .......................................................................... 17 
5.4. 
Other Considerations for Data Analyses and Data Handling 
Conventions ................................................................................................ 17 
6. 
STUDY POPULATION ANALYSES ....................................................................... 18 
6.1. 
Overview of Planned Study Population Analyses ........................................ 18 
7. 
EFFICACY ANALYSES .......................................................................................... 19 
7.1. 
Primary Efficacy Analyses .......................................................................... 19 
7.1.1. 
Endpoint / Variables ..................................................................... 19 
7.1.2. 
Summary Measure ...................................................................... 19 
7.1.3. 
Population of Interest ................................................................... 19 
7.1.4. 
Strategy for Intercurrent (Post-Randomization) Events ................ 19 
7.1.5. 
Statistical Analyses / Methods ..................................................... 19 
7.1.5.1. 
Statistical Methodology Specification .......................... 20 
7.2. 
Secondary Efficacy Analyses ...................................................................... 21 
7.2.1. 
Endpoint / Variables ..................................................................... 21 
7.2.2. 
Summary Measure ...................................................................... 22 
7.2.3. 
Population of Interest ................................................................... 22 
7.2.4. 
Strategy for Intercurrent (Post-Randomization) Events ................ 22 
7.2.5. 
Statistical Analyses / Methods ..................................................... 22 
7.2.5.1. 
Statistical Methodology Specification .......................... 23 
7.3. 
Exploratory Efficacy Analyses ..................................................................... 25 
7.3.1. 
Endpoint / Variables ..................................................................... 25 
8. 
SAFETY ANALYSES ............................................................................................. 26 
8.1. 
Adverse Events Analyses ........................................................................... 26 
8.2. 
Clinical Laboratory Analyses ....................................................................... 26 


 
CONFIDENTIAL 
 
 
 
201214 
4 
 
8.3. 
Other Safety Analyses ................................................................................ 26 
9. 
PHARMACOKINETIC ANALYSES ......................................................................... 27 
9.1. 
Secondary Pharmacokinetic Analyses ........................................................ 27 
9.1.1. 
Endpoint / Variables ..................................................................... 27 
9.1.2. 
Summary Measure ...................................................................... 27 
9.1.3. 
Population of Interest ................................................................... 27 
9.1.4. 
Strategy for Intercurrent (Post-Randomization) Events ................ 27 
9.1.5. 
Statistical Analyses / Methods ..................................................... 27 
9.1.5.1. 
Statistical Methodology Specification .......................... 28 
10. ADDITIONAL ANALYSES DUE TO THE COVID-19 PANDEMIC ........................... 30 
10.1. 
Study Population ......................................................................................... 30 
10.1.1. 
Subject Disposition ...................................................................... 30 
10.1.2. 
Protocol Deviations ...................................................................... 30 
10.2. 
Safety ......................................................................................................... 30 
10.2.1. 
Assessment of COVID-19 AEs .................................................... 30 
10.2.2. 
Impact of COVID-19 Pandemic on Safety Results ....................... 30 
11. REFERENCES ....................................................................................................... 31 
12. APPENDICES ........................................................................................................ 32 
12.1. 
Appendix 1: Protocol Deviation Management and Definitions for PK 
and Efficacy Population .............................................................................. 32 
12.2. 
Appendix 2: Schedule of Activities .............................................................. 33 
12.2.1. 
Protocol Defined Schedule of Events ........................................... 33 
12.3. 
Appendix 3: Assessment Windows ............................................................. 37 
12.3.1. 
Definitions of Assessment Windows for Analyses ........................ 37 
12.4. 
Appendix 4: Study Phases and Treatment Emergent Adverse 
Events ........................................................................................................ 38 
12.4.1. 
Study Phases .............................................................................. 38 
12.4.1.1. Study Phases for Concomitant Medication ................. 38 
12.4.1.2. Phases of COVID-19 Pandemic Measures ................. 38 
12.4.2. 
Treatment Emergent Flag for Adverse Events ............................. 39 
12.5. 
Appendix 5: Data Display Standards & Handling Conventions .................... 40 
12.5.1. 
Reporting Process ....................................................................... 40 
12.5.2. 
Reporting Standards .................................................................... 40 
12.5.3. 
Reporting Standards for Pharmacokinetics .................................. 41 
12.6. 
Appendix 6: Derived and Transformed Data ............................................... 42 
12.6.1. 
General ........................................................................................ 42 
12.6.2. 
Study Population .......................................................................... 42 
12.6.3. 
Efficacy ........................................................................................ 42 
12.6.4. 
Safety .......................................................................................... 43 
12.6.5. 
Pharmacokinetic .......................................................................... 43 
12.7. 
Appendix 7: Reporting Standards for Missing Data ..................................... 45 
12.7.1. 
Premature Withdrawals ................................................................ 45 
12.7.2. 
Handling of Missing Data ............................................................. 45 
12.7.2.1. Handling of Missing and Partial Dates ........................ 45 
12.8. 
Appendix 8: Values of Potential Clinical Importance ................................... 47 
12.8.1. 
Laboratory Values ........................................................................ 47 
12.8.2. 
ECG ............................................................................................. 48 
12.8.3. 
Vital Signs .................................................................................... 48 


 
CONFIDENTIAL 
 
 
 
201214 
5 
 
12.9. 
Appendix 9: Abbreviations & Trade Marks .................................................. 49 
12.9.1. 
Abbreviations ............................................................................... 49 
12.9.2. 
Trademarks ................................................................................. 50 
12.10. Appendix 10: List of Data Displays.............................................................. 51 
12.10.1. Data Display Numbering .............................................................. 51 
12.10.2. Mock Example Shell Referencing ................................................ 51 
12.10.3. Deliverables ................................................................................. 51 
12.10.4. Study Population Tables .............................................................. 52 
12.10.5. Efficacy Tables ............................................................................ 54 
12.10.6. Efficacy Figures ........................................................................... 56 
12.10.7. Safety Tables ............................................................................... 57 
12.10.8. Safety Figures ............................................................................. 60 
12.10.9. Pharmacokinetic Tables ............................................................... 61 
12.10.10. Pharmacokinetic Figures ............................................................. 62 
12.10.11. ICH Listings ................................................................................. 63 
12.10.12. Non-ICH Listings .......................................................................... 66 
12.11. Appendix 11: Example Mock Shells for Data Displays ................................ 67 
 


 
C O N FI D E N TI A L  
 
 
 
2 0 1 2 1 4  
6  
 
1.  
I N T R O D U C TI O N 
T he p ur p ose of t his r e p orti n g a n d a n al ysis pla n ( R A P) is t o descri be t he a n al yses t o b e 
i ncl u de d i n t he Cli nical St u d y Re p ort f or Pr ot oc ol: 
Pr ot oc ol R e visi o n C hr o n ol o g y:  
2 0 1 7 N 3 3 2 0 0 5 _ 0 0  
0 9 -F E B -2 0 1 8  
Ori gi nal  
2 0 1 7 N 3 3 2 0 0 5 _ 0 1  
2 0 -F E B -2 0 1 8  
Pr ot oc ol A me n d me nt 1:  
2 0 1 7 N 3 3 2 0 0 5 _ 0 2  
2 4 -S E P -2 0 1 8  
Pr ot oc ol A me n d me nt 2:  
T he pri mar y m oti vati o n f or t his a me n d me nt was t o 
u p date t he eli gi bilit y crit eria t o i m p ose a mi ni m u m 
re nal f u n cti o n (as defi n e d b y creati ni ne cleara nce) 
i n li g ht of t he first-i n-h u ma n data t hat s h o we d t he 
mai n r o ute of cleara n ce f or G S K 3 0 3 6 6 5 6 is 
t hr o u g h t he ki d ne ys. As a res ult of t he l o n g half-
life of G S K 3 0 3 6 6 5 6, a n u p date d d osi n g str ate g y 
has als o be e n i m ple me nt e d i nc or p orati n g t he us e of 
l oa di n g d oses.  
2 0 1 7 N 3 3 2 0 0 5 _ 0 3  
2 4 -J U L-2 0 1 9  
Pr ot oc ol A me n d me nt 3:  
T o d oc u me nt t he i ncreas e i n e x p os ure li mits a n d 
c ha n ge i n eli gi bilit y criteria f oll o wi n g t h e 
a vaila bilit y of ne w n o n -cli nical data.  
T M F -1 1 8 2 0 6 1 6  
1 7 -F E B -2 0 2 1  
Pr ot oc ol A me n d me nt 4:  
T o all o w f or sta n dar d of care m e dicati o n 
a d mi nistere d i n t he st u d y t o be eit her Rifaf o ur e -
2 7 5 or a n e q ui vale nt ge n eric alter nati ve a n d t o 
all o w f or a n al ysis of t he pri mar y e n d p oi nt data t o 
be perf or me d o n a d diti o n al c o h orts.  
T M F -1 3 3 3 1 4 2 0  
1 2 -M A Y -2 0 2 1  Pr o t oc ol A me n d me nt 5: 
Varia bilit y i n t he rate of c ha n ge of l o g 1 0 C F U 
o bser ve d i n t he trial t o -d ate is l o wer t ha n 
a ntici pate d. D ue t o t his, a n d sl o wer t ha n 
a ntici pate d recr uit me nt, t he st u d y sa m ple siz e has 
bee n re -calc ulate d. T h e p ote ntial t o m o dif y t he 
hae m o g l o bi n e x cl usi o n a n d st o p pi n g criteri a i n 
s u bse q ue nt c o h orts i n vesti gati n g l o wer d oses of 
G S K 3 0 3 6 6 5 6 has bee n a d de d.  
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CONFIDENTIAL 
 
 
 
201214 
7 
 
1.1. 
RAP Amendments 
RAP Version 
Approval 
Date 
Protocol 
Version 
(Date) on 
Which RAP 
is Based 
Change 
Rationale 
Reporting and 
Analysis Plan 
201214 Final 
V1 
11-DEC-
2018 
Protocol 
Amendment 2 
(24-SEP-
2018) 
N/A 
Original Version 
Reporting and 
Analysis Plan 
201214 
Amendment1 
V0.1 
Refer to 
document 
date 
Protocol 
Amendment 5 
(12-MAY-
2021) 
1. Section 2.3: Study 
Design – The number 
of participants per 
treatment arm has been 
changed from 20 to 12-
20. 
2. Section 7.1.5.1: 
Statistical 
Methodology 
Specification – For the 
analysis of the primary 
endpoint a mixed 
model with repeated 
measures analysis has 
been added as the 
primary analysis. Dose 
has been replaced by 
treatment, with data for 
participants receiving 
standard-of-care 
included, and BMI has 
been added as a 
covariate. 
3. Section 10: Additional 
Analyses Due to the 
COVID-19 Pandemic 
– Additional study 
population and safety 
displays have been 
added.  
4. Section 12.4.1.2: 
Phases of COVID-19 
Pandemic measures – 
details have been 
added as to how to 
1. The required 
number of 
participants for the 
later cohorts was 
reduced in protocol 
amendment 5. 
2. A repeated 
measures analysis, 
including day as a 
covariate is more 
appropriate for 
measuring the rate 
of change over the 
entire 14 day 
treatment period. It 
is important to 
understand the 
effect of SoC on the 
endpoint. BMI has a 
potential influence 
on the EBA 
endpoints. 
3. In order to 
understand the 
impact of the 
COVID-19 
pandemic on the 
study conduct and 
the results, 
additional 
summaries are 
required. 
4. The COVID-19 
pandemic began at 
different times in 


 
CONFIDENTIAL 
 
 
 
201214 
8 
 
determine when the 
pandemic began for the 
categorisation of AEs. 
5. Minor clarifications 
and corrections. 
 
different countries 
with multiple 
waves. Guidance is 
therefore required 
for determining 
timings. 
5. Minor clarifications 
and corrections 
have been made 
where wording was 
ambiguous/vague or 
errors were 
identified to 
improve the 
accuracy and 
comprehensiveness 
of the RAP. 
 
 
 


 
CONFIDENTIAL 
 
 
 
201214 
9 
 
2. 
SUMMARY OF KEY PROTOCOL INFORMATION 
2.1. 
Changes to the Protocol Defined Statistical Analysis Plan 
The change or deviation to the originally planned statistical analysis specified in the 
protocol amendment 5 [(Dated: 12/MAY/2021)] is mentioned below. 
Protocol 
RAP 
Rational 
Section 10.3.1: Activity/ 
Pharmacokinetic Analyses 
Section 7.1.5.1:  
Model 2: Bi-linear Bayesian 
regression model 
The model 2 Bi-linear regression 
analysis has been added as an additional 
supportive analysis. This is 
recommended for the analysis of EBA 
endpoints in TB due to them sometimes 
following a bi-linear rate of change. 
 
2.2. 
Study Objective(s) and Endpoint(s) 
Objectives 
Endpoints 
Primary Objectives 
Primary Endpoints 
• To determine the early 
bactericidal activity of 
GSK3036656 over 14 days of 
once daily repeat dosing. 
• Rate of change in log10CFU per ml direct 
respiratory sputum samples over the period 
baseline to Day 14 (EBA CFU0-14). 
Secondary Objectives 
Secondary Endpoints 
• To assess the safety & 
tolerability of GSK3036656 
administered once daily over 14 
days to patients with 
tuberculosis. 
• Adverse events (AE), clinical laboratory values, 
vital signs, electrocardiogram (ECG) 
parameters. 
• To characterise the 
pharmacokinetics of 14-day 
once daily dosing of 
GSK3036656 in tuberculosis 
patients 
• Derived pharmacokinetic parameters for 
GSK3036656 including area under the plasma 
drug concentration versus time curve (AUC(0-
t), AUC (0-24)), maximum observed plasma 
drug concentration (Cmax), and time to 
maximum observed plasma drug concentration 
(tmax), as appropriate. 
 
• To determine the early 
bactericidal activity of 
GSK3036656 over the first 2 
days and the last 12 days with 
14 days of once daily repeat 
dosing.  
 
 
 
• Rate of change in log10CFU per ml direct 
respiratory sputum samples over the period 
baseline to Day 2 (EBA CFU0-2). 
 
• Rate of change in log10CFU per ml direct 
respiratory sputum samples over the period Day 
2 to Day 14 (EBA CFU2-14). 
 
• Rate of change in time to sputum culture 


 
C O N FI D E N TI A L  
 
 
 
2 0 1 2 1 4  
1 0  
 
O bjecti ves  
E n d p oi nts  
 
 
 
 
 
 
 
 
 
 
p ositi vit y ( T T P) o ver t he ti me peri o d baseli ne 
t o Da y 1 4 ( E B A T T P0 -1 4) 
 
•  Rate of c ha n ge i n ti me t o s p ut u m c ult ure 
p ositi vit y o ver t he ti me peri o d baseli ne t o D a y 
2 ( E B A T T P 0 -2) 
 
•  Rate of c ha n ge i n ti me t o s p ut u m c ult ure 
p ositi vit y o ver t he ti me peri o d Da y 2 t o D a y 1 4 
( E B A T T P2 -1 4) 
E x pl or at or y O bjecti ves  
E x pl or at or y E n d p oi nts  
 
F or t he p ur p os e of ass ess me nt of bacterial  
 e n d p oi nts, t he pre -tr eat me nt 
baseli ne will be defi n e d as  t he mea n of Da y -2 a n d Da y -1 ; if data is a vaila ble at o nl y Da y 
– 2 or Da y – 1 t he n t hat val ue will be use d as baseli ne. F or E C G e n d p oi nts, bas eli ne is 
scree ni n g. 
  
C CI
C CI
C CI


 
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2.3. 
Study Design 
Overview of Study Design and Key Features 
   
 
 
Design 
Features 
• A single-centre, open-label trial in up to five sequential cohorts.  
• Each cohort will involve participants being randomised to one of two 
possible treatments: either GSK3036656 or Standard-of-Care (SoC) 
regimen (e.g. Rifafour®e-275) for rifampicin-susceptible (drug 
sensitive) tuberculosis (DS-TB).  
• Screening will be performed on days -9 to -1, followed by 14 days of 
once daily dosing and a follow-up visit 28 days after the first dose.  
• All laboratory staff involved in analysing and reporting the primary 
and secondary change in CFU counts and TTP endpoint results will be 
blinded to treatment allocation. 
Dosing 
• Once daily repeat dosing for 14 days.  
• The starting dose for the GSK3036656 arm is a 15mg loading dose on 
Day 1 and 5mg maintenance dose on Days 2-14, given orally. The 
study will employ dose escalation, where the GSK3036656 dose for 
each cohort will be decided based on reviews of preliminary safety, 
tolerability and pharmacokinetic data; in addition, efficacy data will be 
considered if available. 
Time & 
Events 
• See Appendix 2: Schedule of Activities 
Treatment 
Assignment 
• 12-20 participants in each cohort (excluding possible replacements), 
randomised 3:1 to GSK3036656 or Standard of Care respectively.  
• GSK RandAll NG will be used to generate the randomisation 
schedule.  
Dose 
Escalation 
Analysis 
• No formal interim analysis is planned.  
• Safety, tolerability and pharmacokinetic data will be reviewed before 
each dose escalation. 
• The primary endpoint may be analysed (including data from all 
available cohorts) as part of the dose escalation analyses. The earliest 
this can occur is after the final visit of the last subject on the second 
consecutive cohort that reaches or exceeds the target PK plasma 
exposure for efficacy.. 
 


 
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2.4. 
Statistical Analyses 
The primary endpoint, EBA CFU0-14, will be analysed using a mixed effects model 
including treatment, day, BMI and treatment-by-day as covariates. Secondary endpoints 
of EBA CFU0-2, CFU2-14, TTP0-2, TTP0-14 and TTP2-14 will be analysed similarly to the 
primary endpoint. See Section 7: Efficacy Analyses for further details.  
 
Plasma concentration-time data will be analysed by non-compartmental methods, the 
following pharmacokinetic parameters will be determined: Maximum observed plasma 
drug concentration (Cmax), Time to maximum observed plasma drug concentration 
(tmax), Area under the concentration-time curve from time of dosing to last quantified 
concentration, regardless of time (AUC(0-t)), Area under the concentration-time curve 
from time of dosing extrapolated to 24 hours (AUC(0-24)) and Trough Concentration 
(Cτ). AUC(0-t) or AUC(0-24) and Cmax may be used for assessment of dose 
proportionality. Trough concentration (Cτ) samples will be used to assess attainment of 
steady state. See Section 9 for further details. 
 
Safety data, including AEs, clinical laboratory values, vital signs and ECG, will be 
summarised descriptively according to GSK’s Integrated Data Standards Library (IDSL) 
standards. See Section 8: Safety Analyses for further details. 
 
 


 
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3. 
PLANNED ANALYSES 
3.1. 
Interim Analyses 
No formal interim analyses are planned for this study. However, safety, tolerability and 
pharmacokinetic data will be reviewed before each dose escalation. In addition, the 
primary endpoint may be analysed, including data from all available cohorts, after the 
final visit of the last subject on the second consecutive cohort that reaches or exceeds the 
target PK plasma exposure for efficacy. 
 
Dose Escalation 
Pharmacokinetic (PK) Analysis 
Dose escalation will primarily be based on population PK modelling. 
The population PK model will be a fit for purpose model. Candidate model selection will 
be primarily based on a significant reduction in the objective function value (≥ 3.32, χ2 
<0.05) and improvement in the fits of diagnostic scatter plots.  Inter-individual variability 
will be modelled using an exponential error model and residual error will be described by 
a proportional, proportional plus additive, or additive error model, depending on the data. 
Model performance will be evaluated using a visual predictive check.  Simulations for 
dose recommendations will be conducted to determine the probability of an individual 
participant exceeding the defined exposure margins for AUC0-24 (4.9 μg.h/mL) and Cmax 
(0.443 ug/mL). 
Alternatively, if a population PK model is not feasible, dose escalation will be based on a 
dose-exposure model of the form: 
 
log(AUC) = a + b*log(DOSE) + c*log(BWT/70) 
 
log(CMAX) = d + e*log(DOSE) + f*log(BWT/70) 
 
where a and d are AUC and Cmax values, respectively; c = -0.75 and f = -1.00 are set 
values for allometric scaling; and b and e are scaling factors for dose proportionality. 
Efficacy Analysis 
In addition to the PK modelling, the primary endpoint may be analysed including data 
from all available cohorts, after the final visit of the last subject from the second 
consecutive cohort that reaches or exceeds the target PK plasma exposure for efficacy. 
The purpose of this efficacy analysis is to optimise dosing for subsequent cohorts (e.g. to 
help estimate the dose response curve) as well as to aid internal decision making. If this 
cohort is the fifth (final) cohort then the efficacy analysis will be performed as part of the 
final SAC deliverable. The primary endpoint will be analysed as planned for the final 
analysis, see Section 7: Efficacy Analyses.  


 
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The efficacy analyses will be performed after the completion of the following sequential 
steps: 
1. All participants in the current cohort have completed their Day 15 study visit as 
defined in the protocol.  
2. Data have been made available by Data Management (no specific data cleaning 
requirements for the efficacy analysis). 
3. All criteria for unblinding the randomization codes have been met.  
4. Randomization codes have been distributed according to RandAll NG procedures. 
3.2. 
Final Analyses 
The final planned primary analyses will be performed after the completion of the 
following sequential steps: 
1. All participants have completed the study as defined in the protocol.  
2. All required database cleaning activities have been completed and final database 
release (DBR) and database freeze (DBF) has been declared by Data Management. 
3. All criteria for unblinding the randomization codes have been met.  
4. Randomization codes have been distributed according to RandAll NG procedures. 
4. 
ANALYSIS POPULATIONS 
Population 
Definition / Criteria 
Analyses 
Evaluated 
Screened  
• All participants who were screened for 
eligibility 
• Study 
Population 
Randomized  
 
• All participants who were randomly assigned 
to treatment in the study. 
• This population will be based on the treatment 
the participant was randomized to. 
• Any participant who receives a treatment 
randomization number will be considered to 
have been randomized. 
• Study 
Population 
Enrolled 
• All participants who passed screening and 
entered the study. Included are run-in failures 
and randomized participants. 
• Note: screening failures (who never passed 
screening even if rescreened) and participants 
screened but never enrolled into the study 
(Reserve, Not Used) are excluded from the 
Enrolled population as they did not enter the 
study. 
• Study 
Population 
Safety 
• All randomized participants who received at 
least one dose of study treatment. 
• Safety 


 
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Population 
Definition / Criteria 
Analyses 
Evaluated 
• Participants will be analysed according to the 
treatment they actually received. 
• Note: Participants who were not randomized 
but received at least one dose of study 
treatment should be listed. 
Efficacy 
• All participants in the safety population who 
provided at least two evaluable overnight 
sputum samples.  
• This population will be based on the treatment 
the participant was randomized to. 
• Efficacy 
Pharmacokinetic 
(PK) 
• Participants in the safety population who 
received at least one dose of GSK3036656 and 
have at least one evaluable PK sample.  
• Participants will be analysed according to the 
treatment actually received.  
• PK 
 
For participants who receive the incorrect treatment (i.e. a different treatment to what 
they were randomised to), the participants will be assigned to the actual treatment groups 
if they received that treatment for more than 50% of their doses.  
4.1. 
Protocol Deviations 
Important protocol deviations (including deviations related to study inclusion/exclusion 
criteria, conduct of the trial, patient management or patient assessment) will be 
summarised and listed. 
Protocol deviations will be tracked by the study team throughout the conduct of the study 
in accordance with the latest Protocol Deviation Management Plan (PDMP). 
o Data will be reviewed prior to freezing the database to ensure all important 
deviations and deviations which may lead to exclusion from the analysis are 
captured and categorised on the protocol deviations dataset.  
o This dataset will be the basis for the summaries and listings of protocol 
deviations. 
A separate summary and listing of all inclusion/exclusion criteria deviations will also be 
provided. This summary will be based on data as recorded on the inclusion/exclusion 
page of the electronic case report form (eCRF). 


 
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5. 
CONSIDERATIONS FOR DATA ANALYSES AND DATA 
HANDLING CONVENTIONS 
5.1. 
Study Treatment & Sub-group Display Descriptors 
Treatment Group Descriptions 
RandAll NG  
Data Displays for Reporting  
Code 
Description 
Description[1] 
Order in 
Tables, 
Figures and 
Listings 
SOC 
Standard of Care (Rifafour) 
Rifafour 
1 
D1 
GSK3036656 Dose 1 
GSK3036656 5 mg 
2 
D2 
GSK3036656 Dose 2 
GSK3036656 15 mg 
3 
D3 
GSK3036656 Dose 3 
GSK3036656 30 mg 
4 
D4 
GSK3036656 Dose 4 
GSK3036656 X mg 
5 
D5 
GSK3036656 Dose 5 
GSK3036656 X mg 
6 
Note:  
- 
The decision to proceed to each subsequent dose level will be made by the dose 
escalation committee.  
- 
In tables, figures and listings, treatments should be presented with standard of care 
(Rifafour) first, then in order of increasing dose.  
- 
[1] ‘X mg’ is to be replaced by actual maintenance dose.  
5.2. 
Baseline Definitions 
For all endpoints, except those noted below, the baseline value will be the latest pre-dose 
assessment with a non-missing value, including those from unscheduled visits (e.g. if 
Day 1 (pre-dose) is missing, Day -1 will be used). If there are no pre-dose data, then no 
derivation will be performed, and baseline will be set to missing.  
For bacterial endpoints, baseline will be calculated as the mean of Day -2 and Day -1; if 
data are available at only one of these timepoints then that value will be used as baseline 
(i.e. data prior to Day -2 will not be used for calculation of baseline, even in the event 
there is missing data for both Day -2 and Day -1).  
Unless otherwise stated, the mean of replicate assessments at any given time point will be 
used as the value for that timepoint.  
If time is missing, Day 1 assessments are assumed to be taken prior to first dose and used 
as baseline. 


 
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5.3. 
Examination of Covariates 
For the analysis of CFU and TTP, the demographic variable of Body Mass Index (BMI) 
will be included as a covariate in the model, see Section 7: Efficacy Analyses for further 
details.  
Additional covariates of age (continuous), creatinine clearance (continuous), HIV status 
(yes/no), diabetes status (yes/no), smoking status (<20 or >=20/day) and baseline cavities 
(yes/no) will be investigated in an exploratory manner to assess their importance in future 
possible analyses.  
5.4. 
Other Considerations for Data Analyses and Data Handling 
Conventions 
Other considerations for data analyses and data handling conventions are outlined in the 
appendices: 
Section Component 
12.3 
Appendix 3: Assessment Windows 
12.4 
Appendix 4: Study Phases and Treatment Emergent Adverse Events 
12.5 
Appendix 5: Data Display Standards & Handling Conventions 
12.6 
Appendix 6: Derived and Transformed Data 
12.7 
Appendix 7: Reporting Standards for Missing Data 
12.8 
Appendix 8: Values of Potential Clinical Importance 
 
 


 
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6. 
STUDY POPULATION ANALYSES 
6.1. 
Overview of Planned Study Population Analyses 
The study population analyses will be based on the Safety population, unless otherwise 
specified. 
Study population analyses including analyses of participant’s disposition, protocol 
deviations, demographic and baseline characteristics, prior and concomitant medications, 
and exposure will be based on GSK Core Data Standards.  Details of the planned displays 
are presented in Appendix 10: List of Data Displays. 
Data from the standard of care arm will be pooled for the analysis, except for the display 
of Summary of Participant Disposition at Each Study Epoch, which will be displayed by 
cohort.   
 
 


 
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7. 
EFFICACY ANALYSES 
7.1. 
Primary Efficacy Analyses 
7.1.1. 
Endpoint / Variables 
Rate of change in log10 colony forming units (log10CFU) per ml direct respiratory sputum 
samples over the period baseline to Day 14 (EBA CFU0-14).  
7.1.2. 
Summary Measure 
Mean daily rate of change in log10CFU for each treatment group.  
7.1.3. 
Population of Interest  
The primary efficacy analyses will be based on the efficacy population, unless otherwise 
specified. 
7.1.4. 
Strategy for Intercurrent (Post-Randomization) Events 
The primary treatment effect to be estimated will be the while on treatment effect of 
initial randomised treatment.  
All recorded data up to the time of study withdrawal will be included in the analysis, 
regardless of discontinuation of study medication.  
7.1.5. 
Statistical Analyses / Methods 
Details of the planned displays are provided in Appendix 10: List of Data Displays and 
will be based on GSK data standards and statistical principles. 
Unless otherwise specified, endpoints / variables defined in Section 7.1.1 will be 
summarised using descriptive statistics, graphically presented (where appropriate) and 
listed. 
 


 
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7.1.5.1. 
Statistical Methodology Specification 
Endpoint  
• Rate of change in log10CFU per ml direct respiratory sputum samples over the period 
baseline to Day 14.  
Model Specification 
Model 1: 
• Mixed model repeated measures analysis. Terms in the model: 
• Response: log10CFU 
• Categorical: treatment 
• Continuous: time, BMI  
• Interaction: treatment*time 
• Random: Subject 
 
Model 2: 
In addition, to characterize any bi-linear characteristics a bi- linear Bayesian 
regression model of the following form will also be fitted: 
 
• Where cp=change (node) point as determined by the data (separate nodes for each 
treatment group), and t=time. 
• The model will include terms for intercept, BMI, treatment, treatment*day before 
node, treatment*day after node, subject.  
• This model would utilize uninformative uniform priors for cp and σ2 (discrete 
uniform(2,13) and uniform(0,5) respectively) and uninformative normal priors for the 
intercept, treatment, baseline log10CFU and BMI (normal(0,var=1000000)).  Subject 
will be a random effect with an uninformative prior (normal(0,var), where 
var=uniform(0,5).  
• The efficacy population will be used for both models. 
• Data from the standard of care arm will be pooled for the analysis. 
• Where CFU plate counts are Too Numerous To Count (TNTC) a value of 2500 
should be imputed for both models.   
Model Checking & Diagnostics 
Model 1: Mixed model repeated measures analysis: 
• An autoregressive 1 covariance structure will be used. In the event this fails to 
converge alternative covariance structures may be considered such as VC.  
• The Kenward and Roger method for approximating the denominator degrees of 
freedom will be used.  
• Normality assumptions underlying the model used for analysis will be examined 
by obtaining a normal probability plot of the residuals and a plot of the residuals 
versus the fitted values (i.e. checking the normality assumptions and constant 
variance assumption of the model respectively) to gain confidence that the model 
assumptions are reasonable.  


 
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• If there are any departures from the distributional assumptions, alternative models 
will be explored using appropriate transformed data (e.g. square root).  
Model 2: Bi-linear Bayesian regression model:  
• The convergence will be examined using trace plots: All chains’ trace plots will 
be inspected visually, to assess the mixing of each chain. Convergence is 
indicated when all chains appear to be mixing well and overlapping each other 
randomly (no chain’s convergence is indicated until the chains of all model 
parameters appear well-mixed).  
• Additional convergence diagnostics, such as Monte Carlo Standard Error divided 
by the standard deviation of the posterior distribution (MCSE/SD), Gelman-Rubin 
statistic, effective sample size (ESS) and autocorrelation plots may also be 
reviewed.  
• The modelling will be subject to independent quality control. The final parameter 
estimates for the mean slopes and the mean node point should be within two times 
the Monte Carlo Standard Error (2xMCSE).  
Model Results Presentation 
• Model 1: Summary of the mean daily rate of change, standard deviation and 
associated 95% confidence interval will be presented for each treatment arm.  
• Model 2: The mean and 95% highest posterior density (HDP) interval of the node, 
slope parameter before node and slope parameter after node, will be presented for 
each treatment arm.  
Subgroup Analyses 
• No subgroup analyses are planned for this endpoint.  
Sensitivity and Supportive Analyses 
• A sensitivity analysis will be performed (Model 1 only) excluding participants who 
withdraw from the study before Day 10 and/or who were replaced during the study.  
• Additional covariates (see Section 5.3) will be investigated in an exploratory manner 
using a mixed model repeated measures analysis. Each covariate will be investigated 
separately utilizing the model described for the primary endpoint. First the primary 
endpoint model will be fitted but including the covariate of interest and then the 
primary endpoint model will be fitted including both the covariate and treatment-by-
covariate interaction.  
7.2. 
Secondary Efficacy Analyses 
7.2.1. 
Endpoint / Variables 
- 
Rate of change in log10CFU per ml direct respiratory sputum samples over the 
period baseline to Day 2 (EBA CFU0-2).  
 
- 
Rate of change in log10CFU per ml direct respiratory sputum samples over the 
period Day 2 to Day 14 (EBA CFU2-14).  
 
- 
Rate of change in time to sputum culture positivity (TTP) over the time period 
baseline to Day 14 (EBA TTP0-14) 


 
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- 
Rate of change in time to sputum culture positivity (TTP) over the time period 
baseline to Day 2 (EBA TTP0-2) 
 
- 
Rate of change in time to sputum culture positivity (TTP) over the time period 
Day 2 to Day 14 (EBA TTP2-14) 
 
7.2.2. 
Summary Measure 
Mean daily rate of change in log10CFU or TTP for each treatment group.  
7.2.3. 
Population of Interest  
The secondary efficacy analyses will be based on the efficacy population, unless 
otherwise specified. 
7.2.4. 
Strategy for Intercurrent (Post-Randomization) Events 
The treatment effect to be estimated will be the while on treatment effect of initial 
randomised treatment.  
All applicable recorded data up to the time of study withdrawal will be included in the 
analysis, regardless of discontinuation of study medication.  
7.2.5. 
Statistical Analyses / Methods 
Details of the planned displays are provided in Appendix 10: List of Data Displays and 
will be based on GSK data standards and statistical principles. 
Unless otherwise specified, endpoints / variables defined in Section 7.2.1 will be 
summarised using descriptive statistics, graphically presented (where appropriate) and 
listed. 


 
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7.2.5.1. 
Statistical Methodology Specification 
Endpoint  
• Rate of change in log10CFU per ml direct respiratory sputum samples over the 
period baseline to Day 2.  
• Rate of change in time to sputum culture positivity (TTP) over the time period 
baseline to Day 2 (EBA TTP0-2) 
Model Specification 
• Mixed models repeated measures analysis.  
• Terms in the model: 
• Response: log10CFU or TTP as appropriate 
• Categorical: treatment 
• Continuous:  time, BMI 
• Interaction: treatment*time. 
• Random: Subject 
• Efficacy population 
• Data from the standard of care arm will be pooled for the analysis. 
Model Checking & Diagnostics 
• Normality assumptions underlying the model used for analysis will be examined by 
obtaining a normal probability plot of the residuals and a plot of the residuals versus 
the fitted values (i.e. checking the normality assumptions and constant variance 
assumption of the model respectively) to gain confidence that the model assumptions 
are reasonable.  
• If there are any departures from the distributional assumptions, alternative models 
will be explored using appropriate transformed data (e.g. log transformation (to base 
10 for TTP), square root).  
Model Results Presentation 
• Summary of the mean, standard deviation, standard error and associated 95% 
confidence interval for each treatment arm.  
Subgroup Analyses 
• No subgroup analyses are planned for this endpoint. 
Sensitivity and Supportive Analyses 
• No sensitivity or supportive analyses are planned for this endpoint. 
 
 
 
 
 


 
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Endpoint  
• Rate of change in log10CFU per ml direct respiratory sputum samples over the 
period Day 2 to Day 14.  
• Rate of change in time to sputum culture positivity (TTP) over the time period 
baseline to Day 14 (EBA TTP0-14) 
• Rate of change in time to sputum culture positivity (TTP) over the time period 
Day 2 to Day 14 (EBA TTP2-14) 
Model Specification 
• As described for the primary endpoint, see Section 7.1.5, except:  
o For the models for Days 2-14, baseline log10CFU (or baseline TTP for 
TTP (2-14) should be included as a continuous covariate.  
• For the TTP endpoints, the data may be log transformed using base 10 if the residuals 
do not follow a normal distribution. 
Model Checking & Diagnostics 
• As described for the primary endpoint, see Section 7.1.5. 
Model Results Presentation 
• As described for the primary endpoint, see Section 7.1.5. 
Subgroup Analyses 
• No subgroup analyses are planned for these endpoints. 
Sensitivity and Supportive Analyses 
• No sensitivity or supportive analyses are planned for these endpoints. 
 


 
C O N FI D E N TI A L  
 
 
 
2 0 1 2 1 4  
2 5  
 
7. 3.  
E x pl or at or y Effi c a c y A n al y s e s  
7. 3. 1.  
E n d p oi nt / V ari a bl e s  
T hese e x pl orat or y e n d p oi nts will be a nal ys e d a n d re p orte d se p aratel y.  
C CI


 
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8. 
SAFETY ANALYSES 
The safety analyses will be based on the Safety population, unless otherwise specified. 
8.1. 
Adverse Events Analyses 
Adverse events analyses including the analysis of adverse events (AEs), Serious (SAEs) 
and other significant AEs will be based on GSK Core Data Standards.  
8.2. 
Clinical Laboratory Analyses 
Laboratory evaluations including the analyses of Chemistry laboratory tests, 
Haematology laboratory tests, Urinalysis, and liver function tests will be based on GSK 
Core Data Standards.  
8.3. 
Other Safety Analyses 
The analyses of non-laboratory safety test results including ECGs and vital signs will be 
based on GSK Core Data Standards, unless otherwise specified.  
Listings of the troponin data and mycobacterial data will be produced.  


 
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9. 
PHARMACOKINETIC ANALYSES 
9.1. 
Secondary Pharmacokinetic Analyses 
9.1.1. 
Endpoint / Variables 
Derived PK parameters: AUC(0-t) or AUC(0-24), Cmax, tmax and Cτ.  
9.1.2. 
Summary Measure 
• Dose proportionality of AUC(0-t) or AUC(0-24)  
• Dose proportionality of Cmax 
• Achievement of Steady State (Cτ) 
• Summary statistics for tmax 
9.1.3. 
Population of Interest  
The PK analyses will be based on the PK population, unless otherwise specified. 
9.1.4. 
Strategy for Intercurrent (Post-Randomization) Events 
• The treatment effect to be estimated will be the while on treatment effect of actual 
received treatment.  
• All applicable recorded data up to the time of the intercurrent event will be included 
in the analysis.  
 
9.1.5. 
Statistical Analyses / Methods 
Unless otherwise specified, endpoints / variables defined in Section 9.1.1 will be 
summarised using descriptive statistics, graphically presented (where appropriate) and 
listed. 
For each of the parameters Cmax, tmax, AUC(0-t), AUC(0-24), Cτ the following 
summary statistics will be calculated and tabulated by dose group: 
- 
Untransformed data: N, n, arithmetic mean, 95% confidence interval (CI) for the 
arithmetic mean, SD, median, minimum, maximum 
The following additional summary statistics will be calculated and tabulated by dose 
group, for the parameters Cmax, AUC(0-t), AUC(0-24) and Cτ. 
- 
Log-transformed data: Geometric mean, 95% CI for the geometric mean, SD, 
between participant coefficient of variation (%CVb) 
%CVb will be calculated as: CVb (%) = √ (exp(SD2) - 1) * 100 
Where SD = SD of loge transformed data 


 
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9.1.5.1. 
Statistical Methodology Specification 
The following pharmacokinetic statistical analyses will only be performed if sufficient 
data are available (i.e. if participants have well-defined plasma profiles). 
Endpoint 
• Dose proportionality of AUC(0-t) or AUC(0-24)  
• Dose proportionality of Cmax 
Model Specification 
• This will be analysed using a power model: 
y = α*doseβ 
where y = PK parameter being analysed (i.e. AUC or Cmax) and α = participant.  
• Loge transformed data will be analysed by fitting the following terms in the mixed 
effect model: 
Fixed, continuous effect: loge(dose) 
Random effect: Participant 
• The Kenward Roger method for approximating the denominator degrees of freedom 
and correcting for bias in the estimated variance-covariance of the fixed effects will 
be used.  
• An unstructured (UN) covariance structure for the G matrix will be used. 
• For AUC, AUC(0-24) will be analysed where calculable; where doses do not have 
quantifiable concentrations at 24 hours, AUC(0-t) will be analysed.  
• PK population 
• Data from at least three doses must be available to perform the dose proportionality 
analysis.   
• A slope ≈ 1 implies dose proportionality  
Model Checking & Diagnostics 
•  If the model does not converge, the random participant effect will be removed from 
the model.  
Model Results Presentation 
• Estimates of the mean slopes of loge(dose) will be reported along with corresponding 
90% confidence intervals.  
• A figure of log(dose) vs log(AUC) will be presented in the form of a scatterplot of all 
individual participant values, along with a regression line and associated 95% 
confidence interval. A similar plot will be produced for log(dose) vs log(Cmax).  
 
 
Endpoint 
• Achievement of Steady State (Cτ) 
Model Specification 
• This will be analysed using a mixed model: 


 
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Fixed effects: loge(dose), day, loge(dose)*day 
Random effect: participant  
Day will be treated as a continuous variable, dose as a categorical variable.  
• The dose-by-day interaction will be tested for its significance at the 5% level, if the 
interaction is not significant then a single point estimate for all dose levels pooled will 
be calculated in addition to the individual dose levels.  
• The Kenward Roger method for approximating the denominator degrees of freedom 
and correcting for bias in the estimated variance-covariance of the fixed effects will 
be used.  
• An unstructured (UN) covariance structure for the G matrix will be used.  
• In the event that this model fails to converge, alternative covariance structures 
may be considered such as variance components (VC) or compound symmetry 
(CS).  
• Akaike’s Information Criteria (AIC) will be used to assist with the selection of 
covariance structure.  
Model Checking & Diagnostics 
• Distributional assumptions underlying the model used for analysis will be examined 
by obtaining a normal probability plot of the residuals and a plot of residuals versus 
the fitted values (i.e. checking the normality assumption and constant variance 
assumption of the model respectively).  
• If there are any departures from the distributional assumptions, alternative 
transformations, such as data squared or square root of data, will be explored.  
• Non-parametric analyses will be conducted if the normality assumption does not hold.  
Model Results Presentation 
• The coefficients of the slopes for the day effect for each dose, along with 
corresponding 90% confidence intervals, will be used to determine whether steady 
state was achieved.  
• If the interaction is not significant, then a single point estimate and corresponding 
90% confidence interval for all dose levels pooled will be presented.  
• Trough concentration levels collected pre-morning dose will be plotted by collection 
day and dose.  
 


 
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10. 
ADDITIONAL ANALYSES DUE TO THE COVID-19 
PANDEMIC 
10.1. 
Study Population 
10.1.1. 
Subject Disposition 
The ‘Summary of Subject Status and Subject Disposition for the Study Conclusion 
Record’ and the ‘Summary of Treatment Status and Reasons for Discontinuation of Study 
Treatment’ will include the reason withdrawal/discontinuation due to issues related to the 
COVID-19 pandemic. In addition, these two summaries will be repeated, with the reason 
for withdrawal/discontinuation categorised as related to COVID-19 pandemic, or non-
related to COVID-19 pandemic. The summaries will be based on GSK Core Data 
Standards, and details are provided in Appendix 10: List of Data Displays. 
 
10.1.2. 
Protocol Deviations 
In addition to the overall summary of important protocol deviations, separate summaries 
will be produced of important protocol deviations related to COVID-19, and important 
protocol deviations not related to COVID-19. A listing of non-important protocol 
deviations related to COVID-19 will also be produced. 
 
10.2. 
Safety 
10.2.1. 
Assessment of COVID-19 AEs 
A standardised MedDRA Query (SMQ) will be used to identify all COVID-19 AEs. 
The incidence of AEs and SAEs (Fatal and Non-Fatal) of COVID-19, COVID-19 AEs 
leading to study drug discontinuation and COVID-19 AEs leading to study withdrawal 
will be obtained from standard AE and SAE summaries.  
10.2.2. 
Impact of COVID-19 Pandemic on Safety Results 
The following tables will be produced, showing the incidence rates for events occurring 
before or after the start of the COVID-19 pandemic. The phases (before and after the start 
of the COVID-19 pandemic) are defined in Section 12.4.1.2: 
- 
Summary of exposure adjusted incidence rates of adverse events 
- 
Summary of exposure adjusted incidence rates by age 
- 
Summary of COVID-19 assessments for subjects with COVID-19 Adverse events 
The above displays will be based on GSK Core Data Standards.  Details of the planned 
displays are presented in Appendix 10: List of Data Displays. 


 
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31 
 
11. 
REFERENCES 
Burger D, Schall R. A Bayesian nonlinear mixed-effects regression model for the 
characterisation of early bactericidal activity of tuberculosis drugs. Journal of 
Biopharmaceutical Statistics, 25: 1247-1271 (2015).  
GlaxoSmithKline Document Number 2017N332005_02 (Amendment 2 – 24-SEP-2018): 
A Phase IIa open-label trial to investigate the early bactericidal activity, safety and 
tolerability of GSK3036656 in participants with drug-sensitive pulmonary tuberculosis.  
GlaxoSmithKline Document Number 2018N381501_00: Data Analysis and Reporting 
Plan (DAP) for Population pharmacokinetic studies. 
 GUI_137354, Information for Authors: Reporting and Analysis Plan (RAP), Global 
GUI_51487, Non-Compartmental Analysis of Pharmacokinetic Data, CPMS Global 
SOP_54838, Development, Review & Approval of Reporting & Analysis Plan (RAP), 
Global  


 
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12. 
APPENDICES 
12.1. 
Appendix 1: Protocol Deviation Management and Definitions 
for PK and Efficacy Population 
There are no pre-defined categories leading to exclusion from the PK population, but all 
protocol deviations will be reviewed on a case-by-case basis.  
 
Any participant in the safety population who does not provide at least two evaluable 
overnight sputum samples will be excluded from the efficacy population. All other 
protocol deviations will be reviewed on a case-by-case basis.  
 
 
 
 
 


C O N FI D E N TI A L  
 
 
2 0 1 2 1 4  
3 3  
 
1 2. 2.  
A p p e n di x 2: S c h e d ul e of A cti viti e s  
1 2. 2. 1.  
Pr ot o c ol D efi n e d S c h e d ul e of E v e nt s  
P eri o d  
S cr e e ni n g  
D o si n g  
F oll o w -u p  
Vi sit  
1  
2  
3  
4  
5 t o 
1 0  
1 1  
1 2 
t o 
1 6  
1 7  1 8  
Earl y 
Wit h dra w al  
1 9  
D a y  
(-9 
t o -
3) 
A  
-2 B  
-1  
1  
2 t o 
7 C  
8  
9 t o 
1 3 C  
1 4  1 5  
2 8 
( 
7)  
D oc u m e nt ati o n of Positiv e 
G e n e X p ert a n d/ or T B s m e ar 
( T B cli nic/sit e of i niti al 
di a g n osis)  
X  
 
 
 
 
 
 
 
 
 
 
Writt e n I nf or m e d C o ns e nt  
X  
 
 
 
 
 
 
 
 
 
 
D e m o gr a p hy (i ncl u di n g 
s m oki n g hist ory) 
X  
 
 
 
 
 
 
 
 
 
 
M e dic al & Tr e at m e nt Hist ory  
X  
 
 
 
 
 
 
 
 
 
 
I ncl usi o n/ Excl usi o n/ Eli gi bility 
Ass ess m e nt  
X  
 
 
 
 
 
 
 
 
C h est X -r ay 
X  
 
 
 
 
 
 
 
 
 
P hysic al Ex a mi n ati o n D  
X  
 
 
X  
X  
X  
X  
X  
X  
X  
X  
Vit al Si g ns  E  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
1 2 -L e a d E C G   
X  
 
 
 
 
 
 
X  
X  
X  
R a n d o mis ati o n M  
 
X  
 
 
 
 
 
 
 
 
Ec h oc ar di o gr a m ( m ay b e 
c o n d uct e d at a ny of t h e 
scr e e ni n g visits) 
X  
 
 
 
 
 
 
X S  
X S  
Bl o o d P K F 
 
 
 
 
 
 
X F 
X  
X  
X  
 
S p ot S p ut u m (c o nfir m T B & 
a d e q u at e b act eri al l o a d) G  
X  
 
 
 
 
 
 
 
 
 
 
Rif a m pici n R esist a nc e T est 
(r a pi d)G  
( micr osc o py a n d G e n e X p ert 
t ests m ay b e r e p e at e d o n a n 
ov er ni g ht s p ut u m s a m pl e if 
n e e d e d)  
X  
 
 
 
 
 
 
 
 
 
 
H a e m at ol o gy, Cli nic al 
C h e mistry, Uri n alysis H  
X  
 
 
X  
X  
X  
 
X  
 
X  
X  
C ar di ac s af ety bi o m ark ers T 
X  
X  
X  
 
 
X  
 
 
 
Uri n e Dr u g Scr e e n I 
X  
X I 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HI V T est ( a n d C D 4 C o u nt if 
HI V c o nfir m e d)  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
X  
X  
 
 
X  
 
X  
 
 
 
 
X  
X  
 
 
X  
 
X  
 
 
X  
 
 
 
 
X  
 
 
H os pit al A d missi o n  
X B  
X B  
 
 
 
 
 
 
 
 
 
C CI


C O N FI D E N TI A L  
 
 
2 0 1 2 1 4  
3 4  
 
P eri o d  
S cr e e ni n g  
D o si n g  
F oll o w -u p  
Vi sit  
1  
2  
3  
4  
5 t o 
1 0  
1 1  
1 2 
t o 
1 6  
1 7  1 8  
Earl y 
Wit h dra w al  
1 9  
D a y  
(-9 
t o -
3) 
A  
-2 B  
-1  
1  
2 t o 
7 C  
8  
9 t o 
1 3 C  
1 4  1 5  
2 8 
( 
7)  
Ov er ni g ht S p ut u m L 
X  
X  
X  
X  
X  
X  
X  
X  
 
 
 
I P A d mi nistr ati o n a n d 
C o m pli a nc e C h eck N  
 
 
 
X  
X  
X  
X  
X  
 
 
 
Myc o b act eri ol o gy 
Ass ess m e nts O  
 
X  
X  
 
 
 
 
X  
 
 
 
H os pit al Disc h ar g e  
 
 
 
 
 
 
 
 
X  
X  
 
C o nc o mit a nt M e dic ati o n  
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
A dv ers e Ev e nts P  
 
 
 
X  
X  
X  
X  
X  
X  
X  
X  
P oi nt of C ar e Bl o o d Gl uc os e 
or H b A 1c Q  
 
X  
 
 
 
 
X  
 
 
 
a.  
T h e Visit 1 ( d ay -9 t o -3) ti m e p eri o d will b e u p t o a m axi m u m of 7 d ays b ut will b e k e pt as s h ort as p ossi bl e.  
b.  
 P artici p a nts c a n pr oc e e d wit h t h e Visit 2 ( d ay -2) ass ess m e nts as s o o n as t h eir Visit 1 ( d ay -9 t o -3) ass ess m e nts 
h av e b e e n c o m pl et e d i. e. Visits 1 a n d 2 m ay occ ur o n t h e s a m e d ay as l o n g as t h e scr e e ni n g r es ults ar e av ail a bl e 
i n ti m e f or r a n d o mis ati o n. P artici p a nts m ay b e h os pit alis e d d uri n g t h e e ntir e pr e -tr e at m e nt p eri o d if th e 
I nv esti g at or c o nsi d ers it a dvis a bl e f or r e as o ns of s af ety or c o m pli a nc e. 
c. 
All ev e nts list e d as occ urri n g o n Visit 5 ( d ay 2) t o Visit 1 0 ( d ay 7) a n d Visit 1 2 ( d ay 9) t o Visit 1 6 ( d ay 1 3) will b e 
c o n d uct e d e ac h d ay d uri n g t h es e visits.  
d.  
H ei g ht ( m) will o nly b e c oll ect e d o nc e at Visit 1 ( d ay -9 t o -3). A f ull p hysic al ex a mi n ati o n will b e p erf or m e d at Visit 
1 ( d ay -9 t o -3), wit h sy m pt o m -dir ect e d p hysic al ex a mi n ati o ns at Visit 1 7 ( d ay  1 4), Visit 1 9 ( d ay 2 8) a n d E arly 
Wit h dr a w al Visit ( E W V).  Sy m pt o m dir ect e d p hysic al ex a mi n ati o ns m ay b e c o n d uct e d as r e q uir e d d uri n g t h e st u dy 
(visits 4 t o 1 6).  R e q uir e m e nts f or t h e p hysic al ex a mi n ati o n ar e s p ecifi e d i n t h e S R M. 
e.  
Syst olic bl o o d pr ess ur e ( S B P) a n d di ast olic bl o o d pr ess ur e ( D B P) ( m m H g), h e art r at e ( b e ats p er mi nut e [ b p m]), 
b o dy t e m p er at ur e (° C), r es pir at ory r at e ( br e at h es p er mi n ut e) a n d w ei g ht (k g). T o b e p erf or m e d wit hi n 4 h o urs 
pri or t o t h e first d aily d osi n g o n Visit 4 ( d ay 1) t hr o u g h t o  Visit 1 7 ( d ay 1 4) a n d wit hi n 4 h o urs b ef or e t h e ti m e 
d osi n g w o ul d h av e occ urr e d o n Visit 1 8 ( d ay 1 5). O n d ays w h er e t h e f oll o wi n g ass ess m e nts ar e d o n e t h e or d er 
s h o ul d b e: vit al si g ns b ef or e bl o o d dr a ws f or P K or s af ety ass ess m e nts.  
f. 
P Ks will b e p erf or m e d as n ot e d i n t h e P K t a bl e. A si n gl e pr e -d os e P K s a m pl e will b e c oll ect e d o n e ac h of D ays 1 2 
& 1 3, a n d s eri al P K bl o o d s a m pli n g will occ ur o n D ay 1 4 (s e e P K t a bl e b el o w). At E W V a P K s a m pl e will b e t ak e n 
b ef or e t h e ti m e of t h e pl a n n e d d aily d osi n g.  If t his is n ot p ossi bl e, a s p o nt a n e o us P K s a m pl e will b e t ak e n. 
g.  
S p ut u m s m e ar micr osc o py a n d m ol ec ul ar r a pi d t est f or c o nfir m ati o n of Myc o b act eri u m t u b erc ul osis a n d rif a m pici n 
s usc e pti bility ( G e n e X p ert). If t h e first s p ot s p ut u m or ov er ni g ht s p ut u m s a m pl e s h o ws a n u nf av o ur a bl e r es ult, t h e 
t ests m ay b e r e p e at e d o n a fr es hly c oll ect e d s p ot s p ut u m or ov er ni g ht s p ut u m s a m pl e a n d t h at r es ult us e d 
i nst e a d. 
h.  
R ef er t o A p p e n dix 3  f or d et ails. 
i. 
Uri n e dr u g scr e e n: c oc ai n e, a m p h et a mi n es a n d o pi at es. Uri n e dr u g scr e e n c a n b e r e p e at e d at Visit 2 ( d ay -2) f or 
p artici p a nts w h o w er e n ot h os pit aliz e d at Visit 1 ( d ay -9 t o -3).  
j. 
k. 
l. 
Ov er ni g ht s p ut u m s a m pli n g m ay st art at Scr e e ni n g visit ( d ay -9 t o -3) or o n Visit 2 ( d ay – 2) a n d will c o nti n u e d aily 
u ntil Visit 7 ( d ay 4). A d diti o n al s a m pli n g will b e c o n d uct e d at visit 9 ( d ay 6), Visit 1 1 ( d ay 8), Visit 1 3 ( d ay 1 0), Visit 
C CI


C O N FI D E N TI A L  
 
 
2 0 1 2 1 4  
3 5  
 
1 5 ( d ay 1 2) a n d  Visit 1 7 ( d ay 1 4). S p ut u m s a m pli n g will st o p o n t h e m or ni n g of Visit 1 8 ( d ay 1 5). S p ut u m 
c oll ecti o n will st art i n t h e aft er n o o ns at 1 5: 0 0 h o urs ( 1 h o ur) a n d co nti n u e f or 1 6 h o urs ov er ni g ht. T h e 1 6 -h o ur 
s p ut u m s a m pli n g f or e ac h of t h e s a m pli n g d ays m ust b e fi nis h e d pri or t o t h e a d mi nistr ati o n of t h e n ext d ay’s I P.  
Ov er ni g ht s p ut u m c oll ecti o n m ay b e c oll ect e d as m a ny ti m es as r e q uir e d ov er t h e scr e e ni n g p eri o d u ntil a n 
eli gi bl e s a m pl e is o bt ai n e d. Of t h e pr e -tr e at m e nt p eri o d s a m pl es c oll ect e d, o nly t h e Visit 2 ( d ay-2) a n d Visit 3( d ay 
-1) ov er ni g ht s p ut u m s a m pl es will b e us e d f or t h e effic acy e n d p oi nt t ests.  
T h e d ay s p ut u m c oll ecti o n st arts r efl ects t h e d ay t o w hic h t h at s a m pl e a p pli es. e. g. a s a m pl e w h os e c oll ecti o n 
st arts o n d ay 1 a n d e n ds o n d ay 2, is d es i g n at e d as t h e d ay 1 ov er ni g ht s p ut u m s a m pl e ( a n d r es ults).  
m.  R a n d o miz ati o n m ay occ ur o nc e all t h e scr e e ni n g r es ults ar e av ail a bl e a n d t h e I nv esti g at or h as d et er mi n e d t h at 
t h e p artici p a nt is eli gi bl e f or t h e tri al.  
n.  
Aft er t h e first d os e of I P, s u bs e q u e nt d o s es of I P will b e a d mi nist er e d 2 3 t o 2 5 h o urs aft er t h e pr evi o us d os e.  
o.  
Mi ni m u m i n hi bit ory c o nc e ntr ati o n ( MI C) a n d s p eci ati o n of t h e i nf ecti n g or g a nis m by p oly m er as e c h ai n r e acti o n 
( P C R) will b e esti m at e d fr o m a c ult ur e c oll ect e d o n a pr e-tr e at m e nt d ay ( d ay-1 or d ay -2) a n d fr o m t h e l ast 
av ail a bl e c ult ur e o n a tr e at m e nt d ay ( d ay 1 4 or e arli er, b ut n ot e arli er t h a n d ay 8). Dr u g s usc e pti bility t esti n g of M. 
t u b erc ul osis f or s e nsitivity t o rif a m pici n wit h a m ol ec ul ar m et h o d will b e t est e d at Visit 1.  Susc e pti bility t o I N H, Rif, 
E M B a n d P Z A will b e t est e d o n a c ult ur e gr o w n fr o m a b as eli n e s a m pl e ( d ay -2 or d ay -1). T h e a n alysis of a ny 
b act eri al is ol at es s e nt t o G S K, S p ai n f or f urt h er c h ar act eris ati o n i n t h e ev e nt of MI C c h a n g e will n ot b e r e p ort e d i n 
t h e cli nic al st u dy r e p ort a n d will b e r e p ort e d s e p ar at ely.  
p.  
A dv ers e ev e nts ( A E) will b e c oll ect e d by t h e I nv esti g at or fr o m t h e ti m e a p artici p a nt r ec eiv es his/ h er first d os e of 
I P t hr o u g h t o t h e Visit 1 9 ( d ay 2 8) F oll o w u p Visit. 
q.  
r. 
[ n ot us e d] 
s. 
O nly t o b e p erf or m e d o n p artici p a nts as d et er mi n e d by t h e d os e esc al ati o n c o m mitt e e ( D E C) or o n p artici p a nts 
wit h c h a n g es i n cli nic al st at us w arr a nti n g a f oll o w -u p ec h o i n t h e o pi ni o n of t h e i nv esti g at or. T h e D E C m ay d eci d e 
t o p erf or m t his ass ess m e nt i n a d diti o n al c o h orts wit hi n t his st u dy. 
t. 
S a m pl es will b e ass ay e d f or: Tr o p o ni n I. T h e first t w o s a m pl es at l e ast 2 4 h o urs a p art, o n e d uri n g t h e scr e e ni n g 
p h as e a n d o n e pri or t o t h e first d os e of st u dy tr e at m e nt. D ay 1 4 s a m pl e wi n d o w is ± 2 4 h o urs. T hir d s a m pl e t o b e 
t ak e n o n D ay 3. 
C CI


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PK sampling time and events table 
STUDY VISIT  
Visit 
15 
Visit 
16 
Visit 17 
Visit 
18 
STUDY DAY 
Day 
12 
Day 
13 
Day 14 
Day 
15 
STUDY HOURB  
 
 
0 
0.5 
1 
1.5 
2 
3 
4 
6 
8 
12 
24 
Pharmacokinetic 
samplingC 
XA 
XA 
XD 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
A.  Sample to be taken within 30 minutes pre-dose. 
B. All values are relative to the time of day that the study treatment is administered on Day 14. 
C. PK sampling is only to be performed on participants receiving GSK3036656. PK samples will not be taken 
from participants receiving Rifafour e-275 (or equivalent generic alternative). 
D. Sample to be taken within 10 minutes pre-dose 
 
PK Sample timing window allowances 
Sample timepoint 
Sample collection window allowed 
Pre dose  
Not applicable (see footnotes above) 
0h - 4h post  
  5 min 
> 4h – 12h post 
 15 min 
> 12h – 24h post 
 1 h 
 
 
 
 
 
 
 
 


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12.3. 
Appendix 3: Assessment Windows 
12.3.1. 
Definitions of Assessment Windows for Analyses 
Analysis Set / 
Domain 
Parameter 
(if applicable) 
Target  
Analysis Window 
Analysis 
Timepoint 
Beginning 
Timepoint 
Ending 
Timepoint 
Safety, Efficacy 
All 
Day -3 
Day -9 
Day -3 
Screening 
Safety, Efficacy 
All 
Day -2 
Day -2 
Day -2 
Day -2, 
Screening 
Safety, Efficacy 
All 
Day -1 
Day -1 
Day -1 
Day -1, 
Screening 
Safety, Efficacy 
All 
Day 1 
Day 1 
Day 1 
Day 1 
Safety, Efficacy 
All 
Day 2 
Day 2 
Day 2 
Day 2 
Safety, Efficacy 
All 
Day 3 
Day 3 
Day 3 
Day 3 
Safety, Efficacy 
All 
Day 4 
Day 4 
Day 4 
Day 4 
Safety 
All 
Day 5 
Day 5 
Day 5 
Day 5 
Safety, Efficacy 
All 
Day 6 
Day 6 
Day 6 
Day 6 
Safety 
All 
Day 7 
Day 7 
Day 7 
Day 7 
Safety, Efficacy 
All 
Day 8 
Day 8 
Day 8 
Day 8 
Safety 
All 
Day 9 
Day 9 
Day 9 
Day 9 
Safety, Efficacy 
All 
Day 10 
Day 10 
Day 10 
Day 10 
Safety 
All 
Day 11 
Day 11 
Day 11 
Day 11 
Safety, Efficacy, 
PK 
All 
Day 12 
Day 12 
Day 12 
Day 12 
Safety, PK 
All 
Day 13 
Day 13 
Day 13 
Day 13 
Safety, Efficacy, 
PK 
All 
Day 14 
Day 14 
Day 14 
Day 14 
Safety, PK 
All 
Day 15 
Day 15 
Day 15 
Day 15 
Safety 
All 
Day 28 
Day 21 
Day 35 
Day 28 
NOTES: 
• 
For data summarised by visit, the nominal visit description will be used. Unscheduled and withdrawal 
visit data will be slotted into a scheduled visit window, if no competing visit exists within the window. 
If there are multiple assessments within the same window which are not unscheduled visits, the earliest 
results will be used in the summaries.  
 
 
 


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12.4. 
Appendix 4: Study Phases and Treatment Emergent 
Adverse Events 
12.4.1. 
Study Phases 
Adverse events will be classified according to the time of occurrence relative to the start 
of study treatment. 
Study Phase 
Definition 
Pre-Treatment  Date and Time ≤ Study Treatment Start Date and Time 
On-Treatment 
Study Treatment Start Date and Time < Date and Time ≤ Study 
Treatment Stop Date and Time + 48 hours 
Post-
Treatment 
Date and Time > Study Treatment Stop Date and Time + 48 hours 
 
12.4.1.1. 
Study Phases for Concomitant Medication 
Study Phase 
Definition 
Prior 
If medication end date and time is not missing and is before start of 
study treatment 
Concomitant 
Any medication that is not a prior medication 
NOTES:  
• 
Please refer to Appendix 7: Reporting Standards for Missing Data for handling of missing and partial 
dates for concomitant medication. Use the rules in this table if concomitant medication date is 
completely missing. 
 
12.4.1.2. 
Phases of COVID-19 Pandemic Measures 
Pandemic measures began in different countries at different times. A dataset containing 
the date when pandemic measures began, as determined by the GSK country Issue 
Management Teams (IMT), and available within the HARP reporting environment 
(arcomn folder), will be used to determine the start date of pandemic measures within 
each country. A copy of this dataset will be taken at the time of database freeze (DBF). 
Adverse events will be summarised according to whether the onset date was before or 
after the start of the COVID-19 pandemic measures. 
Pandemic 
Measures Phase 
Definition 
Before 
AE onset date < pandemic measures start date 
After 
Pandemic measures start date ≤ AE onset date  
 
 


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12.4.2. 
Treatment Emergent Flag for Adverse Events 
Flag 
Definition 
Treatment 
Emergent 
• If AE onset date and time is after treatment start date and time and 
before treatment stop date and time + 48 hours, i.e.:  
Study Treatment Start Date and Time ≤ AE Start Date and Time ≤ 
Study Treatment Stop Date and Time + 48 hours. 
NOTES:  
• 
If the study treatment stop date is missing, then the AE will be considered to be Treatment-Emergent. 
 
 
 


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12.5. 
Appendix 5: Data Display Standards & Handling 
Conventions 
12.5.1. 
Reporting Process 
Software 
• The currently supported versions of SAS software will be used. 
Reporting Area 
HARP Server 
: UK1SALX00175 
HARP 
Compound 
: arenv/arprod/GSK3036656/mid201214 
Analysis Datasets  
• Analysis datasets will be created according to legacy GSK Analysis and Reporting 
dataset standards.  
Generation of RTF Files 
• RTF files will be generated for SAC. 
12.5.2. 
Reporting Standards 
General 
• The current GSK Integrated Data Standards Library (IDSL) will be applied for 
reporting, unless otherwise stated: 
• 4.03 to 4.23: General Principles 
• 5.01 to 5.08: Principles Related to Data Listings 
• 6.01 to 6.11: Principles Related to Summary Tables 
• 7.01 to 7.13: Principles Related to Graphics  
Formats 
• GSK IDSL Statistical Principles (5.03 & 6.06.3) for decimal places (DPs) will be 
adopted for reporting of data based on the raw data collected, unless otherwise stated. 
• Numeric data will be reported at the precision collected on the eCRF. 
• The reported precision from non eCRF sources will follow the IDSL statistical 
principles but may be adjusted to a clinically interpretable number of DPs.  
Planned and Actual Time 
• Reporting for tables, figures and formal statistical analyses: 
• Planned time relative to dosing will be used in figures, summaries, statistical 
analyses and calculation of any derived parameters, unless otherwise stated. 
• The impact of any major deviation from the planned assessment times and/or 
scheduled visit days on the analyses and interpretation of the results will be 
assessed as appropriate. 
• Reporting for Data Listings:  
• Planned and actual time relative to study drug dosing will be shown in listings 
(Refer to IDSL Statistical Principle 5.05.1). 
• Unscheduled or unplanned readings will be presented within the participant’s 
listings.  


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Unscheduled Visits 
• Unscheduled visits will not be included in summary tables or figures, unless the data 
has been slotted to a visit (Section 12.3).    
• All unscheduled visits will be included in listings. 
Descriptive Summary Statistics 
Continuous Data 
Refer to IDSL Statistical Principle 6.06.1 
Categorical Data 
N, n, frequency, % 
Graphical Displays 
• Refer to IDSL Statistical Principals 7.01 to 7.13. 
12.5.3. 
Reporting Standards for Pharmacokinetics 
Pharmacokinetic Concentration Data 
PC Windows 
Non-Linear 
(WNL) File 
PC WNL file (CSV format) for the non-compartmental analysis by 
Clinical Pharmacology Modelling and Simulation function will be 
created according to GUI_51487.  
Note: Concentration values will be imputed as per GUI_51487 
Descriptive 
Summary 
Statistics, 
Graphical 
Displays and 
Listings 
Refer to IDSL PK Display Standards. 
Refer to IDSL Statistical Principle 6.06.1. 
Note: Concentration values will be imputed as per GUI_51487for 
descriptive summary statistics/analysis and summarized graphical 
displays only.  
NONMEM/Pop 
PK File 
Pop-PK file (CSV format) for the POP-PK analysis by Clinical 
Pharmacology Modelling and Simulation function will be created 
according to the data specification detailed in the Data Analysis Plan 
(DAP) (GSK Document Number: 2018N381501_00). 
Pharmacokinetic Parameter Derivation 
PK Parameter to 
be Derived by 
Programmer 
All necessary PK parameters as defined in Section 9.1.5 (Cmax, 
tmax, AUC(0-t), AUC(0-24), Cτ) will be derived by the Clinical 
Pharmacology Modelling and Simulation function.  
Pharmacokinetic Parameter Data 
Is non-
quantifiable (NQ) 
impacted PK 
Parameters Rule 
Being Followed 
Yes, refer to Standards for Handling NQ Impacted PK Parameters. 
Descriptive 
Summary 
Statistics, 
Graphical 
Displays and 
Listings 
Refer to IDSL PK Display Standards. 


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12.6. 
Appendix 6: Derived and Transformed Data 
12.6.1. 
General 
Multiple Measurements at One Analysis Time Point 
• Mean of the measurements will be calculated and used in any derivation of summary 
statistics but if listed, all data will be presented. 
• If there are two values within a time window (as per Section 12.3.1) the earliest value 
in that window will be used. 
• Participants having both High and Low values for Normal Ranges at any post-
baseline visit for safety parameters will be counted in both the High and Low 
categories of “Any visit post-baseline” row of related summary tables. This will also 
be applicable to relevant Potential Clinical Importance summary tables. 
Study Day 
• Calculated as the number of days from First Dose Date: 
• Ref Date = Missing              → Study Day = Missing  
• Ref Date < First Dose Date → Study Day = Ref Date – First Dose Date 
• Ref Data ≥ First Dose Date → Study Day = Ref Date – (First Dose Date) + 1     
 
12.6.2. 
Study Population 
Extent of Exposure 
• Number of days of exposure to study drug will be calculated based on the formula:   
Duration of Exposure in Days = Treatment Stop Date – (Treatment Start Date) + 
1 
• Participants who were randomized but did not report a treatment start date will be 
categorised as having zero days of exposure.  
• If there are any treatment breaks during the study, exposure data will be adjusted 
accordingly. 
Demographics 
• Body mass index (BMI) will be calculated as: Weight (kg) at screening / [Height 
(m)]2 
 
12.6.3. 
Efficacy 
 Efficacy 
CFU 
• Baseline CFU will be calculated as: 
Mean (log10(CFU Day -1), log10(CFU Day -2))   
 
• Log(CFU) will be calculated as: 
Log(CFU/ml) =  
log10(mean(Total count 1:Total Count 2)*2*5*10^Dilution) 


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 Efficacy 
where: 
• Total count 1 and total count 2 are the bacterial counts from plates 1 and 2 
respectively. Where plate counts are reported at be Too Numerous To Count 
(TNTC), a value of 2500 will be imputed. If a count is only available for 1 plate, 
then that count will be used instead of the mean.  
• Dilution is the dilution factor for that plate.  
• In the calculation, the *2 represents the 1:1 dilution of the original specimen and 
the *5 represents the 0.2 ml (200 µl) inoculation of the specimen. 
• For bacteria counts with a comment of ”Half of plate X was contaminated so only 
half the plate was counted”, the count for that plate will be doubled for the 
analysis.  
TTP 
• The mean of the time to positivity for both plates (plate 1 and plate 2) at each 
timepoint will be calculated and used in any derivation of summary statistics and 
analyses. If a result is only available for 1 plate, then that value will be used instead 
of the mean. Where listed, all data will be presented. 
 
12.6.4. 
Safety 
Laboratory Parameters 
• If a laboratory value which is expected to have a numeric value for summary 
purposes, has a non-detectable level reported in the database, where the numeric 
value is missing, but typically a character value starting with ‘<x’ or ‘>x’ (or 
indicated as less than or greater than x in the comment field) is present, the number of 
decimal places in the observed values will be used to determine how much to add or 
subtract in order to impute the corresponding numeric value.  
• Example 1: 2 decimal places = ‘< x’ becomes x – 0.01 
• Example 2: 1 decimal place = ‘> x’ becomes x + 0.1 
• Example 3: 0 decimal places = ‘< x’ becomes x – 1 
• 
For values ‘<=x’ or ‘>=x’ the value itself (‘x’) should be imputed as the numeric 
value.  
• Mean arterial blood pressure (BP) will be calculated as: 
Mean arterial BP (mmHg) = 1/3 (systolic BP (mmHg)) + 2/3 (diastolic BP (mmHg)) 
 
12.6.5. 
Pharmacokinetic 
Pharmacokinetic Parameters 
Derived Pharmacokinetic Parameters 
• 
Pharmacokinetic parameters will be calculated by standard non-compartmental 
analysis according to current working practices and using the currently supported 
version of WinNonlin 5.2 or higher.  
• 
All calculations of non-compartmental parameters will be based on actual sampling 
times recorded during the study.  


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Pharmacokinetic Parameters 
• 
The following pharmacokinetic parameters will be determined and summarised, as 
data permit.: 
 
Parameter 
Parameter Description 
AUC(0-t) 
Area under the concentration-time curve from time of dosing to last 
quantified concentration, regardless of time. 
AUC(0-24) 
Area under the concentration-time curve from time of dosing 
extrapolated to 24 hours 
Cmax 
Maximum observed plasma drug concentration, determined directly 
from the concentration-time data. 
tmax 
Time to reach Cmax, determined directly from the plasma drug 
concentration-time data 
Cτ 
Trough concentration 
   
• 
Additional parameters may be calculated.  
• 
All calculated parameters will be listed.  
• 
For graphical displays, IDSL Statistical Principles 7.01 to 7.13 and the standards for 
the transfer and reporting of PK data using HARP will be followed.  
 


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12.7. 
Appendix 7: Reporting Standards for Missing Data 
12.7.1. 
Premature Withdrawals 
Element 
Reporting Detail 
General 
• Participant study completion is defined as a participant who has 
completed all phases of the study including the last visit (the follow-up 
visit).  
• Withdrawn participants may be replaced in the study. 
• All available data from participants who were withdrawn from the study 
will be listed and all available planned data will be included in summary 
tables and figures, unless otherwise specified.  
• Withdrawal visits will be slotted as per Appendix 3: Assessment 
Windows or will be summarised as withdrawal visits. 
12.7.2. 
Handling of Missing Data 
Element 
Reporting Detail 
General 
• Missing data occurs when any requested data is not provided, leading to 
blank fields on the collection instrument: 
o These data will be indicated by the use of a “blank” in participant 
listing displays. Unless all data for a specific visit are missing in 
which case the data are excluded from the listing.  
o Answers such as “Not applicable” and “Not evaluable” are not 
considered to be missing data and should be displayed as such. 
Outliers 
• Any participants excluded from the summaries and/or statistical 
analyses will be documented along with the reason for exclusion in the 
clinical study report. 
12.7.2.1. 
Handling of Missing and Partial Dates 
Element 
Reporting Detail 
General 
• Partial dates will be displayed as captured in participant listing 
displays. 
Adverse 
Events 
• The eCRF allows for the possibility of partial dates (i.e., only month 
and year) to be recorded for AE start and end dates; that is, the day of 
the month may be missing. In such a case, the following conventions 
will be applied for calculating the time to onset and the duration of 
the event: 
o Missing Start Day: First of the month will be used unless this is 
before the start date of study treatment; in this case the study 
treatment start date will be used and hence the event is considered 
On-treatment as per Appendix 4: Study Phases and Treatment 
Emergent Adverse Events. 
o Missing Stop Day: Last day of the month will be used, unless this 
is after the stop date of study treatment; in this case the study 


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Element 
Reporting Detail 
treatment stop date will be used. 
• Completely missing start or end dates will remain missing, with no 
imputation applied. Consequently, time to onset and duration of such 
events will be missing. 
• AEs with entirely missing or unknown start dates will be assumed to 
be on-treatment for reporting.  
• AEs with missing end dates are not anticipated to affect reporting.  
• AEs with missing start or end times which started on the same day as 
study treatment or ended on the same day as study treatment plus 2 
days will be assumed to be on-treatment for reporting and classed as 
treatment emergent for adverse events.  
Concomitant 
Medications/
Medical 
History 
• Partial dates for any concomitant medications recorded in the eCRF 
will be imputed using the following convention: 
o If the partial date is a start date, a ‘01’ will be used for the day 
and ‘Jan’ will be used for the month 
o If the partial date is a stop date, a ‘28/29/30/31’ will be used for 
the day (dependent on the month and year) and ‘Dec’ will be used 
for the month. 
 
 


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12.8. 
Appendix 8: Values of Potential Clinical Importance 
12.8.1. 
Laboratory Values 
Haematology 
Laboratory Parameter 
 
Units 
Category 
Clinical Concern Range 
Low Flag (< x) 
High Flag (>x) 
Hematocrit  
Ratio of 
1 
Male 
 
0.54 
Female 
 
0.54 
Change 
from 
Baseline 
Decrease of 
0.075 
 
Haemoglobin  
g/L 
 
Male 
75 
180 
Female 
75 
180 
Change 
from 
Baseline 
Decrease of 25 
 
Lymphocytes  
x109/ L 
 
0.8 
 
Neutrophil Count  
x109/ L 
 
0.5 
 
Platelet Count  
x109/ L 
 
100 
550 
While Blood Cell Count 
(WBC) 
x109/ L 
 
3 
20 
 
Clinical Chemistry 
Laboratory Parameter 
Units 
Category 
Clinical Concern Range 
Low Flag (< x) 
High Flag (>x) 
Albumin  
g/L 
 
20 
 
Calcium 
mmol/L 
 
2 
2.75 
Creatinine 
% 
Change 
from 
Baseline 
 
Increase of 30% 
Glucose 
mmol/L 
 
3 
11 
Potassium 
mmol/L 
 
3 
5.5 
Sodium 
mmol/L 
 
130 
150 
 
Liver Function 
Test Analyte 
Units 
Category 
Clinical Concern Range 
ALT / SGPT  
IU/L 
High 
≥ 3x ULN 
AST / SGOT  
IU/L 
High 
≥ 3x ULN 
AlkPhos  
IU/L 
High 
≥ 2x ULN 
T Bilirubin  
µmol/L 
High 
≥ 1.5x ULN 
T. Bilirubin + ALT 
µmol/L 
High 
 
 
1.5x ULN T. Bilirubin 


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Liver Function 
Test Analyte 
Units 
Category 
Clinical Concern Range 
+ 
U/L 
≥ 2x ULN ALT 
ULN = Upper Limit of Normal; ALT=Alanine Aminotransferase; AST=Aspartate Aminotransferase; 
SGPT=Serum Glutamic Pyruvic Transaminase; SGOT=Serum Glutamic Oxaloacetic Transaminase; T. 
Bilirubin=Total Bilirubin 
12.8.2. 
ECG 
ECG Parameter 
Units 
Clinical Concern Range 
Lower 
Upper 
Absolute 
Absolute QTcF Interval 
msec 
 
>450 
Absolute PR Interval 
msec 
< 110 
>220 
Absolute QRS Interval 
msec 
< 75 
>110 
Change from Baseline 
Increase from Baseline 
QTcF 
msec 
 
>60 
QTcF=QT Interval corrected for heart rate (Fridericia); PR=Electrocardiographic PR Interval 
12.8.3. 
Vital Signs 
Vital Sign Parameter 
(Absolute) 
Units 
Clinical Concern Range 
Lower 
Upper 
Systolic Blood Pressure 
mmHg 
< 85 
>160 
Diastolic Blood Pressure 
mmHg 
< 45 
>100 
Heart Rate 
bpm 
< 40 
>110 
Respiratory Rate 
Breaths/min 
10 
28 
Temperature 
Degrees C 
35.0 
37.9 
 
 
 
 


C O N FI D E N TI A L  
 
 
2 0 1 2 1 4  
4 9  
 
1 2. 9.  
A p p e n di x 9 : A b br e vi ati o n s & Tr a d e M ar k s  
1 2. 9. 1.  
A b br e vi ati o n s  
A b bre vi ati o n  
Descri pti o n  
% C V b  
Bet wee n partici pa nt  ge o metric c oefficie nt of v ari ati o n  
A E  
A d verse E v e nt  
AI C  
A kai ke’s I nf or mati o n Criteria  
A L T  
Ala ni ne A mi n otra nsferas e  
A S T  
As partate A mi n otra nsferase  
A U C ( 0-t) 
Area u n d er t he c o nce ntr ati o n -ti me c ur ve fr o m ti me of d osi n g t o last 
q ua ntifie d c o nce ntrati o n, re gar dl ess of ti me.  
A U C( 0 -2 4)  
Area u n d er t he c o nce ntr ati o n -ti me c ur ve fr o m ti me of d osi n g 
e xtra p olate d t o 2 4 h o urs  
B MI  
B o d y Mass I n d e x  
B P  
Bl o o d Press ure  
Cτ  
Tr o u g h C o n ce ntrati o n  
C F U  
C ol o n y F or mi n g U nits  
C ma x  
Ma xi m u m o bser ve d plas ma dr u g c o nce ntrati o n  
C S  
C o m p o u n d S y m metr y  
C S R  
Cli nical St u d y Re p ort  
C P M S  
Cli nical P har mac ol o g y M o delli n g & Si m ulati o n  
C P S S O  
Cli nical P har mac ol o g y S cie nce a n d St u d y O perati o ns  
D A P  
Data A nal ysis Pla n  
D B F  
Data base Freeze  
D B R  
Data base R elease  
D S  
Dr u g se nsiti ve (i.e. Rifa m pici n -S usce pti ble)  
E B A  
Earl y Bacterici dal Acti vit y  
E C G  
Electr ocar di o gra m  
e C R F 
Electr o nic Case Re p ort  F or m  
E u dra C T  
E ur o pea n Cli nical Trials Data base  
F D A  
F o o d a n d Dr u g A d mi nistrati o n  
F D A A A  
F o o d a n d Dr u g A d mi nistrati o n A me n d me nts Act  
F D G  
Fl u or o de o x y gl uc os e  
F P D  
F ut ure Pi peli nes Disc o ver y  
G C S P  
Gl o bal Cli nical Safet y a n d P har mac o vi gila nce  
G S K  
Gla x o S mit h Kli ne  
H P D  
Hi g hest P osteri or De nsit y  
I C H 
I nter nati o nal C o nfere nce o n Har m o nizati o n 
I D S L 
I nte grate d Data Sta n dar ds Li brar y 
Me d D R A  
Me dical Dicti o nar y f or R e g ul at or y Acti vities  
Mt b  
M yc o bacteri u m t u berc ul osis  
P CI  
P ote ntial Cli nical I m p orta nce  
P D M P  
Pr ot oc ol De viati o n Ma na ge m e nt Pla n  
P K  
P har mac o ki netic  
C CI


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Abbreviation 
Description 
QD 
Once Daily 
QTc 
QT Interval Corrected for Heart Rate 
QTcF 
Frederica’s QT Interval Corrected for Heart Rate 
RAP 
Reporting and Analysis Plan 
SAC 
Statistical Analysis Complete 
SAE 
Serious Adverse Event 
SERM 
Safety Evaluation and Risk Management 
SGPT 
Serum Glutamic Pyruvic Transaminase 
SGOT 
Serum Glutamic Oxaloacetic Transaminase 
SoC 
Standard-of-Care 
SOP 
Standard Operating Procedure 
SRT 
Safety Review Team 
TB 
Tuberculosis 
tmax 
Time to maximum observed plasma drug concentration 
TNTC 
Too Numerous To Count 
TTP 
Time to Sputum Culture Positivity 
ULN 
Upper Limit of Normal 
UN 
Unstructured 
VC 
Variance Components 
WBC 
White Blood Cell Count 
12.9.2. 
Trademarks 
Trademarks of the GlaxoSmithKline 
Group of Companies 
 
Trademarks not owned by the 
GlaxoSmithKline Group of 
Companies 
NONE 
 
SAS 
 
 
WinNonlin 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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12.10. 
Appendix 10: List of Data Displays 
12.10.1. 
Data Display Numbering 
The following numbering will be applied for RAP generated displays: 
Section 
Tables 
Figures 
Study Population 
1.1 to 1.18 
None 
Efficacy 
2.1 to 2.10 
2.1 to 2.5 
Safety 
3.1 to 3.23 
3.1 to 3.5 
Pharmacokinetic 
4.1 to 4.5 
4.1 to 4.7 
Section 
Listings 
ICH Listings 
1 to 31 
Other Listings 
32 to 39 
 
12.10.2. 
Mock Example Shell Referencing 
Non-integrated data standards library (IDSL) specifications will be referenced as 
indicated and if required example mock-up displays provided in Appendix 11: Example 
Mock Shells for Data Displays. 
Section 
Figure 
Table 
Listing 
Study Population 
POP_Fn 
POP_Tn 
POP_Ln 
Efficacy 
EFF_Fn 
EFF_Tn 
EFF_Ln 
Safety 
SAFE_Fn 
SAFE_Tn 
SAFE_Ln 
Pharmacokinetic 
PK_Fn 
PK_Tn 
PK_Ln 
NOTES:  
• 
Non-Standard displays are indicated in the ‘IDSL / Example Shell’ column as ‘[Non-Standard] + Reference.’ 
 
12.10.3. 
Deliverables 
Delivery 
Description 
DE 
Dose Escalation Efficacy Analysis 
SAC 
Final Statistical Analysis Complete 
 
 
Note, all displays (Tables, Figures and Listings) will use the term ‘subjects’, in place of 
participants. 


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12.10.4. 
Study Population Tables 
Study Population Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
Subject Disposition 
1.1. 
Safety 
ES1 
Summary of Subject Disposition for the Subject Conclusion 
Record 
ICH E3, FDAAA, EudraCT 
Add footnote: “5mg=15mg loading dose 
and 5mg maintenance dose, Xmg=…” 
DE, SAC 
1.2. 
Safety 
ES1 
Summary of Subject Status and Subject Disposition for the 
Study Conclusion Record by Relationship to COVID-19 
Pandemic 
Page by COVID-19 relationship 
Yes/No.  
SAC 
1.3. 
Safety 
SD1 
Summary of Treatment Status and Reasons for Discontinuation 
of Study Treatment 
ICH E3 
SAC 
1.4. 
Safety 
SD1 
Summary of Treatment Status and Reasons for Discontinuation 
of Study Treatment by Relationship to COVID-19 Pandemic 
 
SAC 
1.5. 
Safety 
ES4 
Summary of Subject Disposition at Each Study Epoch 
ICH E3 
Display by cohort (i.e. epoch=cohort).  
SAC 
1.6. 
Screened 
ES6 
Summary of Screening Status and Reasons for Screen Failure 
Journal Requirements 
SAC 
1.7. 
Enrolled 
NS1 
Summary of Number of Participants by Country and Site ID 
EudraCT/Clinical Operations 
SAC 
Protocol Deviation 
1.8. 
Safety 
DV1 
Summary of Important Protocol Deviations 
ICH E3 
SAC 
1.9. 
Safety 
DV1 
Summary of Important COVID-19 Related Protocol Deviations 
 
SAC 
1.10. 
Safety 
DV1 
Summary of Important Non COVID-19 Related Protocol 
Deviations 
 
SAC 
Population Analysed 


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Study Population Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
1.11. 
Screened 
SP1 
Summary of Study Populations  
IDSL 
Include all columns in the IDSL 
template.  
DE, SAC 
1.12. 
Safety 
SP2A 
Summary of Exclusions from the Efficacy Population 
IDSL 
DE, SAC 
1.13. 
Safety 
SP2A 
Summary of Exclusions from the PK Population 
IDSL 
SAC 
Demographic and Baseline Characteristics 
1.14. 
Safety 
DM1 
Summary of Demographic Characteristics 
ICH E3, FDAAA, EudraCT 
Include BMI and smoking status.  
SAC 
1.15. 
Enrolled 
DM11 
Summary of Age Ranges 
EudraCT 
SAC 
1.16. 
Safety 
DM5 
Summary of Race and Racial Combinations 
ICH E3, FDA, FDAAA, EudraCT 
SAC 
Prior and Concomitant Medications 
1.17. 
Safety 
MH1 
Summary of Past Medical Conditions 
ICH E3  
SAC 
1.18. 
Safety 
MH1 
 
Summary of Current Medical Conditions 
ICH E3 
SAC 
 
 


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12.10.5. 
Efficacy Tables 
Efficacy: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
CFU 
2.1.  
Efficacy 
Non-standard 
EFF_T1 
Summary Table of log10CFU Counts Over Time 
 
DE, SAC 
2.2.  
Efficacy 
Non-standard 
EFF_T1 
Summary Table of Change from Baseline in log10CFU Counts 
Over Time 
Include baseline row similar to LB1 
template.  
DE, SAC 
2.3.  
Efficacy 
Non-standard 
EFF_T2 
Rate of Change in log10CFU by Treatment – Mixed Model 
Analysis 
For dose escalation analysis, calculate 
EBA CFU(0-14) only. 
Supportive SAS output to be produced 
and archived 
DE, SAC 
2.4.  
Efficacy 
Non-standard 
EFF_T3 
Node and Slope Parameter Estimates for log10CFU by 
Treatment – Bi-linear Bayesian Model Analysis 
For dose escalation analysis, calculate 
EBA CFU(0-14) only.  
Supportive SAS output to be produced 
and archived 
DE, SAC 
2.5.  
Efficacy 
Non-standard 
EFF_T2 
Rate of Change in log10CFU by Treatment – Mixed Model 
Analysis – Withdrawn/Replaced Participants Excluded 
For endpoints CFU(0-14) and CFU(2-
14) only.  
Supportive SAS output to be produced 
and archived 
SAC 
2.6.  
Efficacy 
Non-standard 
EFF_T4 
Summary of Covariate and Treatment*Covariate Interaction 
Significance For  log10CFU(0-14) Mixed Model Analysis 
.  
Supportive SAS output to be produced 
and archived 
SAC 
TTP 
2.7.  
Efficacy 
Non-standard 
EFF_T1 
Summary Table of TTP Counts Over Time 
 
SAC 


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2.8.  
Efficacy 
Non-standard 
EFF_T1 
Summary Table of Change from Baseline in TTP Counts Over 
Time 
Include baseline row similar to LB1 
template. 
SAC 
2.9.  
Efficacy 
Non-standard 
EFF_T2 
Rate of Change in TTP –Mixed Model Analysis 
Supportive SAS output to be produced 
and archived 
SAC 
2.10. 
Efficacy 
Non-standard 
EFF_T3 
Node and Slope Parameter Estimates for TTP by Treatment –Bi-
linear Bayesian Model Analysis 
For endpoint TTP(0-14) only. 
Supportive SAS output to be produced 
and archived 
 


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12.10.6. 
Efficacy Figures 
Efficacy: Figures 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
Efficacy 
2.1.
Efficacy 
Non-standard 
EFF_F1 
Line Graph of log10CFU Over Time by Treatment 
Include separate lines for each 
dose/treatment group. 
DE, SAC 
2.2.
Efficacy 
Non-standard 
EFF_F1 
Line Graph of Change from Baseline in log10CFU Over Time by 
Treatment 
Include separate lines for each 
dose/treatment group. 
DE, SAC 
2.3.
Efficacy 
Non-standard 
EFF_F2 
Individual Subject Profile Plots of log10(CFU) Count Over Time 
by Treatment 
Include CFU(0-14) regression line and 
95% CI.  
Separate figure for each treatment 
group.  
SAC 
2.4.
Efficacy 
Non-standard 
EFF_F3 
Line Graph of Dose vs log10CFU (0-14) Slope 
Include regression line and 95% CI 
DE, SAC 
2.5.  
Efficacy 
Non-standard 
EFF_F1 
Line Graph of TTP Over Time by Treatment 
Include separate lines for each 
dose/treatment group. 
SAC 
 
 


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12.10.7. 
Safety Tables 
Safety: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
Adverse Events (AEs) 
3.1.  
Safety 
AE5B 
Summary of All Adverse Events by System Organ Class, 
Preferred Term and Maximum Grade 
ICH E3 
SAC 
3.2.  
Safety 
AE5B 
Summary of All Drug-Related Adverse Events by System Organ 
Class, Preferred Term and Maximum Grade 
ICH E3 
SAC 
3.3.  
Safety 
AE15 
Summary of Common (>=5%) Non-serious Adverse Events by 
System Organ Class and Preferred Term (Number of Subjects 
and Occurrences) 
FDAAA, EudraCT 
SAC 
Serious and Other Significant Adverse Events 
3.4.  
Safety 
AE16 
Summary of Serious Adverse Events by System Organ Class 
and Preferred Term (Number of Subjects and Occurrences) 
FDAAA, EudraCT 
 
SAC 
3.5.  
Safety 
AE5B 
Summary of Adverse Events Leading to Permanent 
Discontinuation of Study Treatment by System Organ Class, 
Preferred Term and Maximum Grade 
IDSL 
SAC 
3.6.  
Safety 
AE5B 
Summary of Adverse Events Leading to Withdrawal from Study 
by System Organ Class, Preferred Term and Maximum Grade 
IDSL 
SAC 
3.7.  
Safety 
AE20 
Summary of Serious Fatal and Non-Fatal Drug-Related Adverse 
Events by Overall Frequency 
Plain Language Summary requirements 
(PLS). 
SAC 
3.8.  
Safety 
PAN10 
Summary of Exposure Adjusted Incidence Rates of Adverse 
Events Over Time Relative to COVID-19 Pandemic Measures 
 
SAC 
3.9.  
Safety 
PAN10 
Summary of Exposure Adjusted Incidence Rates of Adverse 
Events Over Time By Age Relative to COVID-19 Pandemic 
Measures 
 
SAC 


CONFIDENTIAL 
 
 
201214 
 
58 
 
Safety: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
Laboratory: Chemistry  
3.10. 
Safety 
LB1 
Summary of Chemistry Changes from Baseline  
ICH E3 
SAC 
3.11. 
Safety 
LB17 
Summary of Worst Case Chemistry Results by PCI Criteria 
Post-Baseline Relative to Baseline 
ICH E3 
SAC 
Laboratory: Haematology 
3.12. 
 Safety 
LB1 
Summary of Haematology Changes from Baseline 
ICH E3 
SAC 
3.13. 
Safety 
LB17 
Summary of Worst Case Haematology by PCI Criteria Post-
Baseline Relative to Baseline 
ICH E3 
SAC 
Laboratory: Urinalysis 
3.14. 
Safety 
UR1 
Summary of Worst Case Urinalysis Results Post-Baseline 
Relative to Baseline 
ICH E3 
SAC 
Laboratory: Hepatobiliary (Liver) 
3.15. 
 Safety 
LIVER1 
Summary of Liver Monitoring/Stopping Event Reporting 
IDSL 
SAC 
3.16. 
 Safety 
LIVER10 
Summary of Hepatobiliary Laboratory Abnormalities 
IDSL 
SAC 
ECG 
3.17. 
 Safety 
EG1 
Summary of ECG Findings  
IDSL 
SAC 
3.18. 
Safety 
EG10 
Summary of Maximum QTc Values Post-Baseline Relative to 
Baseline by Category 
IDSL 
SAC 
3.19. 
Safety 
EG2 
Summary of Change from Baseline in ECG Values by Visit 
IDSL 
SAC 
3.20. 
Safety 
EG11 
Summary of Maximum Increase in QTc Values Post-Baseline 
Relative to Baseline by Category 
IDSL 
SAC 
Vital Signs 
3.21. 
Safety 
VS1 
Summary of Change from Baseline in Vital Signs 
ICH E3 
SAC 


CONFIDENTIAL 
 
 
201214 
 
59 
 
Safety: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
3.22. 
Safety 
VS7 
Summary of Worst Case Vital Signs Results by PCI Criteria 
Post-Baseline Relative to Baseline 
 
IDSL 
SAC 
COVID-19 Assessments 
3.23. 
Safety 
PAN1 
Summary of COVID-19 Assessments for Subjects with COVID-
19 Adverse Events 
 
SAC 


CONFIDENTIAL 
 
 
201214 
 
60 
 
12.10.8. 
Safety Figures 
Safety: Figures 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
Laboratory 
3.1.  
Safety 
LIVER9 
Scatterplot of ALT vs Total Bilirubin by Treatment 
Separate plots for each treatment 
group. 
Include all timepoints.  
SAC 
3.2.  
Safety 
LIVER9 
Scatter Plot of Maximum ALT vs. Maximum Total Bilirubin by 
Treatment 
IDSL 
Separate plots for each treatment 
group.  
 
SAC 
3.3.  
Safety 
LB11 
ALT Profile Plots by Treatment 
Separate plots for each treatment 
group, with individual lines for each 
subject 
SAC 
3.4.  
Safety 
LB11 
Haematology Profile Plots by Treatment 
Separate plots for each treatment 
group, with individual lines for each 
subject.  
SAC 
Vital Signs 
3.5.  
Safety 
LB11 
Vital Signs Profile Plots by Treatment 
Separate plots for each treatment group 
and vital signs parameter (DBP, SBP, 
mean BP, heart rate).  
Display individual lines for each subject, 
within a treatment, for each plot.  
SAC 
 


CONFIDENTIAL 
 
 
201214 
 
61 
 
12.10.9. 
Pharmacokinetic Tables 
Pharmacokinetic: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
Pharmacokinetic Concentration Data 
4.1.  
PK 
PK01 
Summary of Plasma GSK3036656 Pharmacokinetic 
Concentration-Time Data 
 
SAC 
Derived Pharmacokinetic Parameters 
4.2.  
PK 
PK03 
Summary of Derived Plasma GSK3036656 Pharmacokinetic 
Parameters (Untransformed Data) 
AUC(0-t), AUC(0-24), Cmax, tmax, Cτ 
SAC 
4.3.  
PK 
PK05 
Summary of Derived Plasma GSK3036656 Pharmacokinetic 
Parameters (Log-transformed Data) 
AUC(0-t), AUC(0-24), Cmax, tmax, Cτ 
SAC 
4.4.  
PK 
Non-standard 
PK_T1 
Statistical Analysis of Log Transformed Plasma GSK3036656 
Pharmacokinetic Parameters Assessing Dose Proportionality 
(Power Model) 
AUC(0-t) or AUC(0-24), Cmax 
Supportive SAS output to be produced 
and archived.  
SAC 
4.5.  
PK 
Non-standard 
PK_T2 
Statistical Analysis of Log Transformed Plasma GSK3036656 
Trough Concentration Assessing Steady-State 
Cτ 
Supportive SAS output to be produced 
and archived. 
SAC 
 


CONFIDENTIAL 
 
 
201214 
 
62 
 
12.10.10. Pharmacokinetic Figures 
Pharmacokinetic: Figures 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
Pharmacokinetic Concentration Data 
4.1.  
PK 
PK16a 
Individual Plasma GSK3036656 Concentration-Time Plot (Linear 
and Semi-Log) by Subject 
 
SAC 
4.2.  
PK 
PK24 
Individual Plasma GSK3036656 Concentration-Time Plot (Linear 
and Semi-Log) by Treatment 
Include Day 14 and 15 data only. 
SAC 
4.3.  
PK 
PK17 
Mean Plasma GSK3036656 Concentration-Time Plots (Linear 
and Semi-Log) 
Include Day 14 and 15 data only.  
SAC 
4.4.  
PK 
PK18 
Median Plasma GSK3036656 Concentration-Time Plots (Linear 
and Semi-Log) 
Include Day 14 and 15 data only.  
SAC 
Derived Pharmacokinetic Parameters 
4.5.  
PK 
PK25 
Comparative Plot of Individual Subject Plasma GSK3036656 
Pharmacokinetic Parameter By Treatment 
Cτ 
SAC 
4.6.  
PK 
Non-standard 
PK_F1 
Scatterplot of log(dose) vs log(AUC) 
Add footnote: Doses displayed on the 
log scale are Xmg, Xmg, Xmg and 
Xmg.  
SAC 
4.7.  
PK 
Non-standard 
PK_F1 
Scatterplot of log(dose) vs log(Cmax) 
Add footnote: Doses displayed on the 
log scale are Xmg, Xmg, Xmg and 
Xmg. 
SAC 
 
 


CONFIDENTIAL 
 
 
201214 
 
63 
 
12.10.11. ICH Listings 
ICH: Listings 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
Subject Disposition 
1.  
Screened 
ES7 
Listing of Reasons for Screen Failure 
Journal Guidelines 
SAC 
2.  
Safety 
ES2 
Listing of Reasons for Study Withdrawal 
ICH E3 
SAC 
3.  
Safety 
SD2 
Listing of Reasons for Study Treatment Discontinuation 
ICH E3 
SAC 
4.  
Randomised 
TA1 
Listing of Planned and Actual Treatments 
IDSL 
SAC 
Protocol Deviations 
5.  
Safety 
DV2 
Listing of Important Protocol Deviations  
ICH E3 
SAC 
6.  
Safety 
IE3 
Listing of Subjects with Inclusion/Exclusion Criteria Deviations 
ICH E3 
SAC 
Populations Analysed 
7.  
Safety 
SP3 
Listing of Subjects Excluded from Any Population 
ICH E3 
SAC 
Demographic and Baseline Characteristics 
8.  
Safety 
DM2 
Listing of Demographic Characteristics 
ICH E3 
Include BMI and smoking status.  
SAC 
9.  
Safety 
DM9 
Listing of Race 
ICH E3 
SAC 
Prior and Concomitant Medications 
10.  
Safety 
CP_CM3 
Listing of Concomitant Medications 
IDSL 
SAC 
Exposure and Treatment Compliance 
11.  
Safety 
EX3 
Listing of Exposure Data 
ICH E3 
SAC 
Adverse Events 
12.  
Safety 
AE8CP 
Listing of All Adverse Events 
ICH E3 
SAC 


CONFIDENTIAL 
 
 
201214 
 
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ICH: Listings 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
13.  
Safety 
AE7 
Listing of Subject Numbers for Individual Adverse Events 
ICH E3 
SAC 
14.  
Safety 
AE2 
Listing of Relationship Between Adverse Event System Organ 
Classes, Preferred Terms, and Verbatim Text 
IDSL 
SAC 
Serious and Other Significant Adverse Events 
15.  
Safety 
AE8CP 
 
Listing of Serious Adverse Events 
ICH E3 
SAC 
16.  
Safety 
AE14 
Listing of Reasons for Considering as a Serious Adverse Event 
ICH E3 
SAC 
17.  
Safety 
AECP8 
Listing of Adverse Events Leading to Withdrawal from Study / 
Permanent Discontinuation of Study Treatment 
ICH E3 
SAC 
Hepatobiliary (Liver) 
18.  
Safety 
MH2 
Listing of Medical Conditions for Subjects with Liver Stopping 
Events 
IDSL 
SAC 
19.  
Safety 
SU2 
Listing of Substance Use for Subjects with Liver Stopping 
Events 
IDSL 
SAC 
All Laboratory 
20.  
Safety  
LB5 
Listing of All Clinical Chemistry Data for Subjects with Any Value 
of Potential Clinical Importance 
ICH E3 
Display ALL chemistry data for a 
subject who experienced a value of 
potential clinical importance. 
SAC 
21.  
Safety 
LB5 
Listing of Clinical Chemistry Values of Potential Clinical 
Importance 
 
SAC 
22.  
Safety  
LB5 
Listing of All Hematology Data for Subjects with Any Value of 
Potential Clinical Importance 
Display ALL hematology data for a 
subject who experienced a value of 
potential clinical importance. 
SAC 
23.  
Safety 
LB5 
Listing of Hematology Values of Potential Clinical Importance 
 
SAC 


CONFIDENTIAL 
 
 
201214 
 
65 
 
ICH: Listings 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
24.  
Safety 
LB14 
Listing of Laboratory Data with Character Results 
ICH E3 
SAC 
25.  
Safety 
UR2A 
Listing of All Urinalysis Data for Subjects with Any Value of 
Potential Clinical Importance 
ICH E3 
Display ALL urinalysis data for a 
subject who experienced a value of 
potential clinical importance 
SAC 
ECG 
26.  
Safety 
EG3 
Listing of All ECG Values for Subjects with Any Value of 
Potential Clinical Importance 
IDSL 
Display ALL ECG data for a subject 
who experienced a value of potential 
clinical importance. 
SAC 
27.  
Safety 
EG3 
Listing of ECG Values of Potential Clinical Importance 
IDSL 
SAC 
28.  
Safety 
EG5 
Listing of All ECG Findings for Subjects with an Abnormal ECG 
Finding 
IDSL 
SAC 
29.  
Safety 
EG5 
Listing of Abnormal ECG Findings 
IDSL 
SAC 
Vital Signs 
30.  
Safety 
VS4 
Listing of All Vital Signs Data for Subjects with Any Value of 
Potential Clinical Importance 
IDSL 
Display ALL vital signs data for a 
subject who experienced a value of 
potential clinical importance. 
SAC 
31.  
Safety 
VS4 
Listing of Vital Signs of Potential Clinical Importance 
IDSL 
SAC 
 
 
 


CONFIDENTIAL 
 
 
201214 
 
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12.10.12. Non-ICH Listings 
Non-ICH: Listings 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
Protocol Deviation 
32.  
Safety 
DV2 
Listing of All Non-Important COVID-19 Related Protocol 
Deviations 
 
SAC 
Adverse Events 
33.  
Safety 
PAN12 
Listing of COVID-19 Assessments and Symptom Assessments 
for Subjects with COVID-19 Adverse Events 
 
SAC 
Pharmacokinetic 
34.  
PK 
PK07 
Listing of Plasma Pharmacokinetic Concentration-Time Data 
 
SAC 
35.  
PK 
PK13 
Listing of Derived Plasma Pharmacokinetic Parameters 
 
SAC 
Efficacy 
36.  
Efficacy 
Non-standard 
EFF_L1 
Listing of Sputum Counts 
Include CFU, log10CFU and TTP 
SAC 
37.  
Safety 
Non-standard 
EFF_L2 
Listing of Mycobacterial Data 
 
SAC 
38.  
Safety 
Non-standard 
EFF_L3 
Listing of Drug Susceptibility Data at Screening 
 
SAC 
All Laboratory 
39.  
Safety 
Non-standard 
SAFE_L1 
Listing of Troponin Data 
 
SAC 
 


CONFIDENTIAL 
 
 
201214 
 
67 
 
12.11. 
Appendix 11: Example Mock Shells for Data Displays 
Example  
: EFF_T1 
Population : Efficacy  
 
Table EFF_T1 
Summary Table of log10CFU Counts Over Time 
 
 
Treatment      
 
N    
Planned  
Time 
 
n   
 
Mean 
 
     SD   
 
Median 
 
Min. 
 
Max. 
 
 
 
 
 
 
 
 
 
<Rifafour> 
xx   
Baseline 
xx 
 x.xx 
x.xxx 
 x.xx 
 x.x 
 x.x 
 
 
Day 1     
xx    
x.xx 
x.xxx 
x.xx 
x.x 
x.x 
  
  
Day 2     
xx    
x.xx 
x.xxx 
x.xx 
x.x 
x.x 
 
 
…     
… 
… 
… 
… 
… 
… 
 
 
Day 14 
xx 
x.xx 
x.xxx 
x.xx 
x.x 
x.x 
 
 
 
 
 
 
 
 
 
<656 Dose 1> 
xx  
Baseline 
xx 
 x.xx 
x.xxx 
 x.xx 
 x.x 
 x.x 
 
    
Day 1     
xx    
x.xx 
x.xxx 
x.xx 
x.x 
x.x 
 
   
Day 2     
xx    
x.xx 
x.xxx 
x.xx 
x.x 
x.x 
 
 
…     
… 
… 
… 
… 
… 
… 
 
 
Day 14 
xx 
x.xx 
x.xxx 
x.xx 
x.x 
x.x 
 
 
 
 
 
 
 
 
 
... 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
<656 Dose 5> 
xx   
Baseline 
xx 
 x.xx 
x.xxx 
 x.xx 
 x.x 
 x.x 
 
     
Day 1     
xx    
x.xx 
x.xxx 
x.xx 
x.x 
x.x 
 
   
Day 2     
xx    
x.xx 
x.xxx 
x.xx 
x.x 
x.x 
 
 
…     
… 
… 
… 
… 
… 
… 
 
 
Day 14 
xx 
x.xx 
x.xxx 
x.xx 
x.x 
x.x 
 
 
 
 
 
 
 
 
 
 
Baseline (Day 0) is defined as the mean of Day -2 and Day -1; if data was available at only one of 
these timepoints then that value was used as baseline. Where plate counts were Too Numerous To Count 
(TNTC), a value of 2500 was imputed for the analysis.  


CONFIDENTIAL 
 
 
201214 
 
68 
 
Example  
: EFF_T2 
Population : Efficacy  
 
Table EFF_T2 
Rate of Change in log10CFU by Treatment – Mixed Model Analysis 
 
 
Endpoint (units) 
 
Treatment     
 
N    
 
n   
 
Mean 
 
SE 
95% Confidence 
Interval 
 
 
 
 
  
 
EBA CFU0-14 (log10CFU/mL) <Rifafour> 
xx 
xx   
x.xx 
x.xx 
(x.xxx, x.xxx) 
 
<656 Dose 1>  xx   xx 
 x.xx 
 x.xx 
(x.xxx, x.xxx) 
 
<656 Dose 2> xx 
xx   
x.xx 
x.xx 
(x.xxx, x.xxx) 
 
<656 Dose 3> xx 
xx   
x.xx 
x.xx 
(x.xxx, x.xxx) 
 
<656 Dose 4> xx 
xx   
x.xx 
x.xx 
(x.xxx, x.xxx) 
 
<656 Dose 5> xx 
xx   
x.xx 
x.xx 
(x.xxx, x.xxx) 
 
 
 
 
 
 
 
 
EBA CFU0-2 (log10CFU/mL) 
<Rifafour> 
xx 
xx   
x.xx 
x.xx 
(x.xxx, x.xxx) 
 
<656 Dose 1>  xx   xx 
 x.xx 
 x.xx 
(x.xxx, x.xxx) 
 
<656 Dose 2> xx 
xx   
x.xx 
x.xx 
(x.xxx, x.xxx) 
 
<656 Dose 3> xx 
xx   
x.xx 
x.xx 
(x.xxx, x.xxx) 
 
<656 Dose 4> xx 
xx   
x.xx 
x.xx 
(x.xxx, x.xxx) 
 
 
 
 
 
 
 
EBA CFU2-14 (log10CFU/mL) <Rifafour> 
xx 
xx   
x.xx 
x.xx 
(x.xxx, x.xxx) 
 
<656 Dose 1>  xx   xx 
 x.xx 
 x.xx 
(x.xxx, x.xxx) 
 
<656 Dose 2> xx 
xx   
x.xx 
x.xx 
(x.xxx, x.xxx) 
 
<656 Dose 3> xx 
xx   
x.xx 
x.xx 
(x.xxx, x.xxx) 
 
<656 Dose 4> xx 
xx   
x.xx 
x.xx 
(x.xxx, x.xxx) 
 
<656 Dose 5> xx 
xx   
x.xx 
   x.xx     (x.xxx, x.xxx) 
  
 
Mixed model including treatment, day,, BMI and treatment-by-day as covariates. The Day 2-14 model 
also includes log baseline CFU as a covariate.   
Baseline (Day 0) is defined as the mean of Day -2 and Day -1; if data was available at only one of 
these timepoints then that value was used as baseline.  


CONFIDENTIAL 
 
 
201214 
 
69 
 
Example  
: EFF_T3 
Population : Efficacy  
Table EFF_T3 
Node and Slope Parameter Estimates for log10CFU by Treatment – Bi-linear Bayesian Model Analysis 
 
 
 
 
 
Mean (95% HPD Interval) 
 
Endpoint 
(units) 
Treatment      N   n   
Node 
Slope Before Node 
Slope After Node 
 
 
 
 
 
  
EBA CFU0-14 
(log10CFU/mL) 
<Rifafour> 
xx xx  
x.xxx (x.xxx, x.xxx) 
x.xxx (x.xxx, x.xxx) 
x.xxx (x.xxx, x.xxx) 
 
<656 Dose 1>  xx  xx 
x.xxx (x.xxx, x.xxx) 
x.xxx (x.xxx, x.xxx) 
x.xxx (x.xxx, x.xxx) 
 
<656 Dose 2> 
xx xx  
x.xxx (x.xxx, x.xxx) 
x.xxx (x.xxx, x.xxx) 
x.xxx (x.xxx, x.xxx) 
 
<656 Dose …> 
xx xx  
x.xxx (x.xxx, x.xxx) 
x.xxx (x.xxx, x.xxx) 
x.xxx (x.xxx, x.xxx) 
 
<656 Dose 5> 
xx xx  
x.xxx (x.xxx, x.xxx) 
 x.xxx (x.xxx, x.xxx) 
x.xxx (x.xxx, x.xxx) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EBA CFU2-14 
(log10CFU/mL) 
<Rifafour> 
xx xx  
x.xxx (x.xxx, x.xxx) 
x.xxx (x.xxx, x.xxx) 
x.xxx (x.xxx, x.xxx) 
 
<656 Dose 1>  xx  xx 
x.xxx (x.xxx, x.xxx) 
x.xxx (x.xxx, x.xxx) 
x.xxx (x.xxx, x.xxx) 
 
<656 Dose 2> 
xx xx  
x.xxx (x.xxx, x.xxx) 
x.xxx (x.xxx, x.xxx) 
x.xxx (x.xxx, x.xxx) 
 
<656 Dose …> 
xx xx  
x.xxx (x.xxx, x.xxx) 
x.xxx (x.xxx, x.xxx) 
x.xxx (x.xxx, x.xxx) 
 
<656 Dose 5> 
xx xx  
x.xxx (x.xxx, x.xxx) 
 x.xxx (x.xxx, x.xxx) 
x.xxx (x.xxx, x.xxx)  
 
 
 
 
 
 
  
Bi-linear model including treatment, day, BMI and treatment-by-day before node and treatment-by-day 
after node as covariates. The Day 2-14 model also includes log baseline CFU as a covariate.   
Baseline (Day 0) is defined as the mean of Day -2 and Day -1; if data was available at only one of 
these timepoints then that value was used as baseline. 
 


CONFIDENTIAL 
 
 
201214 
 
70 
 
Example  
: EFF_T4 
Population : Efficacy  
 
Table EFF_T4 
Summary of Covariate and Treatment*Covariate Interaction Significance For log10CFU (0-14) Mixed Model 
Analysis 
 
 
 
Terms in the Model 
Numerator 
Degrees of Freedom 
Denominator Degrees 
of Freedom 
 
F-test 
p-value 
 
 
 
 
 
Age [1] 
xx 
xx 
x.xx  
0.xxx 
Treatment*Age [1] 
xx 
xx 
x.xx 
0.xxx 
Creatinine clearance [2] 
xx 
xx 
x.xx 
0.xxx 
Treatment*creatinine clearance [2] 
xx 
xx 
x.xx 
0.xxx 
... 
 
 
 
 
 
 
 
 
Primary model includes treatment, day, BMI and treatment-by-day as covariates. 
[1] Primary model fitted first with age, then with age + age*treatment 
[2] Primary model fitted first with creatinine clearance, then with creatinine clearance creatinine 
clearance*treatment  
… 
 
 
 
 
 
 
 
 


CONFIDENTIAL 
 
 
201214 
 
71 
 
Example  
: EFF_F1 
Population : Efficacy  
 
Table EFF_F1 
Line Graph of Mean log10CFU Over Time by Treatment 
 
 
 
 
 
 
Programming note: Include 95% confidence intervals of the slopes.  
 


CONFIDENTIAL 
 
 
201214 
 
72 
 
Example  
: EFF_F2 
Population : Efficacy  
 
Table EFF_F2 
Individual Subject Profile Plots of log10(CFU) Count Over Time by Treatment 
 
 
 
 
 
 
 
Programming notes: Produce separate figure per treatment group.  
 
 
 
PPD
PPD
PPD
PPD
PPD
PPD


CONFIDENTIAL 
 
 
201214 
 
73 
 
Example  
: EFF_F3 
Population : Efficacy  
 
Table EFF_F3 
Line Graph of Dose vs log10CFU(0-14) Slope 
 
 
 
 
 
 
 
 
Programming note: Include 95% HPD interval of the slopes.  
 
 
 


CONFIDENTIAL 
 
 
201214 
 
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Example  
: PK_T1 
Population : Pharmacokinetic  
 
Table PK_T1 
Statistical Analysis of Log Transformed Plasma GSK3036656 Pharmacokinetic Parameters Assessing Dose 
Proportionality (Power Model) 
 
    
Parameter (Units) 
Timepoint 
Slope 
Log Parameter vs Log Dose 
90% CI of the 
Slope 
<AUC(0-t) (µg.h/mL)> 
Day 14 
x.xx 
(x.xx, x.xx) 
 
 
 
 
Cmax (µg/mL) 
Day 14 
x.xx 
(x.xx, x.xx) 
 
 
 
 
 
Log(dose) is fitted as a fixed effect.  
A slope of 1 indicates the pharmacokinetics are dose proportional. A slope greater than 1 indicates 
the increase in PK is greater than proportional to dose.  
 
 
 
 
 
 
 
 
 


CONFIDENTIAL 
 
 
201214 
 
75 
 
Example  
: PK_T2 
Population : Pharmacokinetic  
Table PK_T2 
 
Statistical Analysis of log transformed plasma GSK3036656 Trough Concentration Assessing Steady 
State 
 
 
Parameter 
(Units) 
Treatment 
Day* 
Back-Transformed 
Slope 
90% Confidence 
Interval 
Ctau (ng/mL) 
<656 Dose 1> 
12-14 
x.xx 
(x.xx, x.xx) 
 
<656 Dose 2> 
12-14 
x.xx 
(x.xx, x.xx) 
 
<656 Dose 3> 
12-14 
x.xx 
(x.xx, x.xx) 
 
<656 Dose 4> 
12-14 
x.xx 
(x.xx, x.xx) 
 
<656 Dose 5> 
12-14 
x.xx 
(x.xx, x.xx) 
 
 
 
 
 
 
Mixed effect model including log(dose), day and log(dose)-by-day interaction as fixed effects and 
subject as a random effect. An unstructured covariance structure was used.   
A slope of 1 indicates steady state.  
*Day 14 includes the Day 14 24 hour PK sample.  
 
 
 
 
 
 
 
 


CONFIDENTIAL 
 
 
201214 
 
76 
 
 
Example  
: PK_F1 
Population : Pharmacokinetic  
Figure PK_F2 
 
 
 


CONFIDENTIAL 
 
 
201214 
 
77 
 
Example  
: EFF_L1 
Population : Efficacy  
Table EFF_L1 
 
Listing of Sputum Counts 
 
Site ID: <11111> 
 
Treatment / 
Unique subject 
Id. / Subject 
Id. 
Age (Years)/ 
Sex/ 
Race Detail 
DateTime /  
Study Day 
 
CFU 
(CFU/mL) 
Log10CFU 
(log10CFU/mL) 
TTP 
(hours) 
xxxxxx /  
xxxxxx / xxxxx 
xx /  
<M/F> / 
xxxxx  
YYYY-MM-
DDTHH:MM / 
xx  
x.xxx 
x.xxx 
x.xxx 
 
 
YYYY-MM-
DDTHH:MM / 
xx 
x.xxx 
x.xxx 
x.xxx 
 
 
 
 
 
 
 
 
 
Note, mean values at each timepoint are displayed.  


CONFIDENTIAL 
 
 
201214 
 
78 
 
Example  
: EFF_L2 
Population : Safety  
Table EFF_L2 
Listing of Mycobacterial Data 
 
Site Id.: <1111111> 
 
 
 
 
 
 
 
 
Treatment 
/ Unique 
subject 
Id. / 
Subject 
Id. 
Age 
(Years)/ 
Sex/ 
Race 
Detail 
Microscopy  
Collection 
Date / Time 
Microscopy 
Result / 
Grading 
GeneXpert 
Collection 
Date / 
Time 
GeneXpert 
Result at 
baseline 
GeneXpert 
Positive 
Rating at 
baseline 
xxxxxx /  
xxxxxx / 
xxxxx 
xx /  
<M/F> /  
xxxxx  
XXXXX 
/HH:MM 
< Positive / 
No AFB seen 
/ No result 
/ Not done> 
/  
< Scanty / 
1+ / 2+ / 3+ 
/ N/A> 
XXXXX 
/HH:MM 
<MTB NOT 
DETECTED / MTB 
DETECTED; Rif 
Resistance NOT 
DETECTED / MTB 
DETECTED; Rif 
Resistance 
DETECTED / MTB 
DETECTED; Rif 
Resistance 
INDETERMINATE / 
Invalid / Error 
/ No result> 
<High positive 
/ Medium 
positive / Low 
positive / 
Very low 
positive / 
N/A> 
… 
 
 
 
 
 
 
 
 
 
 
Footnote: Note, Grading is presented as: 1=1+, 2=2+, 3=3+, 4=4+ 
Programmers note: For repeat results, display all available results, one row per repeat.  
 
 


CONFIDENTIAL 
 
 
201214 
 
79 
 
Example  
: EFF_L3 
Population : Safety  
Table EFF_L3 
Listing of Drug Susceptibility Data at Screening 
 
Site Id.: <11111> 
 
 
 
 
Treatme
nt / 
Unique 
subject 
Id. / 
Subject 
Id. 
 
 
RIF 
 
 
INH 
PZA 
EMB 
Age 
(Years)/ 
Sex/ 
Race 
Detail 
Collecti
on Date 
/ Time 
Result 
Indeterm
inate 
Result 
Due To 
Result 
Indeterm
inate 
Result 
Due To 
Result 
Indeter
minate 
Result 
Due To 
Result 
Indeter
minate 
Result 
Due To 
xxxxxx 
/  
xxxxxx 
/ xxxxx 
xx /  
<M/F> / 
xxxxx 
XXXXX 
/HH:MM 
<Suscept
ible / 
Resistan
t / 
Indeterm
inate / 
Not done 
/ No 
result / 
N/A> 
< 
Control 
tube 
failure 
/ X200 
error / 
X400 
error / 
QC error 
/ N/A > 
<Suscep
tible / 
Resista
nt / 
Indeter
minate 
/ Not 
done / 
No 
result 
/ N/A> 
< 
Control 
tube 
failure 
/ X200 
error / 
X400 
error / 
QC error 
/ N/A > 
<Suscept
ible / 
Resistan
t / 
Indeterm
inate / 
Not done 
/ No 
result / 
N/A> 
< 
Control 
tube 
failure 
/ X200 
error / 
X400 
error / 
QC 
error / 
N/A > 
<Susceptib
le / 
Resistant 
/ 
Indetermin
ate / Not 
done / No 
result / 
N/A> 
< 
Control 
tube 
failure 
/ X200 
error / 
X400 
error / 
QC 
error / 
N/A > 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
RIF=Rifampicin, INH=Isoniazid, PZA=Pyrazinamide, EMB=Ethambutol 
X200 error, X400 error and QC error are machine errors and have no clinical relevance.  
 
Programmers note: For repeat results, display all available results, one row per repeat.  


CONFIDENTIAL 
 
 
201214 
 
80 
 
 
Example  
: SAFE_L1 
Population : Safety  
Table SAFE_L1 
 
Listing of Troponin Data 
 
Site Id.: <11111> 
 
 
 
 
 
Treatment / 
Unique subject 
Id. / Subject 
Id. 
Age (Years)/ 
Sex/ 
Race Detail 
 
Planned Time 
Date / Study 
Day 
 
 
Troponin 
Result (UG/L) 
 
Normal Range 
(UG/L) 
xxxxxx /  
xxxxxx / xxxxx 
xx /  
<M/F> / xxxxx  
 
Screening 
Day 3 
Day 14 
 
 
xxxx / xx 
xxxx / xx 
xxxx / xx 
 
 
 
x.xxx 
x.xxx 
x.xxx 
 
 
<0-0.2 / 0-
0.7> 
xxxxxx /  
xxxxxx / xxxxx 
xx /  
<M/F> / xxxxx  
 
Screening 
Day 3 
Day 14 
 
xxxx / xx 
xxxx / xx 
xxxx / xx 
 
 
x.xxx 
x.xxx 
x.xxx 
 
… 
 
 
 
 
 
 
 
 
 
 
Note: Two Troponin assays were used during the study, the Stratus troponin I assay (normal range: 0-
0.70 UG/L) and the Mini Vidas troponin I assay (normal range: 0-0.20 UG/L).